Research Perspectives|Volume 1, Issue 7|pp 486—499

Adaptors for disorders of the brain? The cancer signaling proteins NEDD9, CASS4, and PTK2B in Alzheimer’s disease

Tim N. Beck, Emmanuelle Nicolas, Meghan C. Kopp, Erica A. Golemis

Abstract

No treatment strategies effectively limit the progression of Alzheimer's disease (AD), a common and debilitating neurodegenerative disorder. The absence of viable treatment options reflects the fact that the pathophysiology and genotypic causes of the disease are not well understood. The advent of genome-wide association studies (GWAS) has made it possible to broadly investigate genotypic alterations driving phenotypic occurrences. Recent studies have associated single nucleotide polymorphisms (SNPs) in two paralogous scaffolding proteins, NEDD9 and CASS4, and the kinase PTK2B, with susceptibility to late-onset AD (LOAD). Intriguingly, NEDD9, CASS4, and PTK2B have been much studied as interacting partners regulating oncogenesis and metastasis, and all three are known to be active in the brain during development and in cancer. However, to date, the majority of studies of these proteins have emphasized their roles in the directly cancer relevant processes of migration and survival signaling. We here discuss evidence for roles of NEDD9, CASS4 and PTK2B in additional processes, including hypoxia, vascular changes, inflammation, microtubule stabilization and calcium signaling, as potentially relevant to the pathogenesis of LOAD. Reciprocally, these functions can better inform our understanding of the action of NEDD9, CASS4 and PTK2B in cancer.

Introduction

Roles in cancer and tumor metastasis are well established for the two paralogous scaffolding proteins NEDD9 (neural precursor cell expressed, developmentally down-regulated 9; also known as HEF1 or Cas-L) and CASS4 (Cas scaffolding protein family member 4; also known as HEPL), and for their interacting partner, the kinase PTK2B (protein tyrosine kinase type 2 beta; also known as PYK2, Cak2β, or RAFTK) [1-4]. Based on early identification of these proteins as regulators of integrin-dependent signaling governing survival, proliferation, migration, and invasion, and the recognition of NEDD9 as a major determinant of cancer metastasis [4-8], the majority of subsequent analyses emphasized their cancer-related roles involving these functions. Unexpectedly, recent genetic studies have implicated single-nucleotide polymorphisms (SNPs) in each of these genes in a completely different domain: Alzheimer's disease [9-14]. In part because independent research groups performed these studies, the fact that three closely interacting proteins have all been linked to increased risk of developing Alzheimer's disease has not been appreciated, limiting consideration of relevant mechanisms by which defects in these proteins might affect disease pathogenesis.

The pathophysiology of Alzheimer's disease is known to reflect important contributions from vascular defects, hypoxia and calcium signaling, microtubular integrity, and inflammation. Interestingly, over the past two decades, several studies have identified roles for NEDD9, CASS4, and PTK2B in these processes, but this literature is typically underappreciated in the context of neurodegenerative diseases, in contrast to the focus on this signaling cluster in cancer and metastasis. In this article, we first introduce the pathological features of Alzheimer's disease, and describe recent data linking NEDD9, CASS4, and PTK2B to this syndrome. We then summarize signaling activities of these proteins with particular focus on literature identifying brain or Alzheimer's-relevant functions. Provocatively, these data suggest a new perspective on the breadth of action of NEDD9, CASS4, and PTK2B, extending their roles into the sphere of neurodegenerative maladies. Finally, we discuss how this assembled body of non-canonical functions for these genes increases appreciation of their roles in cancer.

Pathobiology and genetic basis of Alzheimer's risk

Alzheimer's disease (AD) is the leading cause of dementia, afflicting over 35 million people worldwide [15, 16]. There are currently no effective treatment strategies for AD, and the disease typically leads to death within 3 to 9 years [15, 17, 18]. Significant structural and functional alterations associated with AD include severe loss of brain volume as well as altered neuronal network activities [17]. β-amyloid peptide (Aβ) plaques, dystrophic neuritis and neurofibrillary tangles composed of hyperphosphorylated tau, are dominant histopathological features [15]. The pathophysiological processes are complex, and include mitochondrial dysfunction (Aβ is a mitochondrial poison [19]), oxidative stress, inflammation, disturbance in cell-cycle re-entry, abnormal cholesterol metabolism, and aberrant vascular changes, with 60-90% of patients with AD presenting with ischemic disease [15, 17, 20-22]. Figure 1 summarizes AD-associated processes relevant to this article.

Figure 1. Alzheimer's disease associated processes that involve NEDD9, PTK2B and CASS4 The processes depicted in this figure are: oxidative stress response [115, 116, 118, 121]; inflammatory response (NEDD9 control via PGE2 was described for cancer cells, not neurons) [79, 165, 175]; cell cycle regulation [83, 100]; microtubular alterations [83, 182-184]; vascular alterations [149, 150, 153, 155-157]; and retinoic acid induced signaling and transcription [99, 101, 110, 111]. APP = amyloid precursor protein; Aα = amyloid alpha; R1-R4 = repeat sequences (make up microtubule-binding domain of Tau); RTK = receptor tyrosine kinase.

Two different subtypes of AD have been identified: early-onset AD (EOAD; <65 years of age) and late-onset AD (LOAD; >65 years old). EOAD accounts for >1-6% of all cases [23] and tends to follow an autosomal dominant inheritance pattern [24]. For EOAD, defects in three genes have been described as causative: mutations, predominantly missense, in amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin2 (PSEN2) (Table 1; [24-27]). Presenilin 1 and 2 are critical components of the catalytic site of the γ-secretase complex, a membrane-embedded aspartyl protease required for cleaving the APP C-terminus (Figure 2; [28, 29]).

Table 1. Alzheimer's Disease mutations and NEDD9, PTK2B and CASS4 SNPs

Alzheimer's Disease Gene	Association	Genetic Mechanism	Biochemical Phenotype	References
PSEN1	EOAD (30-70%)	Mostly missense mutations (approx. 140)	Reduced γ-secretase proteolytic activity	[28, 224]
PSEN2	EOAD (<5%)	Mostly missense mutations (approx. 10)	Reduced γ-secretase proteolytic activity	[28, 224]
APP	EOAD (10-15%)	Mostly missense mutations (approx. 16)	Increased amount or longer pieces post-cleaving	[224, 225]
APOE	LOAD	ε4 variant	Increased Aβ aggregation and decreased clearance	[33-35]
PTK2B	LOAD	SNP: rs28834970 (Chr. 8)		[14]
CASS4	LOAD	SNP: rs7274581 (Chr. 20)		[14]
NEDD9	LOAD	SNP: rs760678 (Chr. 6)		[9, 13]

NEDD9, PTK2B and CASS4 as regulators of molecular signaling proposed as relevant in Alzheimer's disease [1, 15, 17, 57, 59, 62, 63, 66, 78, 83, 90, 95-97, 178, 185, 187, 191, 196-198, 200, 226, 227]

Figure 2. NEDD9, PTK2B and CASS4 as regulators of molecular signaling proposed as relevant in Alzheimer's disease [1, 15, 17, 57, 59, 62, 63, 66, 78, 83, 90, 95-97, 178, 185, 187, 191, 196-198, 200, 226, 227] atRA = all-trans retinoic acid; RAR = retinoic acid receptor; RXR = retinoic X receptors.

The genetic complexity of LOAD is much greater than the relatively well understood genotypes of EOAD. Only apolipoprotein E (APOE) has consistently been identified as an AD susceptibility gene for LOAD, possibly due to the role APOE plays in the clearance of Aβ [16, 30-35]. However, it has been estimated that less than 20% of the risk for the development of LOAD is associated with APOE [36-38]. There has hence been considerable interest in identifying additional contributing factors. Systems biology and large scale genomics studies have begun to provide insights into the underlying multifactorial pathophysiology of AD [14, 32, 39-44], supporting the eventual development of effective treatment strategies. NEDD9, CASS4 and PTK2B have previously been much studied in the context of cancer [1-4]: as summarized below. Their recent identification as candidate regulators of the susceptibility of LOAD suggests numerous specific mechanisms by which they may influence LOAD disease onset and severity (Figure 1).

Genetic evidence linking NEDD9, CASS4, PTK2B and associated SNPs to neurodegenerative disease

To identify genetic determinants of LOAD, Lambert et al. performed a two-stage meta-analysis of genome-wide association study (GWAS) data. The study analyzed data from 74,046 individuals of diverse ethnicities, and identified a total of 19 AD susceptibility loci, 8 of which had previously been identified. Newly identified loci included SNPs in CASS4 (rs7274581 - chr20: 55018260 T/C) and PTK2B (rs28834970 - chr8: 27195121 T/C) [14]. These had genome-wide significance (P < 5 × 10-8) in terms of an association with LOAD [14, 32]. Both rs7274581 and rs28834970 are intronic and distant from splice junctions (2996 and 11923 bases respectively) (allele T|C; http://cadd.gs.washington.edu/score; [45]).

Unlike CASS4 and PTK2B, NEDD9 was not identified as an LOAD associated susceptibility loci by Lambert et al.; in spite of NEDD9 having been implicated as such by several previous studies. The NEDD9 rs760678 SNP was first identified by Li et al. (2008) in a patient population of Caucasian descent, and was proposed to be a common genetic factor in LOAD and Parkinson's disease [10]. In this large-scale association study testing 4692 SNPs, the NEDD9 rs760678 SNP (allele C|G) was identified as the second most significant susceptibility marker (P = 0.0051); only rs439401, near APOE on chromosome 19, had a lower p value (P = 2.40x10-11; [10]). rs760678 (chr6: 11334654) C/G is located within intron 2, 28266 bases away from a splice site, and has a global minor allele frequency of 0.2984 (http://www.snpedia.com). A potential role for the NEDD9 rs760678 SNP was reiterated by an independent study of genomic DNA from 214 LOAD patients, 135 EOAD patients and 386 healthy individuals. This study found a positive association between rs760678 and LOAD (CC genotype: P = 0.016; C allele: P = 0.007). No significant difference between EOAD patients and the control group was detected (p > 0.1; [12]). Similar observations were made in an additional study with an independent cohort of Han Chinese patients, which compared 383 patients with LOAD with 369 non-affected individuals. A significant difference for both genotype (P = 0.003) and allele frequency (P = 0.002), between the LOAD group and the control group were determined. Additionally, a significant difference (genotype: P = 0.047; allele frequency: P = 0.024) between the two groups was maintained even if only subjects without the APOE ε4 allele were considered [13]. However, as mentioned, Lambert et al. did not report a significant occurrence of this particular SNP in their study [14] and Chapuis et al. have described the association between NEDD9 and AD as weak at best [46]. The differences between reports may reflect variation in subject selection, disregard of environmental factors, difference in analysis, or it may simply be due to the underlying complexity of AD. Of note, Chapuis et al. did not indicate in their study if the analyzed cases were cases of LOAD, EOAD or both, perhaps explaining the discordant findings [46]. In 2012, a meta-analysis by Wang et al. concluded that more studies with larger number of samples are required for more precise answers [9-13, 47].

The known biology of NEDD9 closely links its function to CASS4 and PTK2B, as summarized below, additionally suggesting NEDD9 as a compelling target for further studies focused on AD. rs760678 maps near a putative GATA1 transcription factor binding site [10], implying a possible role for the SNP in influencing NEDD9 expression. Intriguingly, the two scaffolding proteins and PTK2B have also been associated with the function of the protein TREM2. TREM2 has been strongly linked to AD and general dementia by several studies [40, 48-50], including the study by Lambert et al., which identified an AD susceptibility SNP (rs9381040; P = 6.3 × 10⁻⁷) only 24 kb away from the 5′ end of TREM2 [14]. Mutations in TREM2 significantly downregulate NEDD9 expression [48] and an established signaling relationship exists between TREM2, its signaling partner DAP12, and PTK2B. TREM2 is a membrane bound protein that is activated by as of yet unidentified ligands to trigger SFK dependent phosphorylation of DAP12, leading to SYK activation, which then engages in a reciprocal activation interplay with PTK2B [51-56]. As we continue to discuss the functionality of NEDD9, CASS4, or PTK2B in relation to LOAD, we view it as most likely that the identified SNPs influence the expression levels of these proteins and thus their functional roles.

Canonical biology of NEDD9, CASS4, and PTK2B: interactions between these proteins and evidence for action in the brain

Suggestively, NEDD9 and CASS4 are paralogues, with NEDD9 known to interact directly with PTK2B, and CASS4 retaining the motifs required for this interaction. Hence, association of all three with LOAD suggests a common function in the pathobiology of this disease (Figure 2; [1]), paralleling the interactions among these proteins that underlie development and progression of cancer [1-4, 57, 58].

In thinking about this common function, NEDD9 and CASS4 are expressed in many tissues, including the brain [59-61]. NEDD9 and CASS4 are members of the Crk-associated substrate (CAS) family of scaffolding proteins, which also includes BCAR1/p130Cas and embryonal Fyn substrate (EFS; also known as CAS3, CASS3, HEFS and SIN; [1, 2]). CAS proteins share several conserved sequence motifs, including an amino-terminal Src homology 3 (SH3) domain that allows binding with a number of proteins [2], including focal adhesion kinase (FAK) [62] and the FAK paralog PTK2B (Figure 2; [63, 64]). Additionally, CAS proteins contain a “substrate domain”, with multiple tyrosines that form SH2-binding motifs when phosphorylated [1, 4], a 4-helix bundle that provides a docking site for 14-3-3 proteins [65] and GRB2 [66] as well as a C-terminal helical domain that provides another site for interaction with additional proteins, such as SRC family kinases (SFKs), the CAS protein BCAR1 [1], and other signaling adaptors for integrin and receptor tyrosine kinase signaling, such as NSP2/BCAR3/AND-34, SOS and C3G [66-69].

NEDD9 and CASS4 are regulated by and mediate cellular attachment to the extracellular matrix [59, 70, 71]. In studies predominantly performed in cancer cell lines of epithelial and lymphoid origin, following integrin engagement or mechanical stretching, FAK or PTK2B (discussed further below) directly bind and phosphorylate CAS proteins [62], which subsequently leads to further phosphorylation of the CAS proteins by SRC [63, 72-74]. Crk, Crk-L, and BCR/ABL associate with hyperphosphorylated CAS proteins to induce cell spreading (Figure 2; [4, 75]). Reciprocally, overexpression of NEDD9 or CASS4 activates FAK and SRC kinases [3, 59, 76] and organizes complexes that regulate the actin cytoskeleton, contributing to changes in cell adhesion, migration, and invasion, and involve regulation of RAC, DOCK3, and WAVE2 [77]. These changes may vary dependent on cell context, with most studies showing NEDD9 as a positive regulator [70, 78, 79], but some showing a negative role [71, 80, 81].

In addition, in some cell types, NEDD9 can induce the formation of neurite-like cell extensions that depend on an intact microtubule cytoskeleton [82]. Further, NEDD9 associates with and influences the activity of the kinase AURKA to govern appropriate organization of microtubules into a mitotic spindle [83]. Further interactions between NEDD9 and AURKA in G0/G1 cells regulate integrity of the cell cilium [84], a structure important for brain patterning and function [85, 86] that is organized around a microtubule-based axoneme. NEDD9 also associates with the TGFβ effectors and regulatory proteins SMAD3, SMAD6 and SMAD7 [57, 87-89], positioning it to influence cell differentiation status. To date, very few studies have addressed CASS4 function, although roles in control of cell migration have been established: given the high level of domain and sequence conservation between CASS4 and NEDD9 [59], some of the additional roles described above are likely to be relevant.

Protein tyrosine kinase 2 beta (PTK2B) is highly conserved with FAK (90% sequence identity) and together with FAK comprises the complete focal adhesion protein tyrosine kinase family [90]. Intriguingly, PTK2B is expressed with great tissue selectivity, with preferential expression in the central nervous system [91]. PTK2B has a central kinase region flanked by a FERM (band Four point one (4.1), Ezrin, Radixin, Moesin) N-terminal region and a focal adhesion-targeting (FAT) domain at the C-terminal, which allows binding to paxillin [91-93]. Poly-proline sequences on FAK and PTK2B mediate their interaction with the NEDD9 or CASS4 SH3 domain. Auto-phosphorylation of PTK2B induced in response to integrin ligation triggers recruitment of several proteins, most prominently SFKs and GRB2, to initiate migration-inducing signaling [94-96]. In some studies, FAK was shown to oppose the role of PTK2B in inducing reorganization of actin association with focal adhesions and cell rounding, suggesting balanced function of these proteins may be important for tissue organization [97].

Importantly, NEDD9 and PTK2B are highly active in neurologically relevant settings. NEDD9 is expressed in the developing brain [61, 98], and regulates neural crest cell migration [99]. NEDD9 is also required for TGFβ-initiated cell cycle exit and neuronal differentiation in forebrain-derived embryonic progenitor cells [100]. NEDD9 is upregulated in response to retinoic acid in human neuroblastoma cells [101], regulates morphology in glioma and neuroblastoma [80], and has elevated expression and promotes survival and invasion in glioblastomas [78]. Gene expression profiling of the murine striatum after administration of different classes of psychotropics indicated that a cluster of cell cycle regulators, including NEDD9, were significantly enriched [102]; one study has also shown that NEDD9 is upregulated in response to fluoxetine (Prozac), a psychotropic given to some patients with AD [103]. For PTK2B, expression levels are sharply elevated in the front brain shortly after birth [90, 104]. PTK2B localizes to neurites in rat pheochromocytoma cells upon stimulation with nerve growth factor [105], and is a key component of signaling pathways involved in neurite growth and synapse formation [106]. PTK2B and FAK association with adhesion complexes containing both integrins and receptor tyrosine kinases, such as EGFR, to mediate neurite induction by adhesion and growth factors [107]. Further relevant signaling aspects are based on PTK2B-SRC interactions, which couple signals from G-protein coupled receptors (GPCRs) to MAPK activation [96]. Like NEDD9, PTK2B induces the migration and invasion of glioblastoma cells; a role that distinguishes it from its paralog FAK [108].

Lastly, a recent study using a transgenic AD mouse model found that the retinoid X receptor (RXR) agonist bexarotene, used for the treatment of cutaneous T cell lymphoma [109], enhanced clearance of Aβ and improved cognitive function. Multiple studies have described a significant relationship between retinoic acid and NEDD9. The NEDD9 promoter contains binding elements for the retinoic acid receptor (RAR) and RXR (Figure 1; [110]), and NEDD9 is induced by retinoic acid in neural crest cells and neuroblastoma cells [99, 101]. Furthermore, studies of PTK2B in leukemia cells have found it to be upregulated in response to treatment with all-trans-retinoic acid (atRA) [111]. PTK2B signaling, once induced with atRA, was sustained for extended time periods, suggesting a positive feedback loop. Hypothetically, RXR agonists may also increase PTK2B signaling in AD mouse models, and inhibition of PTK2B limit the bexarotene-dependent reduction of Aβ.

PTK2B and NEDD9 in oxygen responses

In addition to cell-intrinsic defects associated with control of neurite growth and movement, PTK2B, NEDD9, and CASS4 may also influence environmental factors associated with AD. The brain is immensely metabolically active and accounts for roughly 20% of overall oxygen consumption [112]. Even temporary hypoxia can cause permanent damage to neurons [113]. Hypoxia, including particularly chronic hypoxia, has been strongly implicated as causative in neurodegenerative diseases, including AD [114].

While the topic has not yet been significantly addressed for CASS4, Sasaki et al. demonstrated that NEDD9 is highly induced by transient ischemia, and localizes to dendrites and the cytosol of neurons. In this context, NEDD9 helps initiate neural projection formation and may be important for neurite regrowth and tissue recovery following ischemic damage [115]. A study of NEDD9 in colon cancer cells has confirmed that its induction under hypoxic conditions is regulated by hypoxia-inducible factor 1α (HIF1α) and in turn modulates the interaction between HIF1α and its transcriptional coactivator p300 (Figure 1; [116]). While multiple studies find that NEDD9 is upregulated during hypoxia [115-118], one study profiling transcriptomic changes induced by differing states of oxygen tension indicated that a specific set of mRNAs, including NEDD9, is downregulated during hypoxia [119]. The reported discordance may be due to differences in experimental models used (changes in oxygen levels in vitro versus induced ischemia in vivo) and discrepancies in defining hypoxia (Chadwick et al. state that neurons in culture are typically kept at oxygen levels that are too high to be considered endogenous due to high oxygen consumption in the brain [119]). This topic clearly requires more investigation for definitive conclusions to be made.

Under normoxic conditions, PTK2B is expressed, but typically inactive. However, as shown in a study of rat brains, PTK2B is upregulated and increasingly phosphorylated (i.e., activated) in response to induced hypoxia in microglia [120]. Another study using a mouse hind-limb ischemia model showed that hypoxia acts as a stress signal that is detected by PTK2B, which phosphorylates and activates endothelial Nitric Oxide Synthase (eNOS). eNOS in turn produces nitric oxide (NO), which promotes vasodilatation. During this response, PTK2B also stabilizes AKT kinase activity and intracellular Ca2+ mobilization, which promotes VEGF activity [121, 122]. VEGF helps activate eNOS by triggering the phosphorylation of VEGFR1 and VEGFR2, which leads to PTK2B dependent Ser1176 phosphorylation of eNOS, inducing angiogenesis, migration, and cytoskeletal reorganization [121, 123].

PTK2B and NEDD9 in the vascular system

Cerebrovascular pathologies are present in 60-90% of patients with AD [124]. Recent studies have linked the function of both PTK2B and NEDD9 to vascular integrity, angiogenesis, and hypertension. Hypertension is of particular interest, for one, because of its general prevalence, and two, because it can be managed pharmacologically and with lifestyle adjustments [125, 126]. Conflicting reports have been published regarding a correlation between hypertension and AD [127-131]; however, postmortem brain analyzes showed significantly less neuritic plaque and neurofibrillary tangle densities in individuals who had received hypertensive medication [132]. To corroborate these findings, in a large study of 2,248 participants, it was determined that use of anti-hypertensives (diuretics, angiotensin-1 receptor blockers and angiotensin-converting enzyme inhibitors) was associated with reduced risk of AD dementia [133].

PTK2B has been linked to key hypertensive events, such as increased cell growth in vascular smooth muscle cells, associated with angiotensin II induced PTK2B phosphorylation [134, 135], and significantly reduced expression of PTK2B in the hypothalamus of mice with established neurogenic hypertension compared to normotensive mice [136]. In a population-based case-control sample study of 2655 individuals, PTK2B variants were also indentified as associated with essential hypertension [137]; although, this observation was not confirmed in a GWAS, in which PTK2B variants were detected, but not seen as significantly associated with hypertension [138]. Strong evidence exists that suggests a direct signaling link between angiotensin, a critical player in the renin-angiotensin system required for blood pressure regulation, vasoconstriction and sodium/potassium regulation [139, 140], and PTK2B. The angiotensin II receptor type 1 transphosphorylates PTK2B to regulate c-Jun expression [141, 142]. Furthermore, PTK2B is critical for angiotensin II-initiated ERK activity [143]. Intriguingly, it has been shown that angiotensin-converting enzyme-1 (ACE1) is elevated in the brains of patients with AD, so are the PTK2B modulators angiotensin II and angiotensin II receptor type 1 [144-146]. Finally, one recent GWAS study has linked NEDD9 to primary open angle glaucoma (POAG), a disease that could be caused by endothelial defects or hypertension. In this case, a NEDD9 intronic SNP was highly associated with POAG (rs11961171, P = 8.55E⁻¹³; [147, 148]). Further study is indicated.

Vascular insufficiency and chronic cerebral hypo-perfusion are clearly involved to some degree in AD, although the cause and effect relationship has not been clearly defined [15, 124]. Aβ induces the potent angiogenic ligand VEGF [149], reportedly activating VEGF-receptors to increase angiogenesis and cell migration [150, 151]. VEGF is a major driver of angiogensis and it has been reported that angiogenesis increases vascular permeability and hypervascularity in AD [152]. NEDD9 and PTK2B have both been linked to angiogenesis and changes in their expression may contribute to hypo-perfusion and vascular permeability in AD. For example, NEDD9 has been defined as critical for a response to VEGF in cancer cells (Figure 1; [150]). When upregulated and activated, NEDD9, along with FAK, is a required target of VEGF signaling in invadopodia, leading to cell spreading and migration [150]. NEDD9 is also a downstream target of PTK2B, important for the regulation of endothelial cell cytoskeletal reorganization necessary for migration during angiogenesis (Figure 1; [3, 153]). Amyloid fibril exposure also increases PTK2B activation in cultured microglia [154]. If similar activation occurs in endothelial cells, PTK2B is positioned to increase endothelial permeability and regulate cell-cell adhesion through its previously described interaction with VE-cadherin (Figure 1; [155- 157]). Work on two transgenic AD mouse models has shown that the VEGFR inhibitor sunitinib re-establishes proper expression levels of proteins involved in vascular integrity, such as Aβ, thrombin, tumor necrosis factor-α, interleukin-1β, interleukin-6, and matrix metalloproteinase 9; NEDD9 and PTK2B were unfortunately not evaluated in this study [158].

PTK2B and NEDD9 in inflammation

Neuroinflammation has been suggested to play an important role in progression of Alzheimer's disease [33, 159] and epidemiological studies have suggested anti-inflammatory agents may have beneficial effects in AD [160]. Thus far, long term randomized studies have not convincingly shown that anti-inflammatory therapeutics benefit patients with AD; however, the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), a randomized study of 2528 elderly persons, led to the conclusion that nonsteroidal anti-inflammatory drugs (NSAIDs) have an adverse effect in late stage AD, but reduced the incidence of AD after 2-3 years [161]. ADAPT emphasizes that better understanding of the pathophysiology of AD and the involved inflammatory processes is critical if the inflammatory process is to be effectively targeted with therapeutic intent.

Neuroinflammation involves the activation of microglia, astrocytes, marcrophages and lymphocytes, production of inflammatory cytokines, release of neurotransmitters and production of reactive oxygen species [159]. NEDD9 is important both for lymphocyte signaling [73, 162-164] and lymphocyte migration [79]. NEDD9 has also been implicated in T cell-mediated inflammation, predominantly on the basis of an association with ABL [164-166], with phosphorylation of NEDD9 by ABL and subsequent activation of RAP1 (Figure 1; [165]). PTK2B is required for neutrophil degranulation [167] and inhibition of PTK2B blocks inflammation in murine models of acute lung injury [168] and asthma [169]. PTK2B has also been implicated in the activation of T cells [170, 171] and T cell spreading [172, 173]. In light of the effects of NSAIDs on early stage AD, as reported by the ADAPT study, and the implication of NEDD9 and PTK2B not only in the inflammatory process, but also in AD, additional biological observations regarding NEDD9 are particularly relevant. NSAIDs such as ibuprofen, asprin, naproxen and rofecoxib suppress inflammation by inhibiting cyclooxygenase 2 (COX2) activity [161]. Prostaglandin E2 (PGE2) is a downstream product of COX2 and is therefore suppressed by NSAID treatment [174]. In a first study in colorectal cancer, PGE2 was shown to dramatically upregulate NEDD9 expression [175], raising the possibility that a COX2-PGE2-NEDD9 axis is also involved in AD.

NEDD9 in microtubule network stabilization

Tau is one of the hallmark proteins of Alzheimer's disease [15], and involved in the pathological formation of tau neurofibrillary tangles [17, 176]. However, tau normally is involved in the assembly and stabilization of microtubules within neurons (Figure 2; [177]), a critical component of proper neuronal functionality [178] and a process disrupted in AD [179-181]. NEDD9 regulation of AURKA activity was first shown to regulate the appropriate organization of microtubules in mitosis [83]. In a particularly exciting finding, AURKA was found to be active in post-mitotic neurons, and to play a significant role in microtubule remodeling during neurite extension. This involves interactions between AURKA, atypical protein kinase C (aPKC), and NDEL1, a partner of the LIS1 gene (mutated in lissencephaly) that regulates dynein. AURKA phosphorylation of NDEL1 was essential to sustain a robust frequency of microtubules from the centrosome, anchoring neurite projection [182-184]. To date, although PTK2B and NEDD9 are abundant in neurites, a PTK2B-NEDD9-AURKA-NDEL1 axis has not been considered in neurite extension or neurodegenerative diseases. Providing additional linkages, glycogen synthase kinase 3 beta (GSK-3β) phosphorylates tau contained in neurofibrillary tangles, and influences the formation of Aβ [185-188]. The NEDD9-regulated kinase AURKA has been shown in cancer cells to phosphorylate GSK-3β, increasing its activity [189]. In some cell types, the E3 ligase SMURF2 negatively regulates GSK-3β [190], but stabilizes NEDD9, promoting AURKA activity [191], raising the possibility of a feedback loop.

Some “canonical” activities of NEDD9 and PTK2B may also influence the formation of tau neurofibrillary tangles as well as APP-associated plaque formation (Figure 2). The SFK FYN binds NEDD9 (and potentially CASS4) [1, 192, 193], and directly regulates the function of PTK2B [194]. Conversely, studies of some CAS family members have shown that CAS-SFK binding is important for activating the SFK [195]. Importantly, FYN is responsible for increased phosphorylation of tau [196-198], a process that induces the dissociation of tau from microtubules, eventually leading to tangles composed of hyper-phosphorylated tau (Figure 2; [15, 199]). In another linkage, some in vitro studies have suggested that the activity of Aβ as a neurotoxin requires the induction of α2β1 and αVβ1 integrins, which in turn anomalously activate SFKs and PTK2B, and increase NEDD9 and CASS4 phosphorylation [154, 200].

NEDD9 and PTK2B in calcium signaling

Defects in calcium signaling have been suggested to play a significant role in the development of AD, and some evidence suggests that Aβ is responsible for disruption of calcium homeostasis [201, 202]. Aβ affects calcium permeability and signaling in brain tissue [203, 204] as well as calcium channel activity [205]. PTK2B is dependent on calcium for activation [105] and modulates NMDA receptor function and MAPK signaling (Figure 2; [104, 206]). NEDD9 activity also regulates and is regulated by calcium signaling. It has been shown in multiple studies that the calcium-regulating hormone calcitonin induces association and phosphorylation of NEDD9, paxillin, FAK, and PTK2B, promoting changes in cellular shape and motility patterns [207-209]. Although this signaling has been predominantly studied in kidney cells and osteoclasts, it is likely relevant in other tissues. In a second connection to calcium signaling control, NEDD9 activation of AURKA supports phosphorylation of the widely expressed polycystin 2 (PC2) calcium channel, to limit the channel's activity and decreases cytoplasmic calcium. Reciprocally, calcium induction of calmodulin (CaM) binding to AURKA supports the AURKA and NEDD9 interaction [210-212]. Relevant connections between calcium homeostasis and NEDD9 and PTK2B are hence clearly established and it would likely be of immense value to investigate the functional impact of this interplay in the context of AD.

Conclusions, and return to cancer biology

Alzheimer's disease, and particularly LOAD, is immensely complex, and our understanding of this disease on a molecular level is still limited. While genetic analyses to date imply heterogeneous origins for LOAD, the fact that three genes with close functional relatedness have separately been identified as contributing to this disease is highly suggestive of an important conserved pathway. For historical reasons, the bulk of molecular characterizations of NEDD9, CASS4, and PTK2B have stressed their roles in cancer. However, the data summarized above provide a roadmap for systematic investigation of these proteins in the regulation of hypertension, angiogenesis, hypoxia, calcium signaling, inflammatory response, and microtubule dynamics: all phenotypes highly relevant to LOAD. Given the most likely function of the SNPs is to activate or depress signaling of the NEDD9-CASS4-PTK2B axis, their action in LOAD may involve simultaneous subtle regulation of all these phenotypes, with cumulative effects in aged individuals.

Finally, while the main focus of this review has been on the roles of NEDD9, CASS4, and PTK2B in LOAD, many of the LOAD-relevant processes can further highlight the significance of these proteins in cancer. In cancer, discussion of action of the NEDD9-CASS4-PTK2B scaffolding and signaling axis almost invariably focuses on the regulation of cell migration and invasion, following the upregulation of NEDD9 and activation of PTK2B in many tumors. Of note from a therapeutic standpoint, inhibitors of FAK are in clinical development [213-216] and these inhibitors are also active against PTK2B [214]. The data reviewed above suggest that use of these inhibitors may have significant side effects impinging on function of the vascular and immune systems. At this point, whether such effects would be beneficial or negative is difficult to predict; however, we suggest that accumulated data now indicate that specific analysis of this question is worthy of preclinical investigation.

These data also suggest additional ways of thinking about NEDD9, PTK2B, and CASS4 in tumor cells. For example, renal cell carcinoma (RCC) is almost entirely dependent on loss of VHL and induced hypoxic signaling involving VEGFR [217-219]. FAK/PTK2B inhibitors may be expected to behave differently in this class of tumors than others with less dependence on this signaling pathway. We believe that in order to advance cancer therapy it is important to target signaling nodes, functions, and malignant cellular reprogramming in order to maximize prevention, treatment and diagnosis [220-223]. Understanding the roles of scaffolding proteins is important in this regard, as these proteins often interconnect signaling cascades and phenotypic revulators. The described collection of functional relationships for NEDD9, CASS4 and PTK2B in AD is a generalizable approach of thinking about genotypes, phenotypes and ultimately functionality to understand diseases ranging from Alzheimer's to cancer.

Acknowledgments

The authors were supported by U54 CA149147, R21CA181287, and P50 CA083638 from the NIH (to EAG), F30 CA180607 from the NIH (to TNB), and NIH core grant CA06927 (to Fox Chase Cancer Center). We acknowledge the support of the Fox Chase Cancer Center Genomics Facility.

References

1. Tikhmyanova N, Little JL, Golemis EA. CAS proteins in normal and pathological cell growth control.Cellular and molecular life sciences: CMLS.2010;67:71025-1048. [PubMed] https://doi.org/10.1007/s00018-009-0213-1
2. Cabodi S, Camacho-Leal MD, Di Stefano P, Defilippi P. Integrin signalling adaptors: not only figurants in the cancer story.Nat Rev Cancer.2010;10:12858-870. [PubMed] https://doi.org/10.1038/nrc2967
3. Guerrero MS, Parsons JT, Bouton AH. Cas and NEDD9 Contribute to Tumor Progression through Dynamic Regulation of the Cytoskeleton.Genes & cancer.2012;3:5-6371-381. [PubMed] https://doi.org/10.1177/1947601912458585
4. Nikonova AS, Gaponova AV, Kudinov AE, Golemis EA. CAS proteins in health and disease: An update.IUBMB LIFE.2014; https://doi.org/10.1002/iub.1282 [PubMed]
5. O'Neill GM, Seo S, Serebriiskii IG, Lessin SR, Golemis EA. A new central scaffold for metastasis: parsing HEF1/Cas-L/NEDD9.Cancer Res.2007;67:198975-8979. [PubMed] https://doi.org/10.1158/0008-5472.CAN-07-1328
6. Chang JX, Gao F, Zhao GQ, Zhang GJ. Role of NEDD9 in invasion and metastasis of lung adenocarcinoma.Experimental and therapeutic medicine.2012;4:5795-800. [PubMed] https://doi.org/10.3892/etm.2012.693
7. Kondo S, Iwata S, Yamada T, Inoue Y, Ichihara H, Kichikawa Y, Katayose T, Souta-Kuribara A, Yamazaki H, Hosono O, Kawasaki H, Tanaka H, Hayashi Y, Sakamoto M, Kamiya K, Dang NH, et al. Impact of the integrin signaling adaptor protein NEDD9 on prognosis and metastatic behavior of human lung cancer.Clinical cancer research: an official journal of the American Association for Cancer Research.2012;18:226326-6338. [PubMed] https://doi.org/10.1158/1078-0432.CCR-11-2162
8. Miao Y, Li AL, Wang L, Fan CF, Zhang XP, Xu HT, Yang LH, Liu Y, Wang EH. Overexpression of NEDD9 is Associated with Altered Expression of E-Cadherin, beta-Catenin and N-Cadherin and Predictive of Poor Prognosis in non-Small Cell Lung Cancer.Pathol Oncol Res.2013;19:2281-286. [PubMed] https://doi.org/10.1007/s12253-012-9580-2
9. Fu Y, He F, Tang NL, Tam CW, Lui VW, Chiu HF, Lam LC. NEDD9 gene polymorphism influences the risk of Alzheimer disease and cognitive function in Chinese older persons.Alzheimer Dis Assoc Disord.2012;26:188-90. [PubMed] https://doi.org/10.1097/WAD.0b013e3182135ef3
10. Li Y, Grupe A, Rowland C, Holmans P, Segurado R, Abraham R, Jones L, Catanese J, Ross D, Mayo K, Martinez M, Hollingworth P, Goate A, Cairns NJ, Racette BA, Perlmutter JS, et al. Evidence that common variation in NEDD9 is associated with susceptibility to late-onset Alzheimer's and Parkinson's disease.Hum Mol Genet.2008;17:5759-767. [PubMed] https://doi.org/10.1093/hmg/ddm348
11. Wang Y, Bi L, Wang H, Li Y, Di Q, Xu W, Qian Y. NEDD9 rs760678 polymorphism and the risk of Alzheimer's disease: a meta-analysis.Neurosci Lett.2012;527:2121-125. [PubMed] https://doi.org/10.1016/j.neulet.2012.08.044
12. Tedde A, Bagnoli S, Piaceri I, Lucenteforte E, Bessi V, Bracco L, Mugelli A, Sorbi S, Nacmias B. Different implication of NEDD9 genetic variant in early and late-onset Alzheimer's disease.Neurosci Lett.2010;477:3121-123. [PubMed] https://doi.org/10.1016/j.neulet.2010.04.046
13. Xing YY, Yu JT, Yan WJ, Chen W, Zhong XL, Jiang H, Wang P, Tan L. NEDD9 is genetically associated with Alzheimer's disease in a Han Chinese population.Brain Res.2011;1369:230-234. [PubMed] https://doi.org/10.1016/j.brainres.2010.10.113
14. Lambert J-C, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, Jun G, DeStefano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thornton-Wells TA, Jones N, Smith AV, Chouraki V, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.Nat Genet.2013;45:121452-1458. [PubMed] https://doi.org/10.1038/ng.2802
15. Querfurth HW and LaFerla FM. Alzheimer's disease.The New England journal of medicine.2010;362:4329-344. [PubMed] https://doi.org/10.1056/NEJMra0909142
16. O'Brien RJ and Wong PC. Amyloid precursor protein processing and Alzheimer's disease.Annual review of neuroscience.2011;34:185-204. https://doi.org/10.1146/annurev-neuro-061010-113613 [PubMed]
17. Huang Y and Mucke L. Alzheimer mechanisms and therapeutic strategies.Cell.2012;148:61204-1222. [PubMed] https://doi.org/10.1016/j.cell.2012.02.040
18. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease.The New England journal of medicine.2014;370:4311-321. [PubMed] https://doi.org/10.1056/NEJMoa1312889
19. Calkins MJ and Reddy PH. Amyloid beta impairs mitochondrial anterograde transport and degenerates synapses in Alzheimer's disease neurons.Biochim Biophys Acta.2011;1812:4507-513. [PubMed] https://doi.org/10.1016/j.bbadis.2011.01.007
20. Jack CR Jr. and Holtzman DM. Biomarker modeling of Alzheimer's disease.Neuron.2013;80:61347-1358. [PubMed] https://doi.org/10.1016/j.neuron.2013.12.003
21. Iadecola C. The pathobiology of vascular dementia.Neuron.2013;80:4844-866. [PubMed] https://doi.org/10.1016/j.neuron.2013.10.008
22. Yankner BA. Mechanisms of neuronal degeneration in Alzheimer's disease.Neuron.1996;16:5921-932. [PubMed] https://doi.org/10.1016/s0896-6273(00)80115-4
23. Ridge PG, Ebbert MT, Kauwe JS. Genetics of Alzheimer's disease.BioMed research international.2013;2013:254954 [PubMed] https://doi.org/10.1155/2013/254954
24. Bettens K, Sleegers K, Van Broeckhoven C. Current status on Alzheimer disease molecular genetics: from past, to present, to future.Hum Mol Genet.2010;19:R1R4-R11. [PubMed] https://doi.org/10.1093/hmg/ddq142
25. Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: back to the future.Neuron.2010;68:2270-281. [PubMed] https://doi.org/10.1016/j.neuron.2010.10.013
26. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.Nature.1995;375:6534754-760. [PubMed] https://doi.org/10.1038/375754a0
27. Goate AM, Haynes AR, Owen MJ, Farrall M, James LA, Lai LY, Mullan MJ, Roques P, Rossor MN, Williamson R, et al. Predisposing locus for Alzheimer's disease on chromosome 2.Lancet.1989;1:8634352-355. [PubMed] https://doi.org/10.1016/s0140-6736(89)91725-x
28. De Strooper B, Iwatsubo T, Wolfe MS. Presenilins and gamma-secretase: structure, function, and role in Alzheimer Disease.Cold Spring Harbor perspectives in medicine.2012;2:1a006304 [PubMed] https://doi.org/10.1101/cshperspect.a006304
29. Okochi M, Tagami S, Yanagida K, Takami M, Kodama TS, Mori K, Nakayama T, Ihara Y, Takeda M. gamma-secretase modulators and presenilin 1 mutants act differently on presenilin/gamma-secretase function to cleave Abeta42 and Abeta4.Cell reports.2013;3:142-51. [PubMed] https://doi.org/10.1016/j.celrep.2012.11.028
30. Verghese PB, Castellano JM, Garai K, Wang Y, Jiang H, Shah A, Bu G, Frieden C, Holtzman DM. ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions.Proc Natl Acad Sci U S A.2013;110:19E1807-1816. [PubMed] https://doi.org/10.1073/pnas.1220484110
31. Coon KD, Myers AJ, Craig DW, Webster JA, Pearson JV, Lince DH, Zismann VL, Beach TG, Leung D, Bryden L, Halperin RF, Marlowe L, Kaleem M, Walker DG, Ravid R, Heward CB, et al. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease.J Clin Psychiat.2007;68:4613-618. https://doi.org/10.4088/jcp.v68n0419 [PubMed]
32. Kamboh MI, Demirci FY, Wang X, Minster RL, Carrasquillo MM, Pankratz VS, Younkin SG, Saykin AJ, Jun G, Baldwin C, Logue MW, Buros J, Farrer L, Pericak-Vance MA, Haines JL, Sweet RA, et al. Genome-wide association study of Alzheimer's disease.Translational psychiatry.2012;2:e117 [PubMed] https://doi.org/10.1038/tp.2012.45
33. Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy.Nature reviews Neurology.2013;9:2106-118. https://doi.org/10.1038/nrneurol.2012.263 [PubMed]
34. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.Science.1993;261:5123921-923. [PubMed] https://doi.org/10.1126/science.8346443
35. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein, E.high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A.1993;90:51977-1981. https://doi.org/10.1073/pnas.90.5.1977 [PubMed]
36. Slooter AJ, Cruts M, Kalmijn S, Hofman A, Breteler MM, Van Broeckhoven C, van Duijn CM. Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study.Archives of neurology.1998;55:7964-968. [PubMed] https://doi.org/10.1001/archneur.55.7.964
37. Evans DA, Beckett LA, Field TS, Feng L, Albert MS, Bennett DA, Tycko B, Mayeux R. Apolipoprotein E epsilon4 and incidence of Alzheimer disease in a community population of older persons.JAMA: the journal of the American Medical Association.1997;277:10822-824. [PubMed]
38. Corneveaux JJ, Myers AJ, Allen AN, Pruzin JJ, Ramirez M, Engel A, Nalls MA, Chen K, Lee W, Chewning K, Villa SE, Meechoovet HB, Gerber JD, Frost D, Benson HL, O'Reilly S, et al. Association of CR1, CLU, and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals.Hum Mol Genet.2010;19:163295-3301. [PubMed] https://doi.org/10.1093/hmg/ddq221
39. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fievet N, Barberger-Gateau P, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease.Nat Genet.2009;41:101094-U1068. [PubMed] https://doi.org/10.1038/ng.439
40. Cruchaga C, Kauwe JS, Harari O, Jin SC, Cai Y, Karch CM, Benitez BA, Jeng AT, Skorupa T, Carrell D, Bertelsen S, Bailey M, McKean D, Shulman JM, De Jager PL, Chibnik L, et al. GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease.Neuron.2013;78:2256-268. [PubMed] https://doi.org/10.1016/j.neuron.2013.02.026
41. Hu XL, Pickering E, Liu YC, Hall S, Fournier H, Katz E, Dechairo B, John S, Van Eerdewegh P, Soares H. Meta-Analysis for Genome-Wide Association Study Identifies Multiple Variants at the BIN1 Locus Associated with Late-Onset Alzheimer's Disease.PLoS One.2011;6:2 https://doi.org/10.1371/journal.pone.0016616 [PubMed]
42. Boada M, Antunez C, Ramirez-Lorca R, DeStefano AL, Gonzalez-Perez A, Gayan J, Lopez-Arrieta J, Ikram MA, Hernandez I, Marin J, Galan JJ, Bis JC, Mauleon A, Rosende-Roca M, Moreno-Rey C, Gudnasson V, et al. ATP5H/KCTD2 locus is associated with Alzheimer's disease risk.Molecular psychiatry.2014;19:6682-687. [PubMed] https://doi.org/10.1038/mp.2013.86
43. Saykin AJ, Shen L, Foroud TM, Potkin SG, Swaminathan S, Kim S, Risacher SL, Nho K, Huentelman MJ, Craig DW, Thompson PM, Stein JL, Moore JH, Farrer LA, Green RC, Bertram L, et al. Alzheimer's Disease Neuroimaging Initiative biomarkers as quantitative phenotypes: Genetics core aims, progress, and plans.Alzheimers Dement.2010;6:3265-273. [PubMed] https://doi.org/10.1016/j.jalz.2010.03.013
44. Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, Zhang CS, Xie T, Tran L, Dobrin R, Fluder E, Clurman B, Melquist S, Narayanan M, Suver C, Shah H, et al. Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer's Disease.Cell.2013;153:3707-720. [PubMed] https://doi.org/10.1016/j.cell.2013.03.030
45. Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants.Nat Genet.2014;46:3310-315. [PubMed] https://doi.org/10.1038/ng.2892
46. Chapuis J, Moisan F, Mellick G, Elbaz A, Silburn P, Pasquier F, Hannequin D, Lendon C, Campion D, Amouyel P, Lambert JC. Association study of the NEDD9 gene with the risk of developing Alzheimer's and Parkinson's disease.Hum Mol Genet.2008;17:182863-2867. [PubMed] https://doi.org/10.1093/hmg/ddn183
47. Laumet G, Chouraki V, Grenier-Boley B, Legry V, Heath S, Zelenika D, Fievet N, Hannequin D, Delepine M, Pasquier F, Hanon O, Brice A, Epelbaum J, Berr C, Dartigues JF, Tzourio C, et al. Systematic analysis of candidate genes for Alzheimer's disease in a French, genome-wide association study.J Alzheimers Dis.2010;20:41181-1188. [PubMed] https://doi.org/10.3233/JAD-2010-100126
48. Chouery E, Delague V, Bergougnoux A, Koussa S, Serre J, Megarbane A. Mutations in TREM2 Lead to Pure Early-Onset Dementia Without Bone Cysts.Human Mutation.2008;29:9E194-E204. [PubMed] https://doi.org/10.1002/humu.20836
49. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, et al. TREM2 variants in Alzheimer's disease.The New England journal of medicine.2013;368:2117-127. [PubMed] https://doi.org/10.1056/NEJMoa1211851
50. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, et al. Variant of TREM2 Associated with the Risk of Alzheimer's Disease.New Engl J Med.2013;368:2107-116. [PubMed] https://doi.org/10.1056/NEJMoa1211103
51. Peng QS, Malhotra S, Torchia JA, Kerr WG, Coggeshall KM, Humphrey MB. TREM2-and DAP12-Dependent Activation of PIK Requires DAP10 and Is Inhibited by SHIP1.Sci Signal.2010;3:122 https://doi.org/10.1126/scisignal.2000500 [PubMed]
52. Wang L, Gordon RA, Huynh L, Su XD, Min KHP, Han JH, Arthur JS, Kalliolias GD, Ivashkiv LB. Indirect Inhibition of Toll-like Receptor and Type I Interferon Responses by ITAM-Coupled Receptors and Integrins.Immunity.2010;32:4518-530. [PubMed] https://doi.org/10.1016/j.immuni.2010.03.014
53. Ivashkiv LB. A signal-switch hypothesis for cross-regulation of cytokine and TLR signalling pathways.Nature reviews Immunology.2008;8:10816-822. https://doi.org/10.1038/nri2396 [PubMed]
54. Medway C and Morgan K. Review: The genetics of Alzheimer's disease; putting flesh on the bones.Neuropathol Appl Neurobiol.2014;40:297-105. [PubMed] https://doi.org/10.1111/nan.12101
55. Tassiulas I, Hu XY, Ho H, Kashyap Y, Paik P, Hu YM, Lowell CA, Ivashkiv LB. Amplification of IFN-alpha-induced STAT1 activation and inflammatory function by Syk and ITAM-containing adaptors.Nat Immunol.2004;5:111181-1189. [PubMed] https://doi.org/10.1038/ni1126
56. Wang L, Tassiulas I, Park-Min KH, Reid AC, Gil-Henn H, Schlessinger J, Baron R, Zhang JJ, Ivashkiv LB. ‘Tuning’ of type I interferon-induced Jak-STAT1 signaling by calcium-dependent kinases in macrophages.Nat Immunol.2008;9:2186-193. [PubMed] https://doi.org/10.1038/ni1548
57. Singh M, Cowell L, Seo S, O'Neill G, Golemis E. Molecular basis for HEF1/NEDD9/Cas-L action as a multifunctional co-ordinator of invasion, apoptosis and cell cycle.Cell biochemistry and biophysics.2007;48:154-72. [PubMed] https://doi.org/10.1007/s12013-007-0036-3
58. Lipinski CA and Loftus JC. Targeting Pyk2 for therapeutic intervention.Expert opinion on therapeutic targets.2010;14:195-108. [PubMed] https://doi.org/10.1517/14728220903473194
59. Singh MK, Dadke D, Nicolas E, Serebriiskii IG, Apostolou S, Canutescu A, Egleston BL, Golemis EA. A novel Cas family member, HEPL, regulates FAK and cell spreading.Mol Biol Cell.2008;19:41627-1636. [PubMed] https://doi.org/10.1091/mbc.E07-09-0953
60. Konopka G, Friedrich T, Davis-Turak J, Winden K, Oldham MC, Gao F, Chen L, Wang GZ, Luo R, Preuss TM, Geschwind DH. Human-specific transcriptional networks in the brain.Neuron.2012;75:4601-617. [PubMed] https://doi.org/10.1016/j.neuron.2012.05.034
61. Kumar S, Tomooka Y, Noda M. Identification of a set of genes with developmentally down-regulated expression in the mouse brain.Biochem Biophys Res Commun.1992;185:31155-1161. [PubMed] https://doi.org/10.1016/0006-291x(92)91747-e
62. Law SF, Estojak J, Wang B, Mysliwiec T, Kruh G, Golemis EA. Human enhancer of filamentation 1, a novel p130cas-like docking protein, associates with focal adhesion kinase and induces pseudohyphal growth in Saccharomyces cerevisiae.Mol Cell Biol.1996;16:73327-3337. [PubMed] https://doi.org/10.1128/mcb.16.7.3327
63. Astier A, Manie SN, Avraham H, Hirai H, Law SF, Zhang Y, Golemis EA, Fu Y, Druker BJ, Haghayeghi N, Freedman AS, Avraham S. The related adhesion focal tyrosine kinase differentially phosphorylates p130Cas and the Cas-like protein, p105HEF1.J Biol Chem.1997;272:3219719-19724. [PubMed] https://doi.org/10.1074/jbc.272.32.19719
64. Keogh RJ, Houliston RA, Wheeler-Jones CPD. Human endothelial Pyk2 is expressed in two isoforms and associates with paxillin and p130Cas.Biochem Biophys Res Commun.2002;290:51470-1477. [PubMed] https://doi.org/10.1006/bbrc.2002.6350
65. Briknarova K, Nasertorabi F, Havert ML, Eggleston E, Hoyt DW, Li CL, Olson AJ, Vuori K, Ely KR. The serine-rich domain from Crk-associated substrate (p130(cas)) is a four-helix bundle.Journal of Biological Chemistry.2005;280:2321908-21914. [PubMed] https://doi.org/10.1074/jbc.M501258200
66. Vuori K, Hirai H, Aizawa S, Ruoslahti E. Induction of p130(cas) signaling complex formation upon integrin-mediated cell adhesion: A role for Src family kinases.Mol Cell Biol.1996;16:62606-2613. [PubMed] https://doi.org/10.1128/mcb.16.6.2606
67. Garron ML, Arsenieva D, Zhong J, Bloom AB, Lerner A, O'Neill GM, Arold ST. Structural Insights into the Association between BCAR3 and Cas Family Members, an Atypical Complex Implicated in Anti-Oestrogen Resistance.J Mol Biol.2009;386:1190-203. [PubMed] https://doi.org/10.1016/j.jmb.2008.12.010
68. Mace PD, Wallez Y, Dobaczewska MK, Lee JJ, Robinson H, Pasquale EB, Riedl SJ. NSP-Cas protein structures reveal a promiscuous interaction module in cell signaling.Nature structural & molecular biology.2011;18:121381-1387. https://doi.org/10.1038/nsmb.2152 [PubMed]
69. Cai DP, Felekkis KN, Near RI, O'Neill GM, van Seventer JM, Golemis EA, Lerner A. The GDP exchange factor AND-34 is expressed in B cells, associates with HEF1, and activates Cdc42.J Immunol.2003;170:2969-978. [PubMed] https://doi.org/10.4049/jimmunol.170.2.969
70. Law SF, O'Neill GM, Fashena SJ, Einarson MB, Golemis EA. The docking protein HEF1 is an apoptotic mediator at focal adhesion sites.Mol Cell Biol.2000;20:145184-5195. [PubMed] https://doi.org/10.1128/mcb.20.14.5184-5195.2000
71. Zhong J, Baquiran JB, Bonakdar N, Lees J, Ching YW, Pugacheva E, Fabry B, O'Neill GM. NEDD9 stabilizes focal adhesions, increases binding to the extra-cellular matrix and differentially effects 2D versus 3D cell migration.PLoS One.2012;7:4e35058 [PubMed] https://doi.org/10.1371/journal.pone.0035058
72. Tachibana K, Urano T, Fujita H, Ohashi Y, Kamiguchi K, Iwata S, Hirai H, Morimoto C. Tyrosine phosphorylation of Crk-associated substrates by focal adhesion kinase - A putative mechanism for the integrin-mediated tyrosine phosphorylation of Crk-associated substrates.Journal of Biological Chemistry.1997;272:4629083-29090. [PubMed] https://doi.org/10.1074/jbc.272.46.29083
73. Manie SN, Beck AR, Astier A, Law SF, Canty T, Hirai H, Druker BJ, Avraham H, Haghayeghi N, Sattler M, Salgia R, Griffin JD, Golemis EA, Freedman AS. Involvement of p130(Cas) and p105(HEF1), a novel Cas-like docking protein, in a cytoskeleton-dependent signaling pathway initiated by ligation of integrin or antigen receptor on human B cells.J Biol Chem.1997;272:74230-4236. [PubMed] https://doi.org/10.1074/jbc.272.7.4230
74. Sawada Y, Tamada M, Dubin-Thaler BJ, Cherniavskaya O, Sakai R, Tanaka S, Sheetz MP. Force sensing by mechanical extension of the Src family kinase substrate p130Cas.Cell.2006;127:51015-1026. [PubMed] https://doi.org/10.1016/j.cell.2006.09.044
75. de Jong R, van Wijk A, Haataja L, Heisterkamp N, Groffen J. BCR/ABL-induced leukemogenesis causes phosphorylation of Hef1 and its association with Crkl.J Biol Chem.1997;272:5132649-32655. [PubMed] https://doi.org/10.1074/jbc.272.51.32649
76. Ahn J, Sanz-Moreno V, Marshall CJ. The metastasis gene NEDD9 product acts through integrin beta 3 and Src to promote mesenchymal motility and inhibit amoeboid motility.Journal of cell science.2012;125:71814-1826. [PubMed] https://doi.org/10.1242/jcs.101444
77. Sanz-Moreno V, Gadea G, Ahn J, Paterson H, Marra P, Pinner S, Sahai E, Marshall CJ. Rac activation and inactivation control plasticity of tumor cell movement.Cell.2008;135:3510-523. [PubMed] https://doi.org/10.1016/j.cell.2008.09.043
78. Natarajan M, Stewart JE, Golemis EA, Pugacheva EN, Alexandropoulos K, Cox BD, Wang W, Grammer JR, Gladson CL. HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells.Oncogene.2006;25:121721-1732. [PubMed] https://doi.org/10.1038/sj.onc.1209199
79. van Seventer GA, Salmen HJ, Law SF, O'Neill GM, Mullen MM, Franz AM, Kanner SB, Golemis EA, van Seventer JM. Focal adhesion kinase regulates beta1 integrin-dependent T cell migration through an HEF1 effector pathway.Eur J Immunol.2001;31:51417-1427. [PubMed] https://doi.org/10.1002/1521-4141(200105)31:5<1417::AID-IMMU1417>3.0.CO;2-C
80. Zhong J, Bach CT, Shum MS, O'Neill GM. NEDD9 regulates 3D migratory activity independent of the Rac1 morphology switch in glioma and neuroblastoma.Mol Cancer Res.2014;12:2264-273. [PubMed] https://doi.org/10.1158/1541-7786.MCR-13-0513
81. Simpson KJ, Selfors LM, Bui J, Reynolds A, Leake D, Khvorova A, Brugge JS. Identification of genes that regulate epithelial cell migration using an siRNA screening approach.Nat Cell Biol.2008;10:91027-1038. [PubMed] https://doi.org/10.1038/ncb1762
82. Bargon SD, Gunning PW, O'Neill GM. The Cas family docking protein, HEF1, promotes the formation of neurite-like membrane extensions.Biochim Biophys Acta.2005;1746:2143-154. [PubMed] https://doi.org/10.1016/j.bbamcr.2005.10.008
83. Pugacheva EN and Golemis EA. The focal adhesion scaffolding protein HEF1 regulates activation of the Aurora-A and Nek2 kinases at the centrosome.Nat Cell Biol.2005;7:10937-946. [PubMed] https://doi.org/10.1038/ncb1309
84. Pugacheva EN, Jablonski SA, Hartman TR, Henske EP, Golemis EA. HEF1-dependent Aurora A activation induces disassembly of the primary cilium.Cell.2007;129:71351-1363. [PubMed] https://doi.org/10.1016/j.cell.2007.04.035
85. Guemez-Gamboa A, Coufal NG, Gleeson JG. Primary cilia in the developing and mature brain.Neuron.2014;82:3511-521. [PubMed] https://doi.org/10.1016/j.neuron.2014.04.024
86. Valente EM, Rosti RO, Gibbs E, Gleeson JG. Primary cilia in neurodevelopmental disorders.Nature reviews Neurology.2014;10:127-36. https://doi.org/10.1038/nrneurol.2013.247 [PubMed]
87. Nourry C, Maksumova L, Pang M, Liu XH, Wang TW. Direct interaction between Smad3, APC10, CDH1 and HEF1 in proteasomal degradation of HEF1.Bmc Cell Biol.2004;5: https://doi.org/10.1186/1471-2121-5-20 [PubMed]
88. Inamoto S, Iwata S, Inamoto T, Nomura S, Sasaki T, Urasaki Y, Hosono O, Kawasaki H, Tanaka H, Dang NH, Morimoto C. Crk-associated substrate lymphocyte type regulates transforming growth factor-beta signaling by inhibiting Smad6 and Smad7.Oncogene.2007;26:6893-904. [PubMed] https://doi.org/10.1038/sj.onc.1209848
89. Liu X, Elia AE, Law SF, Golemis EA, Farley J, Wang T. A novel ability of Smad3 to regulate proteasomal degradation of a Cas family member HEF1.Embo J.2000;19:246759-6769. [PubMed] https://doi.org/10.1093/emboj/19.24.6759
90. Avraham H, Park SY, Schinkmann K, Avraham S. RAFTK/Pyk2-mediated cellular signalling.Cell Signal.2000;12:3123-133. [PubMed] https://doi.org/10.1016/s0898-6568(99)00076-5
91. Xiong WC, Macklem M, Parsons JT. Expression and characterization of splice variants of PYK2, a focal adhesion kinase-related protein.Journal of cell science.1998;111:1981-1991. [PubMed] https://doi.org/10.1242/jcs.111.14.1981
92. Sasaki H, Nagura K, Ishino M, Tobioka H, Kotani K, Sasaki T. Cloning and characterization of cell adhesion kinase beta, a novel protein-tyrosine kinase of the focal adhesion kinase subfamily.J Biol Chem.1995;270:3621206-21219. [PubMed] https://doi.org/10.1074/jbc.270.36.21206
93. Mitra SK, Hanson DA, Schlaepfer DD. Focal adhesion kinase: in command and control of cell motility.Nature reviews Molecular cell biology.2005;6:156-68. https://doi.org/10.1038/nrm1549 [PubMed]
94. Block ER, Tolino MA, Klarlund JK. Pyk2 activation triggers epidermal growth factor receptor signaling and cell motility after wounding sheets of epithelial cells.J Biol Chem.2010;285:1813372-13379. [PubMed] https://doi.org/10.1074/jbc.M109.083089
95. Blaukat A, Ivankovic-Dikic I, Gronroos E, Dolfi F, Tokiwa G, Vuori K, Dikic I. Adaptor proteins Grb2 and Crk couple Pyk2 with activation of specific mitogen-activated protein kinase cascades.J Biol Chem.1999;274:2114893-14901. [PubMed] https://doi.org/10.1074/jbc.274.21.14893
96. Dikic I, Tokiwa G, Lev S, Courtneidge SA, Schlessinger J. A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation.Nature.1996;383:6600547-550. [PubMed] https://doi.org/10.1038/383547a0
97. Du QS, Ren XR, Xie Y, Wang Q, Mei L, Xiong WC. Inhibition of PYK2-induced actin cytoskeleton reorganization, PYK2 autophosphorylation and focal adhesion targeting by FAK.Journal of cell science.2001;114:Pt 162977-2987. [PubMed] https://doi.org/10.1242/jcs.114.16.2977
98. Aquino JB, Marmigere F, Lallemend F, Lundgren TK, Villar MJ, Wegner M, Ernfors P. Differential expression and dynamic changes of murine NEDD9 in progenitor cells of diverse tissues.Gene Expr Patterns.2008;8:4217-226. [PubMed] https://doi.org/10.1016/j.gep.2008.01.001
99. Aquino JB, Lallemend F, Marmigere F, Adameyko II, Golemis EA, Ernfors P. The retinoic acid inducible Cas-family signaling protein Nedd9 regulates neural crest cell migration by modulating adhesion and actin dynamics.Neuroscience.2009;162:41106-1119. [PubMed] https://doi.org/10.1016/j.neuroscience.2009.05.035
100. Vogel T, Ahrens S, Buttner N, Krieglstein K. Transforming growth factor beta promotes neuronal cell fate of mouse cortical and hippocampal progenitors in vitro and in vivo: identification of Nedd9 as an essential signaling component.Cereb Cortex.2010;20:3661-671. [PubMed] https://doi.org/10.1093/cercor/bhp134
101. Merrill RA, Ahrens JM, Kaiser ME, Federhart KS, Poon VY, Clagett-Dame M. All-trans retinoic acid-responsive genes identified in the human SH-SY5Y neuroblastoma cell line and their regulated expression in the nervous system of early embryos.Biol Chem.2004;385:7605-614. [PubMed] https://doi.org/10.1515/BC.2004.075
102. Piechota M, Korostynski M, Solecki W, Gieryk A, Slezak M, Bilecki W, Ziolkowska B, Kostrzewa E, Cymerman I, Swiech L, Jaworski J, Przewlocki R. The dissection of transcriptional modules regulated by various drugs of abuse in the mouse striatum.Genome Biol.2010;11:5R48 [PubMed] https://doi.org/10.1186/gb-2010-11-5-r48
103. Lauterbach EC. Psychotropic drug effects on gene transcriptomics relevant to Alzheimer disease.Alzheimer Dis Assoc Disord.2012;26:11-7. [PubMed] https://doi.org/10.1097/WAD.0b013e318214b7d0
104. Lev S, Moreno H, Martinez R, Canoll P, Peles E, Musacchio JM, Plowman GD, Rudy B, Schlessinger J. Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions.Nature.1995;376:6543737-745. [PubMed] https://doi.org/10.1038/376737a0
105. Park SY, Avraham H, Avraham S. Characterization of the tyrosine kinases RAFTK/Pyk2 and FAK in nerve growth factor-induced neuronal differentiation.J Biol Chem.2000;275:2619768-19777. [PubMed] https://doi.org/10.1074/jbc.M909932199
106. Wang X, Bao X, Pal R, Agbas A, Michaelis EK. Transcriptomic responses in mouse brain exposed to chronic excess of the neurotransmitter glutamate.BMC Genomics.2010;11:360 [PubMed] https://doi.org/10.1186/1471-2164-11-360
107. Ivankovic-Dikic I, Gronroos E, Blaukat A, Barth BU, Dikic I. Pyk and FAK regulate neurite outgrowth induced by growth factors and integrins.Nat Cell Biol.2000;2:9574-581. [PubMed] https://doi.org/10.1038/35023515
108. Lipinski CA, Tran NL, Menashi E, Rohl C, Kloss J, Bay RC, Berens ME, Loftus JC. The tyrosine kinase pyk2 promotes migration and invasion of glioma cells.Neoplasia.2005;7:5435-445. [PubMed] https://doi.org/10.1593/neo.04712
109. Gniadecki R, Assaf C, Bagot M, Dummer R, Duvic M, Knobler R, Ranki A, Schwandt P, Whittaker S. The optimal use of bexarotene in cutaneous T-cell lymphoma.Brit J Dermatol.2007;157:3433-440. [PubMed] https://doi.org/10.1111/j.1365-2133.2007.07975.x
110. Knutson DC and Clagett-Dame M. atRA Regulation of NEDD9, a gene involved in neurite outgrowth and cell adhesion.Arch Biochem Biophys.2008;477:1163-174. [PubMed] https://doi.org/10.1016/j.abb.2008.06.005
111. Ovcharenko A, Granot G, Shpilberg O, Raanani P. Retinoic acid induces adhesion and migration in NB4 cells through Pyk2 signaling.Leukemia Res.2013;37:8956-962. [PubMed] https://doi.org/10.1016/j.leukres.2013.03.010
112. Raichle ME and Gusnard DA. Appraising the brain's energy budget.Proc Natl Acad Sci U S A.2002;99:1610237-10239. [PubMed] https://doi.org/10.1073/pnas.172399499
113. Banasiak KJ, Xia Y, Haddad GG. Mechanisms underlying hypoxia-induced neuronal apoptosis.Progress in neurobiology.2000;62:3215-249. [PubMed] https://doi.org/10.1016/s0301-0082(00)00011-3
114. Peers C, Dallas ML, Boycott HE, Scragg JL, Pearson HA, Boyle JP. Hypoxia and neurodegeneration.Annals of the New York Academy of Sciences.2009;1177:169-177. [PubMed] https://doi.org/10.1111/j.1749-6632.2009.05026.x
115. Sasaki T, Iwata S, Okano HJ, Urasaki Y, Hamada J, Tanaka H, Dang NH, Okano H, Morimoto C. Nedd9 protein, a Cas-L homologue, is upregulated after transient global ischemia in rats: possible involvement of Nedd9 in the differentiation of neurons after ischemia.Stroke.2005;36:112457-2462. [PubMed] https://doi.org/10.1161/01.STR.0000185672.10390.30
116. Kim SH, Xia D, Kim SW, Holla V, Menter DG, Dubois RN. Human enhancer of filamentation 1 Is a mediator of hypoxia-inducible factor-1alpha-mediated migration in colorectal carcinoma cells.Cancer Res.2010;70:104054-4063. [PubMed] https://doi.org/10.1158/0008-5472.CAN-09-2110
117. Ismail HM. Overexpression of s6 kinase 1 in brain tumours is associated with induction of hypoxia-responsive genes and predicts patients' survival.Journal of oncology.2012;2012:416927 [PubMed] https://doi.org/10.1155/2012/416927
118. Xu J, Li H, Wang B, Xu Y, Yang J, Zhang X, Harten SK, Shukla D, Maxwell PH, Pei D, Esteban MA. VHL inactivation induces HEF1 and Aurora kinase A.J Am Soc Nephrol.2010;21:122041-2046. [PubMed] https://doi.org/10.1681/ASN.2010040345
119. Chadwick W, Boyle JP, Zhou Y, Wang L, Park SS, Martin B, Wang R, Becker KG, Wood WH 3rd, Zhang Y, Peers C, Maudsley S. Multiple oxygen tension environments reveal diverse patterns of transcriptional regulation in primary astrocytes.PLoS One.2011;6:6e21638 [PubMed] https://doi.org/10.1371/journal.pone.0021638
120. Tian D, Litvak V, Lev S. Cerebral ischemia and seizures induce tyrosine phosphorylation of PYK2 in neurons and microglial cells.J Neurosci.2000;20:176478-6487. [PubMed] https://doi.org/10.1523/JNEUROSCI.20-17-06478.2000
121. Matsui A, Okigaki M, Amano K, Adachi Y, Jin D, Takai S, Yamashita T, Kawashima S, Kurihara T, Miyazaki M, Tateishi K, Matsunaga S, Katsume A, Honshou S, Takahashi T, Matoba S, et al. Central role of calcium-dependent tyrosine kinase PYK2 in endothelial nitric oxide synthase-mediated angiogenic response and vascular function.Circulation.2007;116:91041-1051. [PubMed] https://doi.org/10.1161/CIRCULATIONAHA.106.645416
122. Kitamura T, Asai N, Enomoto A, Maeda K, Kato T, Ishida M, Jiang P, Watanabe T, Usukura J, Kondo T, Costantini F, Murohara T, Takahashi M. Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin.Nat Cell Biol.2008;10:3329-337. [PubMed] https://doi.org/10.1038/ncb1695
123. Feliers D, Chen X, Akis N, Choudhury GG, Madaio M, Kasinath BS. VEGF regulation of endothelial nitric oxide synthase in glomerular endothelial cells.Kidney international.2005;68:41648-1659. [PubMed] https://doi.org/10.1111/j.1523-1755.2005.00575.x
124. Kalaria RN, Akinyemi R, Ihara M. Does vascular pathology contribute to Alzheimer changes?J Neurol Sci.2012;322:1-2141-147. [PubMed] https://doi.org/10.1016/j.jns.2012.07.032
125. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008.JAMA: the journal of the American Medical Association.2010;303:202043-2050. https://doi.org/10.1001/jama.2010.650 [PubMed]
126. Elmer PJ, Obarzanek E, Vollmer WM, Simons-Morton D, Stevens VJ, Young DR, Lin PH, Champagne C, Harsha DW, Svetkey LP, Ard J, Brantley PJ, Proschan MA, Erlinger TP, Appel LJ. Effects of comprehensive lifestyle modification on diet, weight, physical fitness, and blood pressure control: 18-month results of a randomized trial.Annals of internal medicine.2006;144:7485-495. [PubMed] https://doi.org/10.7326/0003-4819-144-7-200604040-00007
127. Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S, Mayeux R. Aggregation of vascular risk factors and risk of incident Alzheimer disease.Neurology.2005;65:4545-551. [PubMed] https://doi.org/10.1212/01.wnl.0000172914.08967.dc
128. Peila R, White LR, Petrovich H, Masaki K, Ross GW, Havlik RJ, Launer LJ. Joint effect of the APOE gene and midlife systolic blood pressure on late-life cognitive impairment - The Honolulu-Asia aging study.Stroke.2001;32:122882-2887. [PubMed] https://doi.org/10.1161/hs1201.100392
129. Elias MF, Wolf PA, Dagostino RB, Cobb J, White LR. Untreated Blood-Pressure Level Is Inversely Related to Cognitive-Functioning - the Framingham-Study.Am J Epidemiol.1993;138:6353-364. [PubMed] https://doi.org/10.1093/oxfordjournals.aje.a116868
130. Morris MC, Scherr PA, Hebert LE, Glynn RJ, Bennett DA, Evans DA. Association of incident Alzheimer disease and blood pressure measured from 13 years before to 2 years after diagnosis in a large community study.Archives of neurology.2001;58:101640-1646. [PubMed] https://doi.org/10.1001/archneur.58.10.1640
131. Lindsay J, Laurin D, Verreault R, Hebert R, Helliwell B, Hill GB, McDowell I. Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging.Am J Epidemiol.2002;156:5445-453. [PubMed] https://doi.org/10.1093/aje/kwf074
132. Hoffman LB, Schmeidler J, Lesser GT, Beeri MS, Purohit DP, Grossman HT, Haroutunian V. Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons.Neurology.2009;72:201720-1726. [PubMed] https://doi.org/10.1212/01.wnl.0000345881.82856.d5
133. Yasar S, Xia J, Yao WL, Furberg CD, Xue QL, Mercado CI, Fitzpatrick AL, Fried LP, Kawas CH, Sink KM, Williamson JD, DeKosky ST, Carlson MC, Investigators GS. Antihypertensive drugs decrease risk of Alzheimer disease Ginkgo Evaluation of Memory Study.Neurology.2013;81:10896-903. [PubMed] https://doi.org/10.1212/WNL.0b013e3182a35228
134. Rocic P, Griffin TM, McRae CN, Lucchesi PA. Altered PYK2 phosphorylation by ANG II in hypertensive vascular smooth muscle.American journal of physiology Heart and circulatory physiology.2002;282:2H457-465. [PubMed] https://doi.org/10.1152/ajpheart.00546.2001
135. Sabri A, Govindarajan G, Griffin TM, Byron KL, Samarel AM, Lucchesi PA. Calcium-and protein kinase C-dependent activation of the tyrosine kinase PYK2 by angiotensin II in vascular smooth muscle.Circulation research.1998;83:8841-851. [PubMed] https://doi.org/10.1161/01.res.83.8.841
136. Marques FZ, Campain AE, Davern PJ, Yang YH, Head GA, Morris BJ. Global identification of the genes and pathways differentially expressed in hypothalamus in early and established neurogenic hypertension.Physiological genomics.2011;43:12766-771. [PubMed] https://doi.org/10.1152/physiolgenomics.00009.2011
137. Kamide K, Kokubo Y, Fukuhara S, Hanada H, Yang J, Kada A, Nagura J, Takiuchi S, Horio T, Kawano Y, Okayama A, Tomoike H, Miyata T. Protein tyrosine kinase 2 beta as a candidate gene for hypertension.Pharmacogenet Genom.2007;17:11931-939. https://doi.org/10.1097/FPC.0b013e3282ef640e [PubMed]
138. Miyaki K, Htun NC, Song Y, Ikeda S, Muramatsu M, Shimbo T. The combined impact of 12 common variants on hypertension in Japanese men, considering GWAS results.J Hum Hypertens.2012;26:7430-436. [PubMed] https://doi.org/10.1038/jhh.2011.50
139. Crowley SD, Gurley SB, Herrera MJ, Ruiz P, Griffiths R, Kumar AP, Kim HS, Smithies O, Le TH, Coffman TM. Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney.Proc Natl Acad Sci U S A.2006;103:4717985-17990. [PubMed] https://doi.org/10.1073/pnas.0605545103
140. Pessoa BS, van der Lubbe N, Verdonk K, Roks AJM, Hoorn EJ, Danser AHJ. Key developments in renin-angiotensin-aldosterone system inhibition.Nat Rev Nephrol.2013;9:126-36. [PubMed] https://doi.org/10.1038/nrneph.2012.249
141. Matsubara H, Shibasaki Y, Okigaki M, Mori Y, Masaki H, Kosaki A, Tsutsumi Y, Uchiyama Y, Fujiyama S, Nose A, Iba O, Tateishi E, Hasegawa T, Horiuchi M, Nahmias C, Iwasaka T. Effect of angiotensin II type 2 receptor on tyrosine kinase Pyk2 and c-Jun NH2-terminal kinase via SHP-1 tyrosine phosphatase activity: Evidence from vascular-targeted transgenic mice of AT2 receptor.Biochem Biophys Res Commun.2001;282:51085-1091. [PubMed] https://doi.org/10.1006/bbrc.2001.4695
142. Murasawa S, Matsubara H, Mori Y, Masaki H, Tsutsumi Y, Shibasaki Y, Kitabayashi I, Tanaka Y, Fujiyama S, Koyama Y, Fujiyama A, Iba S, Iwasaka T. Angiotensin II initiates tyrosine kinase Pyk2-dependent signalings leading to activation of Rac1-mediated c-Jun NH2-terminal kinase.Journal of Biological Chemistry.2000;275:3526856-26863. [PubMed] https://doi.org/10.1074/jbc.M909999199
143. Murasawa S, Mori Y, Nozawa Y, Masaki H, Maruyama K, Tsutsumi Y, Moriguchi Y, Shibasaki Y, Tanaka Y, Iwasaka T, Inada M, Matsubara H. Role of calcium-sensitive tyrosine kinase Pyk2/CAK beta/RAFTK in angiotensin II-induced Ras/ERK signaling.Hypertension.1998;32:4668-675. [PubMed] https://doi.org/10.1161/01.hyp.32.4.668
144. Benigni A, Cassis P, Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging.Embo Mol Med.2010;2:7247-257. [PubMed] https://doi.org/10.1002/emmm.201000080
145. Miners JS, Ashby E, Van Helmond Z, Chalmers KA, Palmer LE, Love S, Kehoe PG. Angiotensin-converting enzyme (ACE) levels and activity in Alzheimer's disease, and relationship of perivascular ACE-1 to cerebral amyloid angiopathy.Neuropath Appl Neuro.2008;34:2181 https://doi.org/10.1111/j.1365-2990.2007.00885.x [PubMed]
146. Savaskan E, Hock C, Olivieri G, Bruttel S, Rosenberg C, Hulette C, Muller-Spahn F. Cortical alterations of angiotensin converting enzyme, angiotensin II and AT1 receptor in Alzheimer's dementia.Neurobiol Aging.2001;22:4541-546. [PubMed] https://doi.org/10.1016/s0197-4580(00)00259-1
147. Su W-W, Cheng S-T, Ho W-J, Tsay P-K, Wu S-C, Chang SHL. Glaucoma Is Associated with Peripheral Vascular Endothelial Dysfunction.Ophthalmology.2008;115:71173-1178. e1171. [PubMed] https://doi.org/10.1016/j.ophtha.2007.10.026
148. Gibson J, Griffiths H, De Salvo G, Cole M, Jacob A, Macleod A, Yang Y, Menon G, Cree A, Ennis S, Lotery A. Genome-wide association study of primary open angle glaucoma risk and quantitative traits.Mol Vis.2012;18:1083-1092. [PubMed]
149. Armato U, Chakravarthy B, Pacchiana R, Whitfield JF. Alzheimer's disease: an update of the roles of receptors, astrocytes and primary cilia (review).International journal of molecular medicine.2013;31:13-10. [PubMed] https://doi.org/10.3892/ijmm.2012.1162
150. Lucas JT Jr., Salimath BP, Slomiany MG, Rosenzweig SA. Regulation of invasive behavior by vascular endothelial growth factor is HEF1-dependent.Oncogene.2010;29:314449-4459. [PubMed] https://doi.org/10.1038/onc.2010.185
151. Vincent L, Jin DK, Karajannis MA, Shido K, Hooper AT, Rashbaum WK, Pytowski B, Wu Y, Hicklin DJ, Zhu Z, Bohlen P, Niesvizky R, Rafii S. Fetal stromal-dependent paracrine and intracrine vascular endothelial growth factor-a/vascular endothelial growth factor receptor-1 signaling promotes proliferation and motility of human primary myeloma cells.Cancer Res.2005;65:83185-3192. [PubMed] https://doi.org/10.1158/0008-5472.CAN-04-3598
152. Biron KE, Dickstein DL, Gopaul R, Jefferies WA. Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in Alzheimer's disease.PLoS One.2011;6:8e23789 [PubMed] https://doi.org/10.1371/journal.pone.0023789
153. Tang H, Hao Q, Fitzgerald T, Sasaki T, Landon EJ, Inagami T. Pyk2/CAKbeta tyrosine kinase activity-mediated angiogenesis of pulmonary vascular endothelial cells.J Biol Chem.2002;277:75441-5447. [PubMed] https://doi.org/10.1074/jbc.M110673200
154. Combs CK, Johnson DE, Cannady SB, Lehman TM, Lreth GE. Identification of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of beta-amyloid and prion proteins.J Neurosci.1999;19:3928-939. [PubMed] https://doi.org/10.1523/JNEUROSCI.19-03-00928.1999
155. Cain RJ, Vanhaesebroeck B, Ridley AJ. The PI3K p110alpha isoform regulates endothelial adherens junctions via Pyk2 and Rac1.J Cell Biol.2010;188:6863-876. [PubMed] https://doi.org/10.1083/jcb.200907135
156. Cain RJ, Vanhaesebroeck B, Ridley AJ. Different PI 3-kinase inhibitors have distinct effects on endothelial permeability and leukocyte transmigration.Int J Biochem Cell Biol.2012;44:111929-1936. [PubMed] https://doi.org/10.1016/j.biocel.2012.07.009
157. van Buul JD, Anthony EC, Fernandez-Borja M, Burridge K, Hordijk PL. Proline-rich tyrosine kinase 2 (Pyk2) mediates vascular endothelial-cadherin-based cell-cell adhesion by regulating beta-catenin tyrosine phosphorylation.J Biol Chem.2005;280:2221129-21136. [PubMed] https://doi.org/10.1074/jbc.M500898200
158. Grammas P, Martinez J, Sanchez A, Yin X, Riley J, Gay D, Desobry K, Tripathy D, Luo J, Evola M, Young A. A new paradigm for the treatment of Alzheimer's disease: targeting vascular activation.J Alzheimers Dis.2014;40:3619-630. [PubMed] https://doi.org/10.3233/JAD-2014-132057
159. Lee YJ, Han SB, Nam SY, Oh KW, Hong JT. Inflammation and Alzheimer's disease.Archives of pharmacal research.2010;33:101539-1556. [PubMed] https://doi.org/10.1007/s12272-010-1006-7
160. Imbimbo BP, Solfrizzi V, Panza F. Are NSAIDs useful to treat Alzheimer's disease or mild cognitive impairment?Frontiers in aging neuroscience.2010;2: https://doi.org/10.3389/fnagi.2010.00019 [PubMed]
161. Breitner JC, Baker LD, Montine TJ, Meinert CL, Lyketsos CG, Ashe KH, Brandt J, Craft S, Evans DE, Green RC, Ismail MS, Martin BK, Mullan MJ, Sabbagh M, Tariot PN. Extended results of the Alzheimer's disease anti-inflammatory prevention trial.Alzheimers Dement.2011;7:4402-411. [PubMed] https://doi.org/10.1016/j.jalz.2010.12.014
162. Minegishi M, Tachibana K, Sato T, Iwata S, Nojima Y, Morimoto C. Structure and function of Cas-L, a 105-kD Crk-associated substrate-related protein that is involved in beta 1 integrin-mediated signaling in lymphocytes.J Exp Med.1996;184:41365-1375. [PubMed] https://doi.org/10.1084/jem.184.4.1365
163. Ohashi Y, Tachibana K, Kamiguchi K, Fujita H, Morimoto C. T cell receptor-mediated tyrosine phosphorylation of Cas-L, a 105-kDa Crk-associated substrate-related protein, and its association of Crk and C3G.J Biol Chem.1998;273:116446-6451. [PubMed] https://doi.org/10.1074/jbc.273.11.6446
164. Regelmann AG, Danzl NM, Wanjalla C, Alexropoulos K. The hematopoietic isoform of Cas-Hef1-associated signal transducer regulates chemokine-induced inside-out signaling and T cell trafficking.Immunity.2006;25:6907-918. [PubMed] https://doi.org/10.1016/j.immuni.2006.09.014
165. Gu JJ, Lavau CP, Pugacheva E, Soderblom EJ, Moseley MA, Pendergast AM. Abl family kinases modulate T cell-mediated inflammation and chemokine-induced migration through the adaptor HEF1 and the GTPase Rap1.Sci Signal.2012;5:233ra51 [PubMed] https://doi.org/10.1126/scisignal.2002632
166. Nolz JC, Nacusi LP, Segovis CM, Medeiros RB, Mitchell JS, Shimizu Y, Billadeau DD. The WAVE2 complex regulates T cell receptor signaling to integrins via Abl-and CrkL-C3G-mediated activation of Rap1.J Cell Biol.2008;182:61231-1244. [PubMed] https://doi.org/10.1083/jcb.200801121
167. Kamen LA, Schlessinger J, Lowell CA. Pyk2 Is Required for Neutrophil Degranulation and Host Defense Responses to Bacterial Infection.J Immunol.2011;186:31656-1665. [PubMed] https://doi.org/10.4049/jimmunol.1002093.
168. Duan YL, Learoyd J, Meliton AY, Leff AR, Zhu XD. Inhibition of Pyk2 blocks lung inflammation and injury in a mouse model of acute lung injury.Resp Res.2012;13: https://doi.org/10.1186/1465-9921-13-4 [PubMed]
169. Duan Y, Learoyd J, Meliton AY, Clay BS, Leff AR, Zhu X. Inhibition of Pyk2 blocks airway inflammation and hyperresponsiveness in a mouse model of asthma.Am J Respir Cell Mol Biol.2010;42:4491-497. [PubMed] https://doi.org/10.1165/rcmb.2008-0469OC
170. Berg NN and Ostergaard HL. T cell receptor engagement induces tyrosine phosphorylation of FAK and Pyk2 and their association with Lck.J Immunol.1997;159:41753-1757. [PubMed]
171. Beinke S, Phee H, Clingan JM, Schlessinger J, Matloubian M, Weiss A. Proline-rich tyrosine kinase-2 is critical for CD8 T-cell short-lived effector fate.Proc Natl Acad Sci U S A.2010;107:3716234-16239. [PubMed] https://doi.org/10.1073/pnas.1011556107
172. Li RH, Wong N, Jabali MD, Johnson P. CD44-initiated cell spreading induces Pyk2 phosphorylation, is mediated by Src family kinases, and is negatively regulated by CD45.Journal of Biological Chemistry.2001;276:3128767-28773. [PubMed] https://doi.org/10.1074/jbc.M100158200
173. Ostergaard HL, Lou O, Arendt CW, Berg NN. Paxillin phosphorylation and association with Lck and Pyk2 in anti-CD3-or anti-CD45-stimulated T cells.Journal of Biological Chemistry.1998;273:105692-5696. [PubMed] https://doi.org/10.1074/jbc.273.10.5692
174. Ulrich CM, Bigler J, Potter JD. Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics.Nat Rev Cancer.2006;6:2130-140. [PubMed] https://doi.org/10.1038/nrc1801
175. Xia D, Holla VR, Wang D, Menter DG, DuBois RN. HEF1 is a crucial mediator of the proliferative effects of prostaglandin E on colon cancer cells.Cancer Res.2010;70:2824-831. [PubMed] https://doi.org/10.1158/0008-5472.CAN-09-2105
176. Cohen TJ, Guo JL, Hurtado DE, Kwong LK, Mills IP, Trojanowski JQ, Lee VM. The acetylation of tau inhibits its function and promotes pathological tau aggregation.Nature communications.2011;2:252 https://doi.org/10.1038/ncomms1255 [PubMed]
177. Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I. Tau pathology in Alzheimer disease and other tauopathies.Biochim Biophys Acta.2005;1739:2-3198-210. [PubMed] https://doi.org/10.1016/j.bbadis.2004.09.008
178. Conde C and Caceres A. Microtubule assembly, organization and dynamics in axons and dendrites.Nature reviews Neuroscience.2009;10:5319-332. https://doi.org/10.1038/nrn2631 [PubMed]
179. Zhang B, Maiti A, Shively S, Lakhani F, McDonald-Jones G, Bruce J, Lee EB, Xie SX, Joyce S, Li C, Toleikis PM, Lee VM, Trojanowski JQ. Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model.Proc Natl Acad Sci U S A.2005;102:1227-231. [PubMed] https://doi.org/10.1073/pnas.0406361102
180. Alonso AD, GrundkeIqbal I, Iqbal K. Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules.Nat Med.1996;2:7783-787. [PubMed] https://doi.org/10.1038/nm0796-783
181. Jean DC and Baas PW. It cuts two ways: microtubule loss during Alzheimer disease.Embo J.2013;32:222900-2902. [PubMed] https://doi.org/10.1038/emboj.2013.219
182. Yamada M, Hirotsune S, Wynshaw-Boris A. The essential role of LIS1, NDEL1 and Aurora-A in polarity formation and microtubule organization during neurogensis.Cell Adh Migr.2010;4:2180-184. [PubMed] https://doi.org/10.4161/cam.4.2.10715
183. Mori D, Yamada M, Mimori-Kiyosue Y, Shirai Y, Suzuki A, Ohno S, Saya H, Wynshaw-Boris A, Hirotsune S. An essential role of the aPKC-Aurora A-NDEL1 pathway in neurite elongation by modulation of microtubule dynamics.Nat Cell Biol.2009;11:91057-1068. [PubMed] https://doi.org/10.1038/ncb1919
184. Mori D, Yano Y, Toyo-oka K, Yoshida N, Yamada M, Muramatsu M, Zhang D, Saya H, Toyoshima YY, Kinoshita K, Wynshaw-Boris A, Hirotsune S. NDEL1 phosphorylation by Aurora-A kinase is essential for centrosomal maturation, separation, and TACC3 recruitment.Mol Cell Biol.2007;27:1352-367. [PubMed] https://doi.org/10.1128/MCB.00878-06
185. Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer's disease.Journal of neurochemistry.2008;104:61433-1439. [PubMed] https://doi.org/10.1111/j.1471-4159.2007.05194.x
186. Inestrosa NC and Arenas E. Emerging roles of Wnts in the adult nervous system.Nature reviews Neuroscience.2010;11:277-86. https://doi.org/10.1038/nrn2755 [PubMed]
187. Ly PT, Wu Y, Zou H, Wang R, Zhou W, Kinoshita A, Zhang M, Yang Y, Cai F, Woodgett J, Song W. Inhibition of GSK3beta-mediated BACE1 expression reduces Alzheimer-associated phenotypes.The Journal of clinical investigation.2013;123:1224-235. [PubMed] https://doi.org/10.1172/JCI64516
188. Hanger DP, Anderton BH, Noble W. Tau phosphorylation: the therapeutic challenge for neurodegenerative disease.Trends in molecular medicine.2009;15:3112-119. [PubMed] https://doi.org/10.1016/j.molmed.2009.01.003
189. Dar AA, Belkhiri A, El-Rifai W. The aurora kinase A regulates GSK-3beta in gastric cancer cells.Oncogene.2009;28:6866-875. [PubMed] https://doi.org/10.1038/onc.2008.434
190. Wu Q, Huang JH, Sampson ER, Kim KO, Zuscik MJ, O'Keefe RJ, Chen D, Rosier RN. Smurf2 induces degradation of GSK-3beta and upregulates beta-catenin in chondrocytes: a potential mechanism for Smurf2-induced degeneration of articular cartilage.Experimental cell research.2009;315:142386-2398. [PubMed] https://doi.org/10.1016/j.yexcr.2009.05.019
191. Moore FE, Osmundson EC, Koblinski J, Pugacheva E, Golemis EA, Ray D, Kiyokawa H. The WW-HECT protein Smurf2 interacts with the Docking Protein NEDD9/ HEF1 for Aurora A activation.Cell division.2010;5:22 [PubMed] https://doi.org/10.1186/1747-1028-5-22
192. Kanda H, Mimura T, Hamasaki K, Yamamoto K, Yazaki Y, Hirai H, Nojima Y. Fyn and Lck tyrosine kinases regulate tyrosine phosphorylation of p105CasL, a member of the p130Cas docking protein family, in T-cell receptor-mediated signalling.Immunology.1999;97:156-61. [PubMed] https://doi.org/10.1046/j.1365-2567.1999.00753.x
193. Miyake-Nishijima R, Iwata S, Saijo S, Kobayashi H, Kobayashi S, Souta-Kuribara A, Hosono O, Kawasaki H, Tanaka H, Ikeda E, Okada Y, Iwakura Y, Morimoto C. Role of Crk-associated substrate lymphocyte type in the pathophysiology of rheumatoid arthritis in tax transgenic mice and in humans.Arthritis and rheumatism.2003;48:71890-1900. [PubMed] https://doi.org/10.1002/art.11047
194. Qian DP, Lev S, vanOers NSC, Dikic I, Schlessinger J, Weiss A. Tyrosine phosphorylation of Pyk2 is selectively regulated by Fyn during TCR signaling.J Exp Med.1997;185:71253-1259. [PubMed] https://doi.org/10.1084/jem.185.7.1253
195. Xing LZ, Ge C, Zeltser R, Maskevitch G, Mayer BJ, Alexropoulos K. c-Src signaling induced by the adapters Sin and Cas is mediated by Rap1 GTPas.Mol Cell Biol.2000;20:197363-7377. [PubMed] https://doi.org/10.1128/mcb.20.19.7363-7377.2000
196. Bhaskar K, Yen SH, Lee G. Disease-related modifications in tau affect the interaction between Fyn and tau.Journal of Biological Chemistry.2005;280:4235119-35125. [PubMed] https://doi.org/10.1074/jbc.M505895200
197. Lee G, Thangavel R, Sharma VM, Litersky JM, Bhaskar K, Fang SM, Do LH, Andreadis A, Van Hoesen G, Ksiezak-Reding H. Phosphorylation of tau by fyn: Implications for Alzheimer's disease.Journal of Neuroscience.2004;24:92304-2312. [PubMed] https://doi.org/10.1523/JNEUROSCI.4162-03.2004
198. Lee G, Newman ST, Gard DL, Band H, Panchamoorthy G. Tau interacts with src-family non-receptor tyrosine kinases.Journal of cell science.1998;111:3167-3177. [PubMed] https://doi.org/10.1242/jcs.111.21.3167
199. Gotz J and Ittner LM. Animal models of Alzheimer's disease and frontotemporal dementia.Nature reviews Neuroscience.2008;9:7532-544. https://doi.org/10.1038/nrn2420 [PubMed]
200. Wright S, Malinin NL, Powell KA, Yednock T, Rydel RE, Griswold-Prenner I. Alpha2beta1 and alphaVbeta1 integrin signaling pathways mediate amyloid-beta-induced neurotoxicity.Neurobiol Aging.2007;28:2226-237. [PubMed] https://doi.org/10.1016/j.neurobiolaging.2005.12.002
201. Lim D, Ronco V, Grolla AA, Verkhratsky A, Genazzani AA. Glial Calcium Signalling in Alzheimer's Disease.Reviews of physiology, biochemistry and pharmacology.2014; https://doi.org/10.1007/112_2014_19 [PubMed]
202. Demuro A, Parker I, Stutzmann GE. Calcium signaling and amyloid toxicity in Alzheimer disease.J Biol Chem.2010;285:1712463-12468. [PubMed] https://doi.org/10.1074/jbc.R109.080895
203. Grolla AA, Sim JA, Lim D, Rodriguez JJ, Genazzani AA, Verkhratsky A. Amyloid-beta and Alzheimer's disease type pathology differentially affects the calcium signalling toolkit in astrocytes from different brain regions.Cell death & disease.2013;4:e623 [PubMed] https://doi.org/10.1038/cddis.2013.145
204. Demuro A, Mina E, Kayed R, Milton SC, Parker I, Glabe CG. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers.Journal of Biological Chemistry.2005;280:1717294-17300. [PubMed] https://doi.org/10.1074/jbc.M500997200
205. Rovira C, Arbez N, Mariani J. Abeta(25-35) and Abeta(1-40) act on different calcium channels in CA1 hippocampal neurons.Biochem Biophys Res Commun.2002;296:51317-1321. [PubMed] https://doi.org/10.1016/s0006-291x(02)02072-7
206. Alier KA and Morris BJ. Divergent regulation of Pyk2/ CAKbeta phosphorylation by Ca2+ and cAMP in the hippocampus.Biochim Biophys Acta.2005;1745:3342-349. [PubMed] https://doi.org/10.1016/j.bbamcr.2005.04.003
207. Zhang Z, Neff L, Bothwell ALM, Baron R, Horne WC. Calcitonin induces dephosphorylation of Pyk2 and phosphorylation of focal adhesion kinase in osteoclasts.Bone.2002;31:3359-365. [PubMed] https://doi.org/10.1016/s8756-3282(02)00834-7
208. Zhang ZY, Baron R, Horne WC. Integrin engagement, the actin cytoskeleton, and c-Src are required for the calcitonin-induced tyrosine phosphorylation of paxillin and HEF1, but not for calcitonin-induced Erk1/2 phosphorylation.Journal of Biological Chemistry.2000;275:4737219-37223. [PubMed] https://doi.org/10.1074/jbc.M001818200
209. Zhang ZY, Hernandez-Lagunas L, Horne WC, Baron R. Cytoskeleton-dependent tyrosine phosphorylation of the p130(Cas) family member HEF1 downstream of the G protein-coupled calcitonin receptor - Calcitonin induces the association of HEF1, paxillin, and focal adhesion kinase.Journal of Biological Chemistry.1999;274:3525093-25098. [PubMed] https://doi.org/10.1074/jbc.274.35.25093
210. Plotnikova OV, Nikonova AS, Loskutov YV, Kozyulina PY, Pugacheva EN, Golemis EA. Calmodulin activation of Aurora-A kinase (AURKA) is required during ciliary disassembly and in mitosis.Mol Biol Cell.2012;23:142658-2670. [PubMed] https://doi.org/10.1091/mbc.E11-12-1056
211. Plotnikova OV, Pugacheva EN, Dunbrack RL, Golemis EA. Rapid calcium-dependent activation of Aurora-A kinase.Nature communications.2010;1:64 https://doi.org/10.1038/ncomms1061 [PubMed]
212. Plotnikova OV, Pugacheva EN, Golemis EA. Aurora A kinase activity influences calcium signaling in kidney cells.J Cell Biol.2011;193:61021-1032. [PubMed] https://doi.org/10.1083/jcb.201012061
213. Yoon H, Choi YL, Song JY, Do I, Kang SY, Ko YH, Song S, Kim BG. Targeted Inhibition of FAK, PYK2 and BCL-XL Synergistically Enhances Apoptosis in Ovarian Clear Cell Carcinoma Cell Lines.PLoS One.2014;9:2 https://doi.org/10.1371/journal.pone.0088587 [PubMed]
214. Golubovskaya VM, Figel S, Ho BT, Johnson CP, Yemma M, Huang G, Zheng M, Nyberg C, Magis A, Ostrov DA, Gelman IH, Cance WG. A small molecule focal adhesion kinase (FAK) inhibitor, targeting Y397 site: 1-(2-hydroxyethyl)-3, 7-triaza-1-azoniatricyclo [3.3.1.1(3,7)]decane; bromide effectively inhibits FAK autophosphorylation activity and decreases cancer cell viability, clonogenicity and tumor growth in vivo.Carcinogenesis.2012;33:51004-1013. [PubMed] https://doi.org/10.1093/carcin/bgs120
215. Megison ML, Gillory LA, Stewart JE, Nabers HC, Mrozcek-Musulman E, Beierle EA. FAK Inhibition Abrogates the Malignant Phenotype in Aggressive Pediatric Renal Tumors.Molecular Cancer Research.2014;12:4514-526. [PubMed] https://doi.org/10.1158/1541-7786.MCR-13-0505
216. Schultze A and Fiedler W. Therapeutic potential and limitations of new FAK inhibitors in the treatment of cancer.Expert Opin Inv Drug.2010;19:6777-788. https://doi.org/10.1517/13543784.2010.489548 [PubMed]
217. Comprehensive molecular characterization of clear cell renal cell carcinoma.Nature.2013;499:745643-49. [PubMed] https://doi.org/10.1038/nature12222
218. Cohen HT and McGovern FJ. Renal-cell carcinoma.The New England journal of medicine.2005;353:232477-2490. [PubMed] https://doi.org/10.1056/NEJMra043172
219. Cairns P. Renal Cell Carcinoma.Cancer Biomarkers.2011;9:1-6461-473. [PubMed] https://doi.org/10.3233/CBM-2011-0176
220. Logue JS and Morrison DK. Complexity in the signaling network: insights from the use of targeted inhibitors in cancer therapy.Gene Dev.2012;26:7641-650. [PubMed] https://doi.org/10.1101/gad.186965.112
221. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou SB, Diaz LA, Kinzler KW. Cancer Genome Landscapes.Science.2013;339:61271546-1558. [PubMed] https://doi.org/10.1126/science.1235122
222. Beck TN, Chikwem AJ, Solanki NR, Golemis EA. Bioinformatic Approaches to Augment Study of Epithelial-to-Mesenchymal Transition (EMT) in Lung Cancer.Physiological genomics.2014;in press https://doi.org/10.1152/physiolgenomics.00062.2014 [PubMed]
223. Bagnyukova T, Serebriiskii IG, Zhou Y, Hopper-Borge EA, Golemis EA, Astsaturov I. Chemotherapy and signaling How can targeted therapies supercharge cytotoxic agents?Cancer biology & therapy.2010;10:9843-857. https://doi.org/10.4161/cbt.10.9.13738 [PubMed]
224. Bird TD. 1993;Early-Onset Familial Alzheimer Disease.Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K. GeneReviews(R)Seattle (WA).
225. Tanzi RE and Bertram L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective.Cell.2005;120:4545-555. [PubMed] https://doi.org/10.1016/j.cell.2005.02.008
226. Goedert M, Cohen ES, Jakes R, Cohen P. p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1. Implications for Alzheimer's disease [corrected].FEBS letters.1992;312:195-99. [PubMed] https://doi.org/10.1016/0014-5793(92)81418-l
227. Rosenthal SL and Kamboh MI. Late-Onset Alzheimer's Disease Genes and the Potentially Implicated Pathways.Current genetic medicine reports.2014;2:85-101. [PubMed] https://doi.org/10.1007/s40142-014-0034-x