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.
Highlights
Roles in cancer and tumor metastasis are well established for the two paralogous scaffolding proteins NEDD9 and CASS4 (Cas scaffolding protein family member 4; known as HEPL), and for their interacting partner, the kinase Protein tyrosine kinase 2 beta (PTK2B) [1,2,3,4]
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
This study found a positive association between rs760678 and late-onset AD (LOAD) (CC genotype: P = 0.016; C allele: P = 0.007)
Summary
Roles in cancer and tumor metastasis are well established for the two paralogous scaffolding proteins NEDD9 (neural precursor cell expressed, developmentally down-regulated 9; known as HEF1 or Cas-L) and CASS4 (Cas scaffolding protein family member 4; known as HEPL), and for their interacting partner, the kinase PTK2B (protein tyrosine kinase type 2 beta; known as PYK2, Cak2β, or RAFTK) [1,2,3,4]. Genetic evidence linking NEDD9, CASS4, PTK2B and associated SNPs to neurodegenerative disease 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 their functional roles.
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