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

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.

Keywords: APP; Alzheimer's disease; Amyloid; Brain; CAK-β; CAS; CASS4; Cancer; HEF1; HEPL; NEDD9; Neurodegenerative; PSEN1; PSEN2; PTK2B; PYK2; RAFTK; Tau.

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.

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.