CAS proteins in normal and pathological cell growth control

Abstract

Proteins of the CAS (Crk-associated substrate) family (BCAR1/p130Cas, NEDD9/HEF1/Cas-L, EFS/SIN and CASS4/HEPL) are integral players in normal and pathological cell biology. CAS proteins act as scaffolds to regulate protein complexes controlling migration and chemotaxis, apoptosis, cell cycle, and differentiation, and have more recently been linked to a role in progenitor cell function. Reflecting these complex functions, over-expression of CAS proteins has now been strongly linked to poor prognosis and increased metastasis in cancer, as well as resistance to first-line chemotherapeutics in multiple tumor types including breast and lung cancers, glioblastoma, and melanoma. Further, CAS proteins have also been linked to additional pathological conditions including inflammatory disorders, Alzheimer's and Parkinson's disease, as well as developmental defects. This review will explore the roles of the CAS proteins in normal and pathological states in the context of the many mechanistic insights into CAS protein function that have emerged in the past decade.

Fig. 1

CAS protein structure and interactions. a CAS proteins conserve a common structure marked by four discrete domains: SH3 domain, an unstructured substrate domain, a 4-helix bundle, and an evolutionarily conserved C-terminal domain. Crystal structures have been obtained for the SH3 domain (1wyx) of human BCAR1 and 4-helix bundle (1z23) of rat BCAR1 are shown. Secondary structure predictions for the C-terminal domain are also shown; pattern of α-helices has some features of a focal adhesion-targeting (FAT) domain, but is not exactly the same. Amino acid sequences correspond to those for human BCAR1, and vary slightly for other family members. b For a number of important CAS interacting proteins, exact domains of interaction have been mapped, and are shown. Proteins known to interact with the substrate domain specifically through SH2/phospho-tyrosine interactions are thus indicated. A poly-proline domain common to BCAR1 and EFS is shown (Pro). See text for details

Fig. 2

Upstream regulators of CAS mRNA and protein expression, and protein activation. Signaling proteins inducing transcription of CAS proteins, or influencing their phosphorylation or dephosphorylation, are indicated. In addition, some stimuli such as hypoxia induce dynamic changes in CAS expression or modification, but specific proteins mediating the responses are unknown. See text for details

Fig. 3

CAS proteins in cell migration. Activation or overexpression of CAS proteins activates multiple downstream effectors to promote formation of filopodia, lamellipodia, pseudopodia, invadopodia, and induce additional changes in the cytoskeleton that support migration. See text for details

Fig. 4

CAS proteins in apoptosis. Pro-apoptotic stimuli trigger dephosphorylation and cleavage of CAS proteins, leading to direct dominant-negative mediated focal adhesion disassembly, altering the transcriptional balance between CAS-dependent pro- and anti-survival factors. Overexpression of NEDD9 can induce cell cycle checkpoints that trigger apoptosis through additional routes. See text for details