NSP-CAS Protein Complexes: Emerging Signaling Modules in Cancer

Abstract

The CAS (CRK-associated substrate) family of adaptor proteins comprises 4 members, which share a conserved modular domain structure that enables multiple protein-protein interactions, leading to the assembly of intracellular signaling platforms. Besides their physiological role in signal transduction downstream of a variety of cell surface receptors, CAS proteins are also critical for oncogenic transformation and cancer cell malignancy through associations with a variety of regulatory proteins and downstream effectors. Among the regulatory partners, the 3 recently identified adaptor proteins constituting the NSP (novel SH2-containing protein) family avidly bind to the conserved carboxy-terminal focal adhesion-targeting (FAT) domain of CAS proteins. NSP proteins use an anomalous nucleotide exchange factor domain that lacks catalytic activity to form NSP-CAS signaling modules. Additionally, the NSP SH2 domain can link NSP-CAS signaling assemblies to tyrosine-phosphorylated cell surface receptors. NSP proteins can potentiate CAS function by affecting key CAS attributes such as expression levels, phosphorylation state, and subcellular localization, leading to effects on cell adhesion, migration, and invasion as well as cell growth. The consequences of these activities are well exemplified by the role that members of both families play in promoting breast cancer cell invasiveness and resistance to antiestrogens. In this review, we discuss the intriguing interplay between the NSP and CAS families, with a particular focus on cancer signaling networks.

Association of the Breast Cancer Antiestrogen Resistance Protein 1 (BCAR1) and BCAR3 Scaffolding Proteins in Cell Signaling and Antiestrogen Resistance

“…DOCK180 activates the RHO family GTPase RAC1, which promotes the formation of membrane ruffles and protrusions as well as cell migration and invasiveness. Notably, among the family members only BCAR1 has been shown to confer antiestrogen resistance (11,12,17,23).…”

“…Although they lack enzymatic activity, CAS family proteins play a central role in cell physiology by serving as scaffolds for multiple protein partners to relay signals downstream of integrins and receptor-tyrosine kinases (11,12,20). CAS proteins bind non-receptor-tyrosine kinases, such as the focal adhesion kinase FAK through their SH3 domain and SRC family kinases through their SRC binding domain.…”

“…All four members of the CAS protein family regulate signaling assemblies through their multiple conserved domains. These include an N-terminal SH3 domain, a substrate domain containing multiple tyrosine and serine phosphorylation sites, and two focal adhesion targeting domains that in three of the family members are separated by an intervening SRC binding domain (11).…”

“…This distinctive structure includes an N-terminal segment subject to alternative splicing, a SH2 domain that can bind activated receptor-tyrosine kinases and the PTP␣ phosphatase (at least in the case of BCAR3), and a C-terminal CDC25-type guanine nucleotide exchange factor (GEF)-like domain (11,36,37). Recent x-ray crystallography studies have shown that this GEF-like domain has a unique conformation that is incompatible with the binding of RAS GTPases but is capable of functioning as an adaptor module that mediates extremely tight binding to the C-terminal focal adhesion targeting domain of CAS family proteins.…”

“…Intrinsic or acquired drug resistance and metastatic dissemination are the most serious obstacles to breast cancer eradication (1,2). High expression of the scaffolding protein breast cancer antiestrogen resistance 1 (BCAR1, 3 also known as p130CAS) has been implicated in the intrinsic resistance to antiestrogens and other chemotherapeutic agents as well as the acquisition of more mesenchymal/migratory characteristics and basal-like features (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). BCAR1 also contributes to the malignant characteristics of breast cancer cells overexpressing the HER2/ErbB2 oncogene (15)(16)(17).…”