p130Cas: A key signalling node in health and disease

Abstract

p130Cas/breast cancer anti-oestrogen resistance 1 (BCAR1) is a member of the Cas (Crk-associated substrate) family of adaptor proteins, which have emerged as key signalling nodes capable of interactions with multiple proteins, with important regulatory roles in normal and pathological cell function. The Cas family of proteins is characterised by the presence of multiple conserved motifs for protein–protein interactions, and by extensive tyrosine and serine phosphorylations. Recent studies show that p130Cas contributes to migration, cell cycle control and apoptosis. p130Cas is essential during early embryogenesis, with a critical role in cardiovascular development. Furthermore, p130Cas has been reported to be involved in the development and progression of several human cancers. p130Cas is able to perform roles in multiple processes due to its capacity to regulate a diverse array of signalling pathways, transducing signals from growth factor receptor tyrosine kinases, non-receptor tyrosine kinases, and integrins. In this review we summarise the current understanding of the structure, function, and regulation of p130Cas, and discuss the importance of p130Cas in both physiological and pathophysiological settings, with a focus on the cardiovascular system and cancer.

Introduction

Members of the Cas (Crk-associated substrate) family of adaptor proteins have emerged as highly connected signalling nodes, with important regulatory roles in normal and pathological cell functions. The Cas family of proteins is characterised by the presence of multiple conserved motifs for protein–protein interactions, and by extensive tyrosine and serine phosphorylations. Since the discovery of p130Cas/breast cancer anti-oestrogen resistance 1 (BCAR1) in 1991, three further members of the Cas protein family have been identified: NEDD9 (neural precursor cell expressed, developmentally down-regulated 9; also called human enhancer of filamentation 1 [HEF-1] or Cas-L), EFS (embryonal Fyn-associated substrate), and CASS4 (Cas scaffolding protein family member 4) ([1], and reviewed in [2], [3]).

In this review we will present an overview of the signalling integrated by the prototypical member of the Cas-family, p130Cas, and its downstream consequences for cellular signalling. We will then examine the diverse and important roles played by p130Cas in a range of physiological and pathophysiological settings including the cardiovascular system, carcinogenesis, and the immune system.