p130Cas: a versatile scaffold in signaling networks

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The Cas family of multiadaptor and scaffold molecules has an essential role in intracellular signaling events. Although these proteins do not have enzymatic or transcriptional activity, they spatially and temporally control signaling events through their ability to undergo changes in phosphorylation and to associate with effectors proteins in multimolecular complexes. The involvement of p130Cas in cell motility as a component of the integrin signaling machinery is well established. Here, we discuss recent developments that highlight a fundamental role in cell transformation and microbial pathogenesis and the implications of these developments on p130Cas function under normal and pathological conditions.

Introduction

p130Cas (Crk-associated substrate) was originally identified by its ability to associate with Crk and as a protein that, upon transformation by v-Src and v-Crk oncogenes, is highly phosphorylated on tyrosine residues 1, 2. The presence of many conserved sequence motifs and extensive post-translational modification, mostly tyrosine and serine phosphorylation, led researchers to predict that p130Cas is an adaptor that promotes protein–protein interactions, leading to the formation of multiprotein complexes (Figure 1). A second member of the Cas family is HEF1 (human enhancer of filamentation), also known as Cas-L (Crk-associated substrate in lymphocyte), which was isolated in a screen for human proteins that regulate filamentous budding in yeast and as a 105-kDa tyrosine phosphorylated protein in lymphocytes (reviewed in 3, 4). Another family member Efs/Sin (embryonal fyn substrate/Src interacting), was characterized initially by its binding to the SH3 domain of Fyn (reviewed in [5]). These three Cas family proteins have high structural homology and conserved binding modules and effector proteins. However, their temporal expression, tissue distribution and functional roles are distinct. HEF1 is studied in epithelial and nervous tissues, where it regulates mitosis and neurite outgrowth 6, 7), whereas Efs/Sin functions in T lymphocytes. The genetic ablation of Efs/Sin leads to T-lymphocyte activation and mucosal inflammation, similar to the human intestinal inflammatory disorder Crohn's disease [8].

Here, we focus on p130Cas, which is ubiquitously expressed and its deletion in mice is embryonic lethal [9], suggesting that its function in development does not overlap with that of HEF1 and Efs/Sin. The interaction of p130Cas with other proteins in normal cells modulates cell motility, survival and proliferation. Recently, results from RNA interference (RNAi) suggest that p130Cas has a role in cell transformation and cancer progression. The involvement of p130Cas in bacterial pathogenesis is discussed in Box 1.

Section snippets

p130Cas phosphorylation

The major post-translational modification of p130Cas is phosphorylation on both tyrosine and serine/threonine residues. Most p130Cas tyrosine phosphorylation occurs in the substrate-binding domain, which contains 15 repeats of a YxxP sequence (Figure 1). Phosphorylation of tyrosine residues creates binding sites for the SH2 and PTB domains of effector signaling proteins, summarized in Figure 1. Many growth factors and hormones regulate p130Cas tyrosine phosphorylation 4, 10. FGF-2 [11], VEGF

p130Cas in cell migration

During migration, lamellipodia and filopodia extend from the cell leading edge and create new dynamic adhesions, which form and rapidly disassemble at the base of protrusions (reviewed in 21, 22). The involvement of p130Cas in cell migration depends mainly on its tyrosine phosphorylation by Src and on the assembly of a p130Cas–Crk–DOCK180 scaffold at adhesion sites 23, 24. Scaffold formation drives localized Rac activation, leading to actin polymerization and the recruitment of high affinity

p130Cas in cell survival and apoptosis

p130Cas is an important transducer of survival signals (Figure 2). Pro-survival signals emanating from the ECM and soluble growth factors and hormones proceed through their respective receptors, then through FAK and Src, to p130Cas, activating the small GTPases Ras and Rac, as well as JNK and Erk1/2–MAPK 10, 44. p130Cas is also required for integrin-dependent EGF-receptor activation, which in turn leads to cell survival 10, 45. This implies a dual role for p130Cas in cell survival because it

p130Cas in cell transformation, invasion and cancer

p130Cas is hyperphosphorylated in Src- and Crk-transformed cells 1, 2 and antisense p130Cas constructs partially reverse cellular transformation induced by ornithine decarboxylase, Ha-Ras and v-Src [51]. In addition, p130Cas-null MEFs cannot be transformed by Src [9].

The C-terminal region of p130Cas contains the Src-binding domain and is required for anchorage-independent growth mediated by constitutively active Src, showing that the association between Cas and activated Src kinase is essential

Conclusion and perspectives

p130Cas is involved in interdependent cellular functions, such as survival, proliferation and migration, and is therefore important in pathological processes, such as tumorigenesis and invasion. Systematic mapping of the phosphorylated residues in p130Cas would identify the specific sites involved in apoptosis, migration and the specific recruitment of adaptor proteins and signaling molecules. The dissection of the molecular interactions in response to different stimuli will provide a more

Acknowledgements

We thank Guido Tarone for reading the article. This work was supported by grants of the Italian Association for Cancer Research (AIRC), MIUR (Ministero deIl'Università e Ricerca Scientifica, fondi ex-60%, PRIN and FIRB), Special project ‘Oncology’, Compagnia San Paolo, Torino, Italy and Progetti Regione Piemonte.

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