P130Cas/BCAR1 and p140Cap/SRCIN1 Adaptors: The Yin Yang in Breast Cancer?

Giorgia Centonze,Dora Natalini,Andrea Costamagna,Vincenzo Salemme,Paola Defilippi,Sara Cabodi

doi:10.3389/fcell.2021.729093

Giorgia Centonze, Dora Natalini + Show 4 more

Open Access

https://doi.org/10.3389/fcell.2021.729093

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Abstract

p130Cas/BCAR1 is an adaptor protein devoid of any enzymatic or transcriptional activity, whose modular structure with various binding motifs, allows the formation of multi-protein signaling complexes. This results in the induction and/or maintenance of signaling pathways with pleiotropic effects on cell motility, cell adhesion, cytoskeleton remodeling, invasion, survival, and proliferation. Deregulation of p130Cas/BCAR1 adaptor protein has been extensively demonstrated in a variety of human cancers in which overexpression of p130Cas/BCAR1 correlates with increased malignancy. p140Cap (p130Cas associated protein), encoded by the SRCIN1 gene, has been discovered by affinity chromatography and mass spectrometry analysis of putative interactors of p130Cas. It came out that p140Cap associates with p130Cas not directly but through its interaction with the Src Kinase. p140Cap is highly expressed in neurons and to a lesser extent in epithelial tissues such as the mammary gland. Strikingly, in vivo and in vitro analysis identified its tumor suppressive role in breast cancer and in neuroblastoma, showing an inverse correlation between p140Cap expression in tumors and tumor progression. In this review, a synopsis of 15 years of research on the role of p130Cas/BCAR1 and p140Cap/SRCIN1 in breast cancer will be presented.

Highlights

Deregulation of p130Cas/BCAR1 adaptor protein has been extensively demonstrated in a variety of human cancers in which overexpression of p130Cas/BCAR1 correlates with increased malignancy. p140Cap (p130Cas associated protein), encoded by the SRCIN1 gene, has been discovered by affinity chromatography and mass spectrometry analysis of putative interactors of p130Cas
BCAR1 is localized on chromosome 16 on region q, on the negative strand and has seven exons, with multiple alternative first exons. p130Cas/BCAR1 protein (p130 Crk-associated substrate) is a member of the Cas (Crk-associated substrate) family that consists of five distinct adaptor proteins: p130Cas/BCAR1, Nedd9 (Neural precursor cell expressed, developmentally downregulated 9), Human enhancer of filamentation-1 (HEF-1 or CAs-L), EFS (Embryonal Fyn-associated substrate), and CASS4 (Cas scaffolding protein family member 4)
The structural features of the p130Cas/BCAR1 protein includes an amino (N)-terminal Src-homology 3 (SH3) domain, an adjacent large substrate-binding domain containing 15 repetitions of the YxxP motif, a main site of tyrosine phosphorylation on p130Cas and p140Cap in Breast Cancer the p130Cas/BCAR1 molecule that provides SH2-binding sites, a proline and serine rich region, a C-terminal part composed by binding sites for the SH2 and SH3 domains of Src (YDYVHL and RPLPSPP, respectively) and a highly conserved four-helix bundle [Focal Adhesion Targeting (FAT) domain] (Defilippi et al, 2006; Cabodi et al, 2010; Tikhmyanova et al, 2010)

Summary

Introduction

As a matter of fact, in the highly invasive A17 mouse mammary tumor cells, p130Cas/BCAR1 silencing induces loss of mesenchymal features and acquirement of epithelial-like traits, including the re-expression of the cell-cell adhesion molecule E-cadherin, affecting the EMT process involved in cancer progression. Experiments performed in mouse mammary epithelial cells (MMECs) overexpressing p130Cas demonstrate that p130Cas expression leads to hyperactivation of the tyrosine kinase receptor c-Kit, indicating that high levels of p130Cas, via abnormal c-Kit activation, promote mammary luminal cell plasticity, providing the conditions for the development of basal-like breast cancer (Figure 2C; Tornillo et al, 2013).

Results

Conclusion