Integrin-Mediated Endothelial Cell Adhesion and Activation of c-Src, EGFR and ErbB2 are Required for Endothelial-Mesenchymal Transition

Abstract

The adhesion of cells to the extracellular matrix (ECM) is a critical requisite to generate cell shape, migration, proliferation, differentiation, and gene expression (Geiger & Yamada, 2011; Papusheva & Heisenberg, 2010). Beyond this role, cell-ECM adhesion promotes various intracellular signalling pathways and effectors modulating cell survival or apoptosis and tumor growth (Geiger & Yamada, 2011). Cells use a number of different cell surface receptors that mediate cell-ECM adhesion, being one of the best studied the integrins (Jean et al., 2011; Schwartz, 2010). It is known that binding of integrins to their ligands is dependent on the presence of divalent cations including Ca2+, Mg2+, and Mn2+ (CierniewskaCieslak et al., 2002; Cluzel et al., 2005; Leitinger et al., 2000; Luo & Springer, 2006). These heterodimeric transmembrane proteins which lack intrinsic enzymatic activity, in addition to being considered as indispensable to mediate cell-ECM adhesion, promote the assembly of cell-to-cell adhesion also promote receptor tyrosine kinase (RTK) activation triggering signalling cascades that regulate cell growth, proliferation and control cell death. Of note, growth factors that activate RTK may also modulate some of the cellular events that are mediated by integrins (Streuli & Akhtar, 2009). Now, it is clear that binding of certain integrins to their ligands as well as mechanical stimuli including shear stress, compression and tensile forces, promotes integrin clustering and that clustered integrins provoke recruitment and activation of other signalling molecules, including the RTKs, and therefore controlling cell survival, proliferation and migration (Guo & Giancotti, 2004; Ivaska and Heino, 2010; Streuli & Akhtar, 2009; Yamada & Even-Ram, 2002). Interestingly, functional cooperation between integrins and RTKs is actually considered as critical during normal vascular development and in vascular and inflammatory diseases (Eliceiri, 2001; Streuli & Akhtar, 2009) as well as in tumor progression and metastasis (Desgrosellier & Cheresh, 2010; Guo & Giancotti, 2004). In this context, studies have demonstrated that during cell-ECM adhesion some members of the epidermal growth factor (EGF) receptor family such as