The interplay between Src and integrins in normal and tumor biology

Abstract

Src family nonreceptor protein tyrosine kinases transduce signals that control normal cellular processes such as cell proliferation, adhesion and motility. Normally, cellular Src is held in an inactive state, but in several cancer types, abnormal events lead to elevated kinase activity of the protein and cause pleiotropic cellular responses inducing transformation and metastasis. A prerequisite of the ability of a cancer cell to undergo metastasis into distant tissues is to penetrate surrounding extracellular matrices. These processes are facilitated by the integrin family of cell adhesion molecules. As is the case with Src, altered integrin activity or substrate affinity can contribute to the neoplastic phenotype. Therefore, understanding the interplay between Src and integrin function has been of intense interest over the past few years. This review focuses on the role of Src and integrin signaling in normal cells and how this is deregulated in human cancer. We will identify the key players in the integrin-mediated signaling pathways involved in cell motility and apoptosis, such as FAK, paxillin and p130 CAS , and discuss how Src signaling affects the formation of focal adhesions and the extracellular matrix.

TIMP-2 upregulates RECK expression via dephosphorylation of paxillin tyrosine residues 31 and 118

“…However, orthovanadate pretreatment did not reverse the TIMP-2 mediated increase in FAK phosphorylation at Tyr397, suggesting that phosphorylation at this site is independent of protein tyrosine phosphatase activity. Studies showed that phosphorylated Tyr-397 residue of FAK serves as a binding site for Src, which in turn promotes Src kinase activation (Playford and Schaller, 2004). Our immunoprecipitation using anti-Src antibody, however, showed no significant changes in the association of FAK-Src upon TIMP-2 treatment (data not shown), suggesting that TIMP-2 may affect Src kinase activity independently of FAK.…”

“…Several signaling molecules that localize at focal adhesions include focal adhesion kinase (FAK), Src tyrosine kinase, and paxillin. It has been demonstrated that upon integrin stimulation, tyrosine phosphorylation of FAK and Src kinase is enhanced (Parsons, 2003;Playford and Schaller, 2004). As TIMP-2 signaling requires its selective interaction with integrin a3b1 (Seo et al, 2003;Oh et al, 2004;Perez-Martinez and Jaworski, 2005), we sought to determine the effects of TIMP-2 on the phosphorylation status of FAK and Src.…”

“…Src kinase activity is reportedly regulated by phosphorylation of the autophosphorylation site, Tyr416, and dephosphorylation of the negative regulatory site, Tyr527 (Harrison, 2003). Studies showed that a phosphorylated, C-terminal Tyr-527 residue of Src leads to an intramolecular interaction with its SH2 domain, promotes an intramolecular SH3 domain-mediated interaction, which inhibits catalytic activity, and loss of Tyr527 phosphorylation is a common mechanism that leads to oncogenic activation of c-Src (Playford and Schaller, 2004). Interestingly, TIMP-2 treatment did not significantly affect phosphorylation levels at Tyr416 but increased those at Tyr527 reproducibly ( Figure 1a).…”

Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro

“…Moesin is a member of the ERM (Ezrin/ Radixin/Moesin) family of proteins which have been shown to interact with src in adhesion-mediated signaling [34,35]. As stated above YAP-1 directly interacts with src and another SFK proto-oncogene yes, possibly in the tight junction and adherens pathways [21,36].…”

Reduced Glioma Infiltration in Src-deficient Mice

“…While in vitro studies have shown that Src can regulate many different molecules including intracellular signaling intermediates, integrins, matrix metalloproteases, and ECM proteins, the specific role of Src in vivo is poorly understood [67][68][69][70][71][72][73][74][75][76]. Based on knockout studies, it is known that other Src-related family kinases can compensate for the absence of Src particularly during development.…”