Abstract
Integrin adhesion complexes regulate cytoskeletal dynamics during cell migration. Adhesion activates phosphorylation of integrin-associated signaling proteins, including Cas (p130Cas, BCAR1), by Src-family kinases. Cas regulates leading-edge protrusion and migration in cooperation with its binding partner, BCAR3. However, it has been unclear how Cas and BCAR3 cooperate. Here, using normal epithelial cells, we find that BCAR3 localization to integrin adhesions requires Cas. In return, Cas phosphorylation, as well as lamellipodia dynamics and cell migration, requires BCAR3. These functions require the BCAR3 SH2 domain and a specific phosphorylation site, Tyr 117, that is also required for BCAR3 downregulation by the ubiquitin-proteasome system. These findings place BCAR3 in a co-regulatory positive-feedback circuit with Cas, with BCAR3 requiring Cas for localization and Cas requiring BCAR3 for activation and downstream signaling. The use of a single phosphorylation site in BCAR3 for activation and degradation ensures reliable negative feedback by the ubiquitin-proteasome system.
Highlights
Animal cells migrate by adhesive crawling or amoeboid blebbing (Trepat et al, 2012)
While many aspects of cell migration can be explained by biomechanics, integrin adhesions activate biochemical signaling molecules, including focal adhesion kinase (FAK), Src-family kinases (SFKs), and small GTPases (Burridge et al, 1992; Huang et al, 1993; Miyamoto et al, 1995; Schaller et al, 1992)
We previously reported that CRL5 inhibits Src activity and Src-dependent transformation of MCF10A epithelial cells, in part by targeting pY proteins such as pY-Cas for degradation by the ubiquitin-proteasome system (Teckchandani et al, 2014)
Summary
Animal cells migrate by adhesive crawling or amoeboid blebbing (Trepat et al, 2012). During crawling, transmembrane receptors called integrins provide attachment to the extracellular matrix and organize the actin cytoskeleton (Bachir et al, 2017; Legate et al, 2009). Rearward flowing actin engages with integrin-associated proteins such as talin and vinculin, forming catch bonds, clustering the integrins, and recruiting additional regulatory and scaffold proteins to form transient structures called nascent adhesions (Case and Waterman, 2015; del Rio et al, 2009; Galbraith et al, 2002; Partridge and Marcantonio, 2006; Puklin-Faucher and Sheetz, 2009; Tadokoro et al, 2003). While many aspects of cell migration can be explained by biomechanics, integrin adhesions activate biochemical signaling molecules, including focal adhesion kinase (FAK), Src-family kinases (SFKs), and small GTPases (Burridge et al, 1992; Huang et al, 1993; Miyamoto et al, 1995; Schaller et al, 1992). Some FAK and SFK-dependent phosphorylations regulate adhesion assembly (Pasapera et al, 2010; Stutchbury et al, 2017; Zaidel-Bar et al, 2007), while others coordinate adhesion with lamellipodium dynamics and other aspects of cell biology, such as cell survival (Mitra and Schlaepfer, 2006)
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