A Cas-BCAR3 co-regulatory circuit controls lamellipodia dynamics

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 p...

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Published ineLife Vol. 10
Main Authors Steenkiste, Elizabeth M, Berndt, Jason D, Pilling, Carissa, Simpkins, Christopher, Cooper, Jonathan A
Format Journal Article
LanguageEnglish
Published Cambridge eLife Science Publications, Ltd 25.06.2021
eLife Sciences Publications Ltd
eLife Sciences Publications, Ltd
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Summary: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.
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Seagen, Bothell, United States.
These authors contributed equally to this work.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.67078