A Cas-BCAR3 co-regulatory circuit controls lamellipodia dynamics
- Fred Hutchinson Cancer Research Center, United States
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files, with the exception of the raw mass spectrometry data, which have been deposited in the Dryad Digital Repository.
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Data from: Phosphotyrosine peptide abundance in control and Cul5-deficient MCF10A cellsDryad Digital Repository, doi:10.5061/ dryad.tmpg4f4zn.
Article and author information
Author details
Elizabeth M Steenkiste
Christopher Simpkins
Funding
National Institutes of Health (T32 GM007270)
- Elizabeth M Steenkiste
National Institutes of Health (R01 GM109463)
- Elizabeth M Steenkiste
- Jason D Berndt
- Carissa Pilling
- Christopher Simpkins
- Jonathan A Cooper
National Institutes of Health (P30 CA015704)
- Elizabeth M Steenkiste
- Jason D Berndt
- Carissa Pilling
- Christopher Simpkins
- Jonathan A Cooper
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Steenkiste et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A Cas-BCAR3 co-regulatory circuit controls lamellipodia dynamics
eLife 10:e67078.
https://doi.org/10.7554/eLife.67078
