1. Cell Biology
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A Cas-BCAR3 co-regulatory circuit controls lamellipodia dynamics

  1. Elizabeth M Steenkiste
  2. Jason D Berndt
  3. Carissa Pilling
  4. Christopher Simpkins
  5. Jonathan A Cooper  Is a corresponding author
  1. Fred Hutchinson Cancer Research Center, United States
Research Article
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Cite this article as: eLife 2021;10:e67078 doi: 10.7554/eLife.67078

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.

The following data sets were generated

Article and author information

Author details

  1. Elizabeth M Steenkiste

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6452-2340
  2. Jason D Berndt

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  3. Carissa Pilling

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  4. Christopher Simpkins

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3174-6609
  5. Jonathan A Cooper

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States
    For correspondence
    jcooper@fhcrc.org
    Competing interests
    Jonathan A Cooper, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8626-7827

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.

Reviewing Editor

  1. Margaret C Frame, University of Edinburgh, United Kingdom

Publication history

  1. Received: January 30, 2021
  2. Accepted: June 21, 2021
  3. Accepted Manuscript published: June 25, 2021 (version 1)
  4. Version of Record published: July 8, 2021 (version 2)

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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