Synergistic phase separation of two pathways promotes integrin clustering and nascent adhesion formation

  1. Lindsay B Case  Is a corresponding author
  2. Milagros De Pasquale
  3. Lisa Henry
  4. Michael K Rosen  Is a corresponding author
  1. Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, United States
  2. Massachusetts Institute of Technology, United States

Abstract

Integrin adhesion complexes (IACs) are integrin-based plasma membrane-associated compartments where cells sense environmental cues. The physical mechanisms and molecular interactions that mediate initial IAC formation are unclear. We found that both p130Cas ('Cas') and Focal adhesion kinase ('FAK') undergo liquid-liquid phase separation in vitro under physiologic conditions. Cas- and FAK- driven phase separation is sufficient to reconstitute kindlin-dependent integrin clustering in vitro with recombinant mammalian proteins. In vitro condensates and IACs in mouse embryonic fibroblasts (MEFs) exhibit similar sensitivities to environmental perturbations including changes in temperature and pH. Furthermore, mutations that inhibit or enhance phase separation in vitro reduce or increase the number of IACs in MEFs, respectively. Finally, we find that the Cas and FAK pathways act synergistically to promote phase separation, integrin clustering, IAC formation and partitioning of key components in vitro and in cells. We propose that Cas- and FAK- driven phase separation provides an intracellular trigger for integrin clustering and nascent IAC formation.

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Article and author information

Author details

  1. Lindsay B Case

    Department of Biophysics, Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    lcase@mit.edu
    Competing interests
    No competing interests declared.
  2. Milagros De Pasquale

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  3. Lisa Henry

    Department of Biophysics, Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  4. Michael K Rosen

    Department of Biophysics, Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    michael.rosen@utsouthwestern.edu
    Competing interests
    Michael K Rosen, is a co-founder of Faze Medicines.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0775-7917

Funding

Damon Runyon Cancer Research Foundation (postdoctoral fellowship,DRG-2249-16)

  • Lindsay B Case
  • Michael K Rosen

Damon Runyon Cancer Research Foundation (Dale Frey Scientist Award,DFS-38-20)

  • Lindsay B Case

Howard Hughes Medical Institute (Investigator)

  • Michael K Rosen

Welch Foundation (I-1544)

  • Michael K Rosen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2022, Case 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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  1. Lindsay B Case
  2. Milagros De Pasquale
  3. Lisa Henry
  4. Michael K Rosen
(2022)
Synergistic phase separation of two pathways promotes integrin clustering and nascent adhesion formation
eLife 11:e72588.
https://doi.org/10.7554/eLife.72588

Share this article

https://doi.org/10.7554/eLife.72588

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