Discrete spatial organization of TGFβ receptors couples receptor multimerization and signaling to cellular tension

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Abstract

Cell surface receptors are central to the cell's ability to generate coordinated responses to the multitude of biochemical and physical cues in the microenvironment. However, the mechanisms by which receptors enable this concerted cellular response remain unclear. To investigate the effect of cellular tension on cell surface receptors, we combined novel high-resolution imaging and single particle tracking with established biochemical assays to examine TGFβ signaling. We find that TGFβ receptors are discretely organized to segregated spatial domains at the cell surface. Integrin-rich focal adhesions organize TβRII around TβRI, limiting the integration of TβRII while sequestering TβRI at these sites. Disruption of cellular tension leads to a collapse of this spatial organization and drives formation of heteromeric TβRI/TβRII complexes and Smad activation. This work details a novel mechanism by which cellular tension regulates TGFβ receptor organization, multimerization, and function, providing new insight into the mechanisms that integrate biochemical and physical cues.

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Joanna P Rys

University of California, Berkeley-University of California, San Francisco Graduate Program in Bioengineering, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Christopher C DuFort

Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
David A Monteiro

University of California, Berkeley-University of California, San Francisco Graduate Program in Bioengineering, University of California, Berkeley, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Michelle A Baird

National High Magnetic Field Laboratory, Department of Biological Science, Florida State University, Tallahassee, United States

Competing interests
The authors declare that no competing interests exist.
Juan A Oses-Prieto

Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States

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The authors declare that no competing interests exist.
Shreya Chand

Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States

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The authors declare that no competing interests exist.
Alma L Burlingame

Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States

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The authors declare that no competing interests exist.
Michael W Davidson

National High Magnetic Field Laboratory, Department of Biological Science, Florida State University, Tallahassee, United States

Competing interests
The authors declare that no competing interests exist.
Tamara N Alliston

University of California, Berkeley-University of California, San Francisco Graduate Program in Bioengineering, University of California, Berkeley, Berkeley, United States

For correspondence
tamara.alliston@ucsf.edu

Competing interests
The authors declare that no competing interests exist.

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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.