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Integrin α6 and EGFR Signaling Converge at Mechanosensitive Calpain 2

Alyssa D Schwartz, Christopher L Hall, Lauren E Barney, Courtney C Babbitt, View ORCID ProfileShelly R Peyton
doi: https://doi.org/10.1101/164525
Alyssa D Schwartz
University of Massachusetts Amherst;
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Christopher L Hall
University of Massachusetts Amherst;
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Lauren E Barney
University of Massachustts Amherst
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Courtney C Babbitt
University of Massachusetts Amherst;
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Shelly R Peyton
University of Massachusetts Amherst;
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  • ORCID record for Shelly R Peyton
  • For correspondence: speyton@umass.edu
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Abstract

Cells sense and respond to mechanical cues from the extracellular matrix (ECM) via integrins. ECM stiffening is known to increase integrin clustering and sensitivity to epidermal growth factor (EGF), but we lack information on when or if these mechanosensitive growth factor receptors and integrins converge intracellularly. Towards closing this knowledge gap, we combined a biomaterial platform with transcriptomics, molecular biology, and functional assays to link integrin-mediated mechanosensing and epidermal growth factor receptor (EGFR) signaling. We found that high integrin α6 expression controlled breast cancer cell adhesion and motility on soft, laminin-coated substrates, and this mimicked the response of cells to EGF stimulation. The mechanisms that drove both mechanosensitive cell adhesion and motility converged on calpain 2, an intracellular protease important for talin cleavage and focal adhesion turnover. EGF stimulation enhanced adhesion and motility on soft substrates, but required integrin α6 and calpain 2 signaling. In sum, we identified a new role for integrin α6 mechanosensing in breast cancer, wherein cell adhesion to laminin on soft substrates mimicked EGF stimulation. We identified calpain 2, downstream of both integrin α6 engagement and EGFR phosphorylation, as a common intracellular signaling node, and implicate integrin α6 and calpain 2 as potential targets to inhibit the migration of cancer cells in stiff tumor environments.

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The copyright holder for this preprint is the author/funder. It is made available under a CC-BY 4.0 International license.
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  • Posted April 15, 2018.

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Integrin α6 and EGFR Signaling Converge at Mechanosensitive Calpain 2
Alyssa D Schwartz, Christopher L Hall, Lauren E Barney, Courtney C Babbitt, Shelly R Peyton
bioRxiv 164525; doi: https://doi.org/10.1101/164525
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Integrin α6 and EGFR Signaling Converge at Mechanosensitive Calpain 2
Alyssa D Schwartz, Christopher L Hall, Lauren E Barney, Courtney C Babbitt, Shelly R Peyton
bioRxiv 164525; doi: https://doi.org/10.1101/164525

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