PT  - JOURNAL ARTICLE
AU  - AD Schwartz
AU  - CL Hall
AU  - LE Barney
AU  - CC Babbitt
AU  - SR Peyton
TI  - Mechanosensing of Integrin α<sub>6</sub> and EGFR Converges at Calpain 2
AID  - 10.1101/164525
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 164525
4099  - http://biorxiv.org/content/early/2017/07/17/164525.short
4100  - http://biorxiv.org/content/early/2017/07/17/164525.full
AB  - Cells sense and respond to mechanical cues from the extracellular matrix (ECM) via integrins. ECM stiffness is known to enhance integrin clustering and response to epidermal growth factor (EGF), but we lack information on when or if these mechanosensitive receptors 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 cell adhesion and motility on soft, laminin-coated substrates, and this mimicked the response of cells to EGF stimulation. Signaling pathways downstream of mechanosensitive cell adhesion and motility converged on calpain 2, an intracellular protease important for talin cleavage and focal adhesion turnover. Inhibiting calpain 2 shifted the biphasic dependence of cell migration on substrate stiffness. EGF stimulation enhanced both adhesion and motility on soft substrates, but required the presence of both integrin α6 and calpain 2. In sum, we identified a new role for integrin α6 mechanosensing, where high integrin α6 binding to laminin mimicked the effect of EGF stimulation. Downstream of both integrin α6 and EGFR, calpain 2 is known to control focal adhesion dynamics and motility, implicating integrin α6 and calpain 2 as potential targets to inhibit the migration of cancer cells in stiff tumor environments.