The integrin expression profile modulates orientation and dynamics of force transmission at cell–matrix adhesions

Abstract

Integrin adhesion receptors connect the extracellular matrix (ECM) to the cytoskeleton and serve as bidirectional mechanotransducers. During development, angiogenesis, wound healing and cancer progression, the relative abundance of fibronectin receptors, including integrins a5b1 and avb3, changes, thus altering the integrin composition of cell-matrix adhesions. Here, we show that enhanced avb3 expression can fully compensate for loss of a5b1 and other b1 integrins to support outside-in and inside-out force transmission. a5b1 and avb3 each mediate actin cytoskeletal remodeling in response to stiffening or cyclic stretching of the ECM. Likewise, a5b1 and avb3 support cellular traction forces of comparable magnitudes and similarly increase these forces in response to ECM stiffening. However, cells using avb3 respond to lower stiffness ranges, reorganize their actin cytoskeleton more substantially in response to stretch, and show more randomly oriented traction forces. Centripetal traction force orientation requires long stress fibers that are formed through the action of Rho kinase (ROCK) and myosin II, and that are supported by a5b1. Thus, altering the relative abundance of fibronectin-binding integrins in cell-matrix adhesions affects the spatiotemporal organization of force transmission.

Fibronectin-guided migration of carcinoma collectives

“…α5β1 is generally considered to be the β1-based integrin that drives invasive carcinoma migration in FN-rich matrices4647. Indeed, the ability of this integrin to sense substrate rigidity and generate traction forces for migration in FN environments has been extensively studied (typically on plasma FN) in fibroblasts and in various tumour cells4748495051. Viewed in this context, our findings that blocking α9β1, rather than α5β1, efficiently phenocopy the effect of pan-β1-blocking antibodies on cohort migration are unexpected and hence thought provoking.…”

Selective binding and lateral clustering ofα5β1 andαvβ3 integrins: Unraveling the spatial requirements for cell spreading and focal adhesion assembly

“…Recently, Balcioglu HE et al 14 . reported that αvβ3 integrin-mediated adhesion enables FA assembly even at low matrix stiffness, while traction force magnitude remains unvaried.…”

Integrin diversity brings specificity in mechanotransduction

“…The traction forces are dependent on the integrin subtype. In particular, α 5 β 1 and α V β 3 mediate cellular tractions differently [Roca‐Cusachs et al., ; Rossier et al., ; Balcioglu et al., ]. The activation of β 1 integrin by increased FN density or Mn 2+ increases traction forces in fibroblasts.…”