Integrins control motile strategy through a Rho–cofilin pathway

Abstract

During wound healing, angiogenesis, and tumor invasion, cells often change their expression profiles of fibronectin-binding integrins. Here, we show that β1 integrins promote random migration, whereas β3 integrins promote persistent migration in the same epithelial cell background. Adhesion to fibronectin by αvβ3 supports extensive actin cytoskeletal reorganization through the actin-severing protein cofilin, resulting in a single broad lamellipod with static cell–matrix adhesions at the leading edge. Adhesion by α5β1 instead leads to the phosphorylation/inactivation of cofilin, and these cells fail to polarize their cytoskeleton but extend thin protrusions containing highly dynamic cell–matrix adhesions in multiple directions. The activity of the small GTPase RhoA is particularly high in cells adhering by α5β1, and inhibition of Rho signaling causes a switch from a β1- to a β3-associated mode of migration, whereas increased Rho activity has the opposite effect. Thus, alterations in integrin expression profiles allow cells to modulate several critical aspects of the motile machinery through Rho GTPases.

Control of gastrula cell motility by the Goosecoid/Mix.1/ Siamois network: Basic patterns and paradoxical effects

“…RhoA-dependent polarization of protrusive activity has been described for Xenopus gastrula trunk mesoderm cells (Tahinci and Symes, 2003), HL-60 cells (Xu et al, 2003), mesenchymal stromal cells (Jaganathan et al, 2007) and leucocytes (Worthylake and Burridge, 2003), although RhoA has the opposite effect in epithelial cells (Danen et al, 2005). Interestingly, in primary fibroblasts and in macrophages, respectively, it is the modulation of Rac activity that switches similarly between polarization states (Pankov et al, 2005;Wheeler et al, 2006).…”

“…Cell morphology is similarly affected: knockdown of Rac reduces lamellipodia number in fibroblasts (Pankov et al, 2005), but increases it in macrophages (Wheeler et al, 2006). Likewise, RhoA activation reduces lamellipodia number in stromal cells (Jaganathan et al, 2007) and leucocytes (Worthylake and Burridge, 2003), but increases it in epithelial cells (Danen et al, 2005). p21-activated kinase-1 (Pak1) prompts migration in several cell lines (Alahari et al, 2004;Kiosses et al 1999), but blocks it in embryo fibroblasts (Leisner et al 2005).…”

On the move: endocytic trafficking in cell migration

“…This is due to the fact that different integrins affect focal adhesion dynamics in distinct ways thus having diverging effects on directionality. While a5b1 integrins promote focal adhesion turnover and thereby random cell motility, the heterodimer avb3 rather suppresses focal adhesion dynamics thereby promoting directionally persistent migration [75]. Thus, the balance between the different integrin heterodimers has to be tightly controlled to achieve the degree of directionality adapted to the acute cellular need.…”

NGAL decreases E-cadherin-mediated cell–cell adhesion and increases cell motility and invasion through Rac1 in colon carcinoma cells

“…As dynamic regulation of the F-actin network is critical to cell motility, 17 we hypothesized that the F-actin reorganization induced by NGAL overexpression might increase the motility of the tumor cells. We performed time-lapse live-cell imaging analysis to observe cell movement.…”