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Integrin-mediated adhesion regulates cell polarity and membrane protrusion through the Rho family of GTPases
E A Cox1, S K Sastry, A Huttenlocher
1Department of Pediatrics, University of Wisconsin, Madison, Wisconsin 53706, USA.
Abstract:
Integrin-mediated adhesion is a critical regulator of cell migration. Here we demonstrate that integrin-mediated adhesion to high fibronectin concentrations induces a stop signal for cell migration by inhibiting cell polarization and protrusion. On fibronectin, the stop signal is generated through alpha 5 beta 1 integrin-mediated signaling to the Rho family of GTPases. Specifically, Cdc42 and Rac1 activation exhibits a biphasic dependence on fibronectin concentration that parallels optimum cell polarization and protrusion. In contrast, RhoA activity increases with increasing substratum concentration. We find that cross talk between Cdc42 and Rac1 is required for substratum-stimulated protrusion, whereas RhoA activity is inhibitory. We also show that Cdc42 activity is inhibited by Rac1 activation, suggesting that Rac1 activity may down-regulate Cdc42 activity and promote the formation of stabilized rather than transient protrusion. Furthermore, expression of RhoA down-regulates Cdc42 and Rac1 activity, providing a mechanism whereby RhoA may inhibit cell polarization and protrusion. These findings implicate adhesion-dependent signaling as a mechanism to stop cell migration by regulating cell polarity and protrusion via the Rho family of GTPases.
Insights
High fibronectin concentrations trigger a cell migration stop signal by inhibiting cell polarization and protrusion. This involves alpha 5 beta 1 integrin signaling to Rho family GTPases, with RhoA activity inhibiting protrusion.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Biology
Background:
- Integrin-mediated adhesion is crucial for regulating cell migration dynamics.
- Cell polarization and protrusion are key events enabling cell movement.
Purpose of the Study:
- To investigate how integrin-mediated adhesion to fibronectin influences cell migration.
- To elucidate the role of Rho family GTPases in adhesion-dependent cell migration regulation.
Main Methods:
- Utilized fibronectin concentration gradients to study cell behavior.
- Measured Rho family GTPase (Cdc42, Rac1, RhoA) activities in response to fibronectin.
- Investigated signaling crosstalk between GTPases and their impact on cell protrusion.
Main Results:
- High fibronectin concentrations induce a stop signal, inhibiting cell polarization and protrusion.
- Alpha 5 beta 1 integrin signaling to Rho GTPases mediates this stop signal.
- Cdc42 and Rac1 activation show biphasic dependence on fibronectin, correlating with protrusion, while RhoA activity increases with concentration and inhibits protrusion.
- RhoA activity down-regulates Cdc42 and Rac1, explaining inhibition of cell polarization and protrusion.
Conclusions:
- Adhesion-dependent signaling regulates cell migration by controlling cell polarity and protrusion via Rho family GTPases.
- Integrin-mediated adhesion to high fibronectin concentrations acts as a stop signal for cell migration.