Lfc subcellular localization and activity is controlled by & alpha;v-class integrin

Fibronectin (FN)-binding integrins control a variety of cellular and & alpha;5 & beta;1, are known to induce different effects on cell morphology and motility. Here, we report that FN-bound & alpha;v & beta;3 integrin, but not FNbound & alpha;5 & beta;1 integrin, triggers the dissociation of the RhoA GEF Lfc (also known as GEF-H1 and ARHGEF2 in humans) from microtubules (MTs), leading to the activation of RhoA, formation of stress fibres and maturation of focal adhesions (FAs). Conversely, loss of Lfc expression decreases RhoA activity, stress fibre formation and FA size, suggesting that Lfc is the major GEF downstream of FNbound & alpha;v & beta;3 that controls RhoA activity. Mechanistically, FN-engaged & alpha;v & beta;3 integrin activates a kinase cascade involving MARK2 and MARK3, which in turn leads to phosphorylation of several phosphosites on Lfc. In particular, S151 was identified as the main site involved in the regulation of Lfc localization and activity. Our findings indicate that activation of Lfc and RhoA is orchestrated in FNadherent cells in an integrin-specific manner.