Integrin-mediated muscle cell spreading - The role of protein kinase C in outside-in and inside-out signaling and evidence of integrin cross-talk

Muscle cell survival depends upon the presence of various integrins with af finities for different extracellular matrix proteins. The absence of either alpha(5) or alpha(7) integrins leads to degenerative disorders of skeletal muscle, muscular dystrophies. To understand the cell survival signals that are mediated by integrin engagement with matrix proteins, we studied the e arly signaling events initiated by the attachment of muscle cells to fibron ectin, an interaction that is mediated primarily by alpha(5) integrins, Cel ls that express alpha(5) integrin rapidly spread on fibronectin, and this p rocess is associated with the phosphorylation of focal adhesion kinase (FAK ). Cells deficient in alpha(5) integrin failed to spread or promote FAK pho sphorylation when plated on fibronectin, For alpha(5)-expressing cells, bot h spreading and FAK phosphorylation could be blocked by inhibitors of prote in kinase C (PKC), indicating that PKC is necessary for this "outside-in si gnaling" mediated by alpha(5) integrin. Surprisingly, activators of PKC cou ld promote spreading and FAK phosphorylation in alpha(5)-deficient muscle c ells plated on fibronectin, This PKC-induced cell spreading appeared to be due to activation of alpha(4) integrins ("inside-out signaling") since it c ould be blocked by peptides that specifically inhibit alpha(4) integrin bin ding to fibronectin, A model of integrin signaling in muscle cells is prese nted in which there is a positive feedback loop involving PHC in both outsi de-in and inside-out signaling, and the activation of this cycle is essenti al for cell spreading and downstream signaling to promote cell survival. In addition, the data indicate a cross-talk that occurs between integrins in which the outside-in signaling via one integrin can promote the activation of another integrin via inside-out signaling.