Integrin regulation of the ERK/MAPK pathway: Complex, interdendent modulation of RAF by RAS, PI 3'-K and PKC

Attachment of integrins to their extracellular matrix ligands causes activation of multiple Jntracellular signaling pathways and cytoskeletal rearrangements that are important in regulating cell proliferation, differentiation, survival, migration and spreading. We have been investigating how integrins induce these changes in cell behavior by examining multiple signaling enzymes that are activated by attachment to fibronectin or fibrinogen. These studies have revealed a complex regulator, pathway controling activation of Erk MAPKs. Pl-3'-K and AKT activit; \\ete found to be stimulated following spreading on fibronectin and PI 3'-K aetivitj was required for integrin-induced activation of Hrk2/MAP kinase, Mek and Kaf, but not for GTP-loading of Ras. Inhibition of classic and novel PKCs b> kmg-îerm TPA treatment. Calphostin C or dominant-inhibitory PKC' d or c, also blocks activation of F.rk2, Mek-1 and Raf, but not Ras, FAK or paxillin. These results suggest that both PI 3'-K and PKC activities are required for integrin-mediated Raf activation. possibly through co-stimulatory event(s) acting in conjunction with Ras Coupled with studies in other laboratories, these results indicate mat PI 3' K, PKC and Ras are involved in events downstream from, or independent of, F-'AK that arc required for integrin-induced activation of Frk/MAPK. We are currently attempting to elucidate the precise mechanisms involved in integrin regulation of Raf nc!i\ it\ and to understand the specific contributions of PI,V-K, PKC and Ras.