Vinexin forms a signaling complex with Sos and modulates epidermal growth factor-induced c-Jun N-terminal kinase/stress-activated protein kinase activities

Vinexin, a novel protein that plays a hey role in cell spreading and cytosk eletal organization, contains three SH3 domains and binds to vinculin throu gh its first and second SH3 domains. We show here that the third SH3 domain binds to Sos, a guanine nucleotide exchange factor for Pas and Pac, both i n vitro and in vivo. Point mutations in the third SH3 domain abolished the vinexin-Sos interaction. Stimulation of NIH/3T3 cells with serum, epidermal growth factor (EGF), or platelet derived growth factor (PDGF) decreased th e electro phoretic mobility of Sos and concomitantly inhibited formation of the vinexin-Sos complex. Phosphatase treatment of lysates restored the bin ding of Sos to vinexin, suggesting that signaling from serum, EGF, or PDGF regulates the vinexin-Sos complex through the Sos phosphorylation. To evalu ate the function of vinexin downstream of growth factors, we examined the e ffects of wild-type and mutant vinexin expression on extracellular signal-r egulated kinase (Erk) and c-Jun N-terminal kinase/stress activated protein kinase (JNK/SAPK) activation in response to EGF. Exogenous expression of vi nexin beta in NIH/3T3 cells enhanced JNK/SAPK activation but did not affect Erk activation. Moreover mutations in the third SH3 domain abolished EGF a ctivation of JNK/SAPK in a dominant-negative fashion, whereas they slightly stimulated Erk. Together these results suggest that vinexin can selectivel y modulate EGF-induced signal transduction pathways leading to JNK/SAPK kin ase activation.