The Ras-mitogen-activated protein kinase pathway is critical for the activation of matrix metalloproteinase secretion and the invasiveness in v-crk-transformed 3Y1

To search for the intracellular signaling pathway critical for the secretio n of matrix metalloproteinases (MMP), we studied the effects of dominant ne gative Ras (S17N Ras) and dominant negative MEK1 (MEK1AA) expression in v-c rk-transformed 3Y1. Expression of either S17N Ras or MEK1AA dramatically su ppressed the augmented secretion of MMP-2 and MMP-9 in v-crk-transfected 3Y 1. Similarly, a Ras farnesyltransferase inhibitor, manumycin A, and a MEK1 inhibitor, U0126, suppressed MMP secretion in a dose-dependent manner, wher eas a PI3 kinase inhibitor, wortmannin, could not. In addition, the suppres sion of MMP secretion by S17N Ras showed good correlation with the inhibiti on of in vitro invasiveness of the cells. In contrast, expression of domina nt negative C3G did not suppress MMP secretion, although it substantially b locked the c-Jun N-terminal kinase activation. Taken together, the Ras-MEK1 pathway, but not the C3G-JNK pathway, seems to play a key role in the acti vation of MMP secretion and, hence, the invasiveness of v-crk-transformed c ells.