The Ras-Mitogen-activated Protein Kinase Pathway Is Critical for the Activation of Matrix Metalloproteinase Secretion and the Invasiveness in v-crk-transformed 3Y1
2000
To search for the intracellular signaling pathway critical for the
secretion of matrix metalloproteinases (MMP), we studied the effects of
dominant negative Ras (S17N Ras) and dominant negative MEK1 (MEK1AA)
expression in v -crk -transformed 3Y1. Expression of
either S17N Ras or MEK1AA dramatically suppressed the augmented
secretion of MMP-2 and MMP-9 in v -crk -transfected 3Y1.
Similarly, a Ras farnesyltransferase inhibitor, manumycin A, and a MEK1
inhibitor, U0126, suppressed MMP secretion in a dose-dependent manner,
whereas a PI3 kinase inhibitor, wortmannin, could not. In addition, the
suppression of MMP secretion by S17N Ras showed good correlation with
the inhibition of in vitro invasiveness of the cells. In
contrast, expression of dominant negative C3G did not suppress MMP
secretion, although it substantially blocked 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 activation of MMP
secretion and, hence, the invasiveness of
v -crk -transformed cells.
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