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The Ras-Mitogen-activated Protein Kinase Pathway Is Critical for the Activation of Matrix Metalloproteinase Secretion and the Invasiveness in v-crk-transformed 3Y1¹

Departments of Obstetrics and Gynecology [E. L., F. K., A. N., S. Mi.] and Molecular Pathogenesis [A. A. T., S. Ma., M. H.], and The Third Internal Medicine [H. K.], Nagoya University School of Medicine, Showaku, Nagoya 466-8550, Japan, and Laboratory of Molecular Oncology, Rockefeller University, New York, New York 10021 [S. T., H. H.]

ABSTRACT

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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