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 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.
Liu
E
E
Department of Obstetrics and Gynecology, Nagoya University School of Medicine, Japan.
Thant
A A
AA
Kikkawa
F
F
Kurata
H
H
Tanaka
S
S
Nawa
A
A
Mizutani
S
S
Matsuda
S
S
Hanafusa
H
H
Hamaguchi
M
M
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002461:Cell Line, Transformed; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology; D020735:Guanine Nucleotide-Releasing Factor 2 / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D015151:Immunoblotting; D007797:Laminin / Q000378:metabolism; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D050736:Oncogene Protein v-crk; D011090:Polyenes / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D015398:Signal Transduction; D000077191:Wortmannin; D018631:ras Proteins / Q000378:metabolism*; D018909:src Homology Domains
D000730:Androstadienes; D002070:Butadienes; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D020735:Guanine Nucleotide-Releasing Factor 2; D007797:Laminin; D061965:Matrix Metalloproteinase Inhibitors; D009570:Nitriles; D050736:Oncogene Protein v-crk; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D011509:Proteoglycans; D015682:Retroviridae Proteins, Oncogenic; C113580:U 0126; C059485:matrigel; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D018631:ras Proteins; C054474:manumycin; D000077191:Wortmannin