Met-induced JNK activation is mediated by the adapter protein Crk and correlates with the Gab1 - Crk signaling complex formation.
Constitutive activation of the Met tyrosine kinase results in transformation of cells of diverse origin. Recent studies have demonstrated a role for the c-Jun N-terminal kinase (JNK) in Met-induced transformation, but little is known about the molecular mechanisms that connect Met to JNK activation. Our studies show that activated Met associates with, and phosphorylates, the docking protein Gab1, which in turn binds to the src homology 2 (SH2)-domain of the adapter protein Crk and recruits Crk to the Met signaling complex. Formation of the Gab1 - Crk complex correlates with Met-induced JNK activation, and mutant forms of Met that fail to induce the complex formation also fail to activate JNK. Importantly, expression of a loss-of-function mutant of Crk severely impairs activation of the JNK pathway by Met. We also show here that Met controls the transcription of the matrix metalloproteinase-1 (MMP-1) gene in carcinoma cells and that this transcriptional regulation occurs in a Crk - JNK-dependent manner through an AP-1 element in the MMP-1 promoter. Taken together, our data implicate the Gab1 - Crk signaling complex in Met-induced JNK activation and suggest that the Gab1 - Crk complex formation may be an important event in regulating the tumorigenic phenotype of Met-transformed cells.
Garcia-Guzman
M
M
Cancer Research Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California, CA 92037, USA.
Dolfi
F
F
Zeh
K
K
Vuori
K
K
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D006367:HeLa Cells; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases / Q000235:genetics; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D008715:Methionine; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050737:Proto-Oncogene Proteins c-crk; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; C098587:GAB1 protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D018808:Transcription Factor AP-1; D017228:Hepatocyte Growth Factor; D008715:Methionine; D008156:Luciferases; D019859:Proto-Oncogene Proteins c-met; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1