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The proto-oncogene c-Cbl is a positive regulator of Met-induced MAP kinase activation: a role for the adaptor protein Crk

Abstract

Hepatocyte growth factor triggers a complex biological program leading to invasive cell growth by activating the c-Met receptor tyrosine kinase. Following activation, Met signaling is elicited via its interactions with SH2-containing proteins, or via the phosphorylation of the docking protein Gab1, and the subsequent interaction of Gab1 with additional SH2-containing effector molecules. We have previously shown that the interaction between phosphorylated Gab1 and the adaptor protein Crk mediates activation of the JNK pathway downstream of Met. We report here that c-Cbl, which is a Gab1-like docking protein, also becomes tyrosine-phosphorylated in response to Met activation and serves as a docking molecule for various SH2-containing molecules, including Crk. We further show that Cbl is similarly capable of enhancing Met-induced JNK activation, and several lines of experimentation suggests that it does so by interacting with Crk. We also show that both Cbl and Gab1 enhance Met-induced activation of another MAP kinase cascade, the ERK pathway, in a Crk-independent manner. Taken together, our studies demonstrate a previously unidentified functional role for Cbl in Met signaling and suggest that Met utilizes at least two docking proteins, Gab1 and Cbl, to activate downstream signaling pathways.

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Acknowledgements

We thank WY Langdon for the Cbl-construct, M Matsuda for the Crk-construct, A Wong and M Holgado-Madruga for the Gab1 cDNA and GF Vande Woude and M Jeffers for the wild-type Tpr/Met construct, Met (L1213V/M1268T) construct and anti-Met antibodies. This work was supported by NIH grants CA71560 and CA76037 (to K Vuori). M Garcia-Guzman was supported by a fellowship from the Human Frontier Science Program. K Vuori is a PEW scholar in biomedical sciences.

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Garcia-Guzman, M., Larsen, E. & Vuori, K. The proto-oncogene c-Cbl is a positive regulator of Met-induced MAP kinase activation: a role for the adaptor protein Crk. Oncogene 19, 4058–4065 (2000). https://doi.org/10.1038/sj.onc.1203750

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