Cbl competitively inhibits epidermal growth factor-induced activation of phospholipase C-gamma 1
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- Cbl competitively inhibits epidermal growth factor-induced activation of phospholipase C-gamma 1
- Choi, Jang Hyun; Bae, SS; Park, JB; Ha, SH; Song, H; Kim, JH; Cocco, L; Ryu, SH; Suh, Pann-Ghill
- Issue Date
- KOREAN SOC MOLECULAR & CELLULAR BIOLOGY
- MOLECULES AND CELLS, v.15, no.2, pp.245 - 255
- Phospholipase C-gamma1 (PLC-gamma1) plays pivotal roles in cellular growth and proliferation through its two Src homology (SH) 2 domains and its single SH3 domain, which interact with signaling molecules in response to various growth factors and hormones. However, the role of the SH domains in the growth factor-induced regulation of PLC-gamma1 is unclear. By peptide-mass fingerprinting analysis we have identified Cbl as a binding protein for the SH3 domain of PLC-gamma1 from rat pheochromatocyte PC12 cells. Association of Cbl with PLC-gamma1 was induced by epidermal growth factor (EGF) but not by nerve growth factor (NGF). Upon EGF stimulation, both Cbl and PLC-gamma1 were recruited to the activated EGF receptor through their SH2 domains. Mutation of the SH2 domains of either Cbl or PLC-gamma1 abrogated the EGF-induced interaction of PLC-gamma1 with Cbl, indicating that SH2-mediated translocation is essential for the association of PLC-gamma1 and Cbl. Overexpression of Cbl attenuated EGF-induced tyrosine phosphorylation and the subsequent activation of PLC-gamma1 by interfering competitively with the interaction between PLC-gamma1 and EGFR. Taken together, these results provide the first indications that Cbl may be a negative regulator of intracellular signaling following EGF-induced PLC-gamma1 activation.
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