Grb2 negatively regulates epidermal growth factor-induced phospholipase C-gamma 1 activity through the direct interaction with tyrosine-phosphorylated phospholipase C-gamma 1
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- Grb2 negatively regulates epidermal growth factor-induced phospholipase C-gamma 1 activity through the direct interaction with tyrosine-phosphorylated phospholipase C-gamma 1
- Choi, Jang Hyun; Hong, WP; Yun, S; Kim, HS; Lee, JR; Park, JB; Bae, YS; Ryu, SH; Suh, Pann-Ghill
- Issue Date
- ELSEVIER SCIENCE INC
- CELLULAR SIGNALLING, v.17, no.10, pp.1289 - 1299
- Phospholipase C-γ1 (PLC-γ1) plays pivotal roles in cellular growth and proliferation. Upon the stimulation of growth factors and hormones, PLC-γ1 is rapidly phosphorylated at three known sites; Tyr771, Tyr783 and Tyr1254 and its enzymatic activity is up-regulated. In this study, we demonstrate for the first time that Grb2, an adaptor protein, specifically interacts with tyrosine-phosphorylated PLC-γ1 at Tyr783. The association of Grb2 with PLC-γ1 was induced by the treatment with epidermal growth factor (EGF). Replacement of Tyr783 with Phe completely blocked EGF-induced interaction of PLC-γ1 with Grb2, indicating that tyrosine phosphorylation of PLC-γ1 at Tyr783 is essential for the interaction with Grb2. Interestingly, the depletion of Grb2 from HEK-293 cells by RNA interference significantly enhanced increased EGF-induced PLC-γ1 enzymatic activity and mobilization of the intracellular Ca2+, while it did not affect EGF-induced tyrosine phosphorylation of PLC-γ1. Furthermore, overexpression of Grb2 inhibited PLC-γ1 enzymatic activity. Taken together, these results suggest Grb2, in addition to its key function in signaling through Ras, may have a negatively regulatory role on EGF-induced PLC-γ1 activation.
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