Siah proteins induce the epidermal growth factor-dependent degradation of phospholipase C epsilon
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- Siah proteins induce the epidermal growth factor-dependent degradation of phospholipase C epsilon
- Yun, Sanguk; Moeller, Andreas; Chae, Suhn-Kee; Hong, Won-Pyo; Bae, Young Ju; Bowtell, David D. L.; Ryu, Sung Ho; Suh, Pann-Ghill
- Issue Date
- AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
- JOURNAL OF BIOLOGICAL CHEMISTRY, v.283, no.2, pp.1034 - 1042
- Phospholipase C epsilon (PLC epsilon) is activated by various growth factors or G-protein-coupled receptor ligands via different activation mechanisms. The Ras association ( RA) domain of PLC epsilon is known to be important for its ability to bind with Ras-family GTPase upon growth factor stimulation. In the present study, we identified Siah1 and Siah2 as novel binding partners of the PLC epsilon RA domain. Both Siah1 and Siah2 interacted with the RA2 domain of PLC epsilon, and the mutation of Lys-2186 of the PLC epsilon RA2 domain abolished this association. Moreover, Siah induced the ubiquitination and degradation of PLC epsilon upon epidermal growth factor (EGF) stimulation, and Siah proteins were phosphorylated on multiple tyrosine residues via an Src-dependent pathway upon EGF treatment. The Src inhibitor abolished the EGF-dependent ubiquitination of PLC epsilon, and the Siah1 phosphorylation-deficient mutant could not increase the EGF-dependent ubiquitination and degradation of PLC epsilon. The EGF-dependent degradation of PLC epsilon was blocked in mouse embryonic fibroblast (MEF) cells derived from Siah1a/Siah2 double knockout mice, and the extrinsic expression of wild-type Siah1 restored the degradation of PLC epsilon, whereas the phosphorylation-deficient mutant did not. Siah1 expression abolished PLC epsilon-dependent potentiation of EGF-dependent cell growth. In addition, the expression of wild-type Siah1 in Siah1a/Siah2-double knockout MEF cells inhibited EGF-dependent cell growth, and this inhibition was abolished by PLC epsilon knockdown. Our results suggest that the Siah-dependent degradation of PLC epsilon plays a role in the regulation of growth factor-dependent cell growt
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