Modulation of fatty acid synthase degradation by concerted action of p38 MAP kinase, E3 ligase COP1, and SH2-tyrosine phosphatase Shp2
Program in Molecular Medicine
Medical Subject Headings
3T3 Cells; Animals; Fatty Acid Synthase, Type I; HeLa Cells; Humans; Lipid Metabolism; Liver; Mice; Mice, Knockout; Nuclear Proteins; Pancreas; Protein Tyrosine Phosphatase, Non-Receptor Type 11; *Proteolysis; Ubiquitin-Protein Ligases; p38 Mitogen-Activated Protein Kinases
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
The Src-homology 2 (SH2) domain-containing tyrosine phosphatase Shp2 has been known to regulate various signaling pathways triggered by receptor and cytoplasmic tyrosine kinases. Here we describe a novel function of Shp2 in control of lipid metabolism by mediating degradation of fatty acid synthase (FASN). p38-phosphorylated COP1 accumulates in the cytoplasm and subsequently binds FASN through Shp2 here as an adapter, leading to FASN-Shp2-COP1 complex formation and FASN degradation mediated by ubiquitination pathway. By fasting p38 is activated and stimulates FASN protein degradation in mice. Consistently, the FASN protein levels are dramatically elevated in mouse liver and pancreas in which Shp2/Ptpn11 is selectively deleted. Thus, this study identifies a new activity for Shp2 in lipid metabolism.
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Citation: J Biol Chem. 2013 Feb 8;288(6):3823-30. doi: 10.1074/jbc.M112.397885. Epub 2012 Dec 26. Link to article on publisher's site
Yu, Jianxiu; Deng, Rong; Zhu, Helen H.; Zhang, Sharon S.; Zhu, Changhong; Montminy, Marc; Davis, Roger J.; and Feng, Gen-Sheng, "Modulation of fatty acid synthase degradation by concerted action of p38 MAP kinase, E3 ligase COP1, and SH2-tyrosine phosphatase Shp2" (2013). Davis Lab. 5.