title: Modulation of fatty acid synthase degradation by concerted action of p38 MAP kinase, E3 ligase COP1, and SH2-tyrosine phosphatase Shp2.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China. Jianxiu.Yu@gmail.com
authors.forename: Jianxiu
authors.initials: J
authors.lastname: Yu
authors.forename: Rong
authors.initials: R
authors.lastname: Deng
authors.forename: Helen H
authors.initials: HH
authors.lastname: Zhu
authors.forename: Sharon S
authors.initials: SS
authors.lastname: Zhang
authors.forename: Changhong
authors.initials: C
authors.lastname: Zhu
authors.forename: Marc
authors.initials: M
authors.lastname: Montminy
authors.forename: Roger
authors.initials: R
authors.lastname: Davis
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
mesh_terms: D016475:3T3 Cells; D000818:Animals; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010179:Pancreas / Q000201:enzymology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; C471981:COP1 protein, human; C471982:COP1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D048051:p38 Mitogen-Activated Protein Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse