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.Background: FASN is a key enzyme in lipid metabolism, and its overexpression is associated with a variety of human malignancies.Results: Shp2 promotes FASN ubiquitination by acting as an adapter linking FASN with COP1 and p38.Conclusion: Shp2 may act as an adaptor in targeting FASN for its degradation.Significance: This study identifies a new function for Shp2 in lipid metabolism and tumor suppression. 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. Background: FASN is a key enzyme in lipid metabolism, and its overexpression is associated with a variety of human malignancies. Results: Shp2 promotes FASN ubiquitination by acting as an adapter linking FASN with COP1 and p38. Conclusion: Shp2 may act as an adaptor in targeting FASN for its degradation. Significance: This study identifies a new function for Shp2 in lipid metabolism and tumor suppression.