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.
Highlights
fatty acid synthase (FASN) is a key enzyme in lipid metabolism, and its overexpression is associated with a variety of human malignancies
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
We examined the expression levels of FASN in various mouse tissues, and found that FASN contents were most abundant in liver and adipose tissues, with low levels detected in the heart (Fig. 1C)
Summary
FASN is a key enzyme in lipid metabolism, and its overexpression is associated with a variety of human malignancies. Increased amounts of FASN protein (Fig. 2C), indicating a role of Shp2 in facilitating FASN degradation in cells. Results shown here demonstrate that Shp2 ablation in the liver led to elevated FASN protein levels, as compared with wild-type mouse liver (Fig. 2D).
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