Modulation of Fatty Acid Synthase Degradation by Concerted Action of p38 MAP Kinase, E3 Ligase COP1, and SH2-Tyrosine Phosphatase Shp2*
Modulation of Fatty Acid Synthase Degradation by Concerted Action of p38 MAP Kinase, E3 Ligase COP1, and SH2-Tyrosine Phosphatase Shp2*
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DOI：
10.1074/jbc.m112.397885
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发表时间：
2012-12
期刊：
影响因子：
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通讯作者：
Jianxiu Yu;R. Deng;H. Zhu;Sharon S. Zhang;Changhong Zhu;M. Montminy;R. Davis;G. Feng
中科院分区：
文献类型：
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作者：
Jianxiu Yu;R. Deng;H. Zhu;Sharon S. Zhang;Changhong Zhu;M. Montminy;R. Davis;G. Feng
背景：FASN是脂质代谢中的关键酶，其过度表达与多种人类恶性肿瘤相关。结果：Shp2 通过充当连接 FASN 与 COP1 和 p38 的适配器来促进 FASN 泛素化。结论：Shp2 可能作为针对 FASN 降解的接头。意义：本研究确定了 Shp2 在脂质代谢和肿瘤抑制中的新功能。已知含有 Src 同源 2 (SH2) 结构域的酪氨酸磷酸酶 Shp2 可以调节由受体和细胞质酪氨酸激酶触发的各种信号传导途径。在这里，我们描述了 Shp2 通过介导脂肪酸合酶 (FASN) 降解来控制脂质代谢的新功能。 p38 磷酸化的 COP1 在细胞质中积累，随后通过 Shp2 作为接头结合 FASN，导致 FASN-Shp2-COP1 复合物形成，并通过泛素化途径介导 FASN 降解。小鼠禁食后，p38 被激活并刺激 FASN 蛋白降解。一致地，在选择性删除 Shp2/Ptpn11 的小鼠肝脏和胰腺中，FASN 蛋白水平显着升高。因此，本研究确定了 Shp2 在脂质代谢中的新活性。
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.