ubiquitination and degradation of the hominoid-specific oncoprotein tbc1d3 is mediated by cul7 e3 ligase泛素化和退化的hominoid-specific癌蛋白tbc1d3由cul7 e3连接酶介导.pdfVIP

Ubiquitination and Degradation of the Hominoid- Specific Oncoprotein TBC1D3 Is Mediated by CUL7 E3 Ligase 1 1 1¤a 1¤b 1¤c Chen Kong , Dmitri Samovski , Priya Srikanth , Marisa J. Wainszelbaum , Audra J. Charron , 1 1¤d 1¤e 2 3 1 Jialiu Liu , Jeffrey J. Lange , Pin-I Chen , Zhen-Qiang Pan , Xiong Su *, Philip D. Stahl * 1 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, United States of America, 2 Department of Oncological Sciences, Icahn Medical Institute, New York, New York, United States of America, 3 Department of Internal Medicine, Center for Human Nutrition Washington University School of Medicine, St. Louis, Missouri, United States of America Abstract Expression of the hominoid-specific TBC1D3 oncoprotein enhances growth factor receptor signaling and subsequently promotes cellular proliferation and survival. Here we report that TBC1D3 is degraded in response to growth factor signaling, suggesting that TBC1D3 expression is regulated by a growth factor-driven negative feedback loop. To gain a better understanding of how TBC1D3 is regulated, we studied the effects of growth factor receptor signaling on TBC1D3 post- translational processing and turnover. Using a yeast two-hybrid screen, we identified CUL7, the scaffolding subunit of the CUL7 E3 ligase complex, as a TBC1D3-interacting protein. We show that CUL7 E3 ligase ubiquitinates TBC1D3 in response to serum stimulation. Moreover, TBC1D3 recruits F-box 8 (Fbw8), the substrate recognition domain