YWK-II/APLP2 inhibits TGF-β signaling by interfering with the TGFBR2–Hsp90 interaction |
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| Institution: | 1. Department of Biochemistry and Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China;2. Guizhou Prenatal Diagnosis Center, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou, China;3. Department of Clinical Biochemistry, School of Medical Laboratory Science, Guizhou Medical University, Guiyang 550004, Guizhou, China;1. Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, Jiangsu 215123, China;2. Department of Pharmacy, Medical Center of Soochow University, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, Jiangsu 215123, China;1. Basic Medical Sciences Center, Shanxi Medical University, Taiyuan, PR China;2. Department of Orthopedics, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, PR China;3. Key Laboratory of Cellular Physiology (Shanxi Medical University), Taiyuan, PR China;4. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, PR China;1. Department of Pharmaceutical Sciences, Fisch College of Pharmacy, The University of Texas At Tyler, Tyler, TX, USA;2. Stevens Institute of Technology, Hoboken, NJ, USA;3. Memorial Sloan Kettering Cancer Center, NY, NY, USA;4. New York University, Grossman School of Medicine, NY, NY, USA;5. European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany;6. Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Zurich, Switzerland;1. Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China;2. Department of Clinical Laboratory, Weifang People''s Hospital, Weifang, Shandong 261000, China;3. Department of Medical Laboratory, The Second Affiliated Hospital of Xiamen Medical College, Xiamen 361004, China;4. Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen 361004, China;1. Department of Medical Cosmetology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China;2. Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China;3. Department of Plastic Surgery, China-Japan Friendship Hospital, Beijing 100029, China |
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| Abstract: | Transforming growth factor-β (TGF-β) regulates multiple cellular biological processes by activating TGF-β type I receptors (TGFBR1) and type II receptors (TGFBR2), and Hsp90 stabilizes these receptors through specific interactions. In many malignancies, one of the most deregulated signaling pathways is the TGF-β signaling pathway, which is often inactivated by mutations or deregulation of TGF-β type II receptors (TGFBR2). However, the molecular mechanisms are not well understood. In this study, we show that YWK-II/APLP2, an immediately early response gene for TGF-β signaling, inhibits TGF-β signaling by promoting the degradation of the TGFBR2 protein. Knockdown of YWK-II/APLP2 increases the TGFBR2 protein level and sensitizes cells to TGF-β stimulation, while YWK-II/APLP2 overexpression destabilizes TGFBR2 and desensitizes cells to TGF-β. Mechanistically, YWK-II/APLP2 is associated with TGFBR2 in a TGF-β activity-dependent manner, binds to Hsp90 to interfere with the interaction between TGFBR2 and Hsp90, and leads to enhanced ubiquitination and degradation of TGFBR2. Taken together, YWK-II/APLP2 is involved in negatively regulating the duration and intensity of TGF-β/Smad signaling and suggests that aberrantly high expression of YWK-II/APLP2 in malignancies may antagonize the growth inhibition mediated by TGF-β signaling and play a role in carcinogenesis. |
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