title: Serine/Threonine Kinase Unc-51-like Kinase-1 (Ulk1) Phosphorylates the Co-chaperone Cell Division Cycle Protein 37 (Cdc37) and Thereby Disrupts the Stability of Cdc37 Client Proteins.
abstract: The serine/threonine kinase Unc-51-like kinase-1 (Ulk1) is thought to be essential for induction of autophagy, an intracellular bulk degradation process that is activated by various stresses. Although several proteins have been suggested as Ulk1 substrates during autophagic process, it still remains largely unknown about Ulk1's physiological substrates. Here, by performingin vitroandin vivophosphorylation assay, we report that the co-chaperone cell division cycle protein 37 (Cdc37) is a Ulk1 substrate. Ulk1-mediated phosphorylation of Ser-339 in Cdc37 compromised the recruitment of client kinases to a complex comprising Cdc37 and heat shock protein 90 (Hsp90) but only modestly affected Cdc37 binding to Hsp90. Because the recruitment of protein kinase clients to the Hsp90 complex is essential for their stability and functions, Ser-339 phosphorylation of Cdc37 disrupts its ability as a co-chaperone to coordinate Hsp90. Hsp90 inhibitors are cancer chemotherapeutic agents by inducing depletion of clients, many of which are oncogenes. Upon treatment with an Hsp90 inhibitor in cancer cells, Ulk1 promoted the degradation of Hsp90-Cdc37 client kinases, resulting in increased cellular sensitivity to Hsp90 inhibitors. Thus, our study provides evidence for an anti-proliferative role of Ulk1 in response to Hsp90 inhibition in cancer cells.
authors.affiliation: From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Li
authors.affiliation: From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Fengjie
authors.initials: F
authors.lastname: Yuan
authors.affiliation: From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Wan
authors.initials: W
authors.lastname: Fu
authors.affiliation: From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Luyao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ma
authors.affiliation: From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.|the Center for Life Sciences, Peking-Tsinghua University, Beijing 100871, China, and.|the Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China.
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zhu
authors.affiliation: From the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China, zhaoying0812@bjmu.edu.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000071189:Autophagy-Related Protein-1 Homolog / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D018833:Chaperonins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D055550:Protein Stability
chemical_list: C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000071189:Autophagy-Related Protein-1 Homolog; C484754:ULK1 protein, human; D018833:Chaperonins
keywords: AMP-activated kinase (AMPK); Hsp90 inhibitor; Ulk1; autophagy; cdc37; cell death; heat shock protein 90 (Hsp90); protein kinase