title: USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51-AKT signaling.
abstract: The AKT pathway is a fundamental signaling pathway that mediates multiple cellular processes, such as cell proliferation and survival, angiogenesis, and glucose metabolism. We recently reported that the immunophilin FKBP51 is a scaffolding protein that can enhance PHLPP-AKT interaction and facilitate PHLPP-mediated dephosphorylation of AKT at Ser473, negatively regulating AKT activation. However, the regulation of FKBP51-PHLPP-AKT pathway remains unclear. Here we report that a deubiquitinase, USP49, is a new regulator of the AKT pathway. Mechanistically, USP49 deubiquitinates and stabilizes FKBP51, which in turn enhances PHLPP's capability to dephosphorylate AKT Furthermore, USP49 inhibited pancreatic cancer cell proliferation and enhanced cellular response to gemcitabine in a FKBP51-AKT-dependent manner. Clinically, decreased expression of USP49 in patients with pancreatic cancer was associated with decreased FKBP51 expression and increased AKT phosphorylation. Overall, our findings establish USP49 as a novel regulator of AKT pathway with a critical role in tumorigenesis and chemo-response in pancreatic cancer.
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China.|Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Kuntian
authors.initials: K
authors.lastname: Luo
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yujiao
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Chenming
authors.initials: C
authors.lastname: Wu
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Medical Scientist Training Program, Mayo Clinic School of Medicine, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA.
authors.forename: Somaira
authors.initials: S
authors.lastname: Nowsheen
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Zhenkun
authors.identifier: 0000-0003-1938-3091
authors.initials: Z
authors.lastname: Lou
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China yuanjian229@hotmail.com.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China.|Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jian
authors.identifier: 0000-0002-2801-8849
authors.initials: J
authors.lastname: Yuan
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D063646:Carcinogenesis; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004351:Drug Resistance; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*; D046888:Tissue Array Analysis; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D000093542:Gemcitabine; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D009687:Nuclear Proteins; D010749:Phosphoprotein Phosphatases; D051057:Proto-Oncogene Proteins c-akt; D022021:Tacrolimus Binding Proteins; D043222:Ubiquitin Thiolesterase; D000093542:Gemcitabine; D000099159:Tacrolimus Binding Protein 5; C571993:USP49 protein, human; C400601:PHLPP1 protein, human
keywords: 
  AKT
  ; FKBP51; chemoresistance; deubiquitination