title: Negative regulation of type I IFN signaling by phosphorylation of STAT2 on T387.
abstract: The transcription factor ISGF3, comprised of IRF9 and tyrosine-phosphorylated STATs 1 and 2, transmits the signal from the type I interferon receptor to the genome. We have discovered a novel phosphorylation of STAT2 on T387 that negatively regulates this response. In most untreated cell types, the majority of STAT2 is phosphorylated on T387 constitutively. In response to interferon-β, the T387A mutant of STAT2 is much more effective than wild-type STAT2 in mediating the expression of many interferon-stimulated genes, in protecting cells against virus infection, and in inhibiting cell growth. Interferon-β-treated cells expressing wild-type STAT2 contain much less ISGF3 capable of binding to an interferon-stimulated response element than do cells expressing T387A STAT2. T387 lies in a cyclin-dependent kinase (CDK) consensus sequence, and CDK inhibitors decrease T387 phosphorylation. Using CDK inhibitors to reverse the constitutive inhibitory phosphorylation of T387 of U-STAT2 might enhance the efficacy of type I interferons in many different clinical settings.
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education Ocean University of China, Qingdao, Shandong, China.|Department of Cancer Biology, Lerner Research Institute The Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, Lerner Research Institute The Cleveland Clinic Foundation, Cleveland, OH, USA.|Institute of Cancer Biology & Drug Screening, School of Life Sciences Lanzhou University, Lanzhou, Gansu, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Nan
authors.affiliation: Proteomics and Metabolomics Laboratory, Lerner Research Institute The Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Belinda
authors.initials: B
authors.lastname: Willard
authors.affiliation: Department of Immunology, Lerner Research Institute The Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education Ocean University of China, Qingdao, Shandong, China starkg@ccf.org yangjb@ouc.edu.cn.|Institute of Cancer Biology & Drug Screening, School of Life Sciences Lanzhou University, Lanzhou, Gansu, China.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cancer Biology, Lerner Research Institute The Cleveland Clinic Foundation, Cleveland, OH, USA starkg@ccf.org yangjb@ouc.edu.cn.
authors.forename: George R
authors.identifier: 0000-0002-8776-9597
authors.initials: GR
authors.lastname: Stark
mesh_terms: D002460:Cell Line; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D050795:STAT2 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D050832:Interferon-Stimulated Gene Factor 3; D050795:STAT2 Transcription Factor; D016899:Interferon-beta
keywords: STAT2; T387 phosphorylation; negative regulation; type I interferon