title: F-box only protein 31 (FBXO31) negatively regulates p38 mitogen-activated protein kinase (MAPK) signaling by mediating lysine 48-linked ubiquitination and degradation of mitogen-activated protein kinase kinase 6 (MKK6).
abstract: The p38 MAPK signal transduction pathway plays an important role in inflammatory and stress responses. MAPKK6 (MKK6), a dual specificity protein kinase, is a p38 activator. Activation of the MKK6-p38 pathway is kept in check by multiple layers of regulations, including autoinhibition, dimerization, scaffold proteins, and Lys-63-linked polyubiquitination. However, the mechanisms underlying deactivation of MKK6-p38, which is crucial for maintaining the magnitude and duration of signal transduction, are not well understood. Lys-48-linked ubiquitination, which marks substrates for proteasomal degradation, is an important negative posttranslational regulatory machinery for signal pathway transduction. Here we report that the accumulation of F-box only protein 31 (FBXO31), a component of Skp1 · Cul1 · F-box protein E3 ligase, negatively regulated p38 activation in cancer cells upon genotoxic stresses. Our results show that FBXO31 binds to MKK6 and mediates its Lys-48-linked polyubiquitination and degradation, thereby functioning as a negative regulator of MKK6-p38 signaling and protecting cells from stress-induced cell apoptosis. Taken together, our findings uncover a new mechanism of deactivation of MKK6-p38 and substantiate a novel regulatory role of FBXO31 in stress response.
authors.affiliation: From the Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China and.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: From the Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China and.
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.affiliation: From the Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China and.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: From the Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China and.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: From the Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China and.
authors.forename: Michael S Y
authors.initials: MS
authors.lastname: Huen
authors.affiliation: the Center for Molecular Medicine, NHLBI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Xin
authors.initials: X
authors.lastname: Pan
authors.affiliation: From the Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China and.
authors.forename: Sai Wah
authors.initials: SW
authors.lastname: Tsao
authors.affiliation: From the Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China and lmcheung@hku.hk.
authors.forename: Annie L M
authors.initials: AL
authors.lastname: Cheung
mesh_terms: D017209:Apoptosis; D001483:Base Sequence; D045744:Cell Line, Tumor; D044783:F-Box Proteins / Q000235:genetics / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D048669:MAP Kinase Kinase 6 / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009838:Oligodeoxyribonucleotides; D018384:Oxidative Stress; D059748:Proteolysis; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D044783:F-Box Proteins; C507917:FBXO31 protein, human; D009838:Oligodeoxyribonucleotides; D025521:Tumor Suppressor Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; D008239:Lysine
keywords: Apoptosis; Cancer; F-box Protein; FBXO31; MKK6; Protein Degradation; Stress Response; Ubiquitination; p38 MAPK