title: Human TRIB2 Oscillates during the Cell Cycle and Promotes Ubiquitination and Degradation of CDC25C.
abstract: Tribbles homolog 2 (TRIB2) is a member of the mammalian Tribbles family of serine/threonine pseudokinases (TRIB1-3). Studies of TRIB2 indicate that many of the molecular interactions between the single Drosophila Tribbles (Trbl) protein and interacting partners are evolutionary conserved. In this study, we examined the relationship between TRIB2 and cell division cycle 25 (CDC25) family of dual-specificity protein phosphatases (mammalian homologues of Drosophila String), which are key physiological cell cycle regulators. Using co-immunoprecipitation we demonstrate that TRIB2 interacts with CDC25B and CDC25C selectively. Forced overexpression of TRIB2 caused a marked decrease in total CDC25C protein levels. Following inhibition of the proteasome, CDC25C was stabilized in the nuclear compartment. This implicates TRIB2 as a regulator of nuclear CDC25C turnover. In complementary ubiquitination assays, we show that TRIB2-mediated degradation of CDC25C is associated with lysine-48-linked CDC25C polyubiquitination driven by the TRIB2 kinase-like domain. A cell cycle associated role for TRIB2 is further supported by the cell cycle regulated expression of TRIB2 protein levels. Our findings reveal mitotic CDC25C as a new target of TRIB2 that is degraded via the ubiquitin proteasome system. Inappropriate CDC25C regulation could mechanistically underlie TRIB2 mediated regulation of cellular proliferation in neoplastic cells.
authors: Paul O'Gorman Leukemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0ZD, UK. 111220352@umail.ucc.ie.|School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland. 111220352@umail.ucc.ie.
authors: Kai Ling
authors: KL
authors: Liang
authors: Stem Cell and Leukaemia Proteomics Laboratory, University of Manchester, Manchester M20 3LJ, UK. Roberto.Paredes@manchester.ac.uk.
authors: Roberto
authors: R
authors: Paredes
authors: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK. ruaidhri.carmody@glasgow.ac.uk.
authors: Ruaidhri
authors: R
authors: Carmody
authors: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK. Patrick.eyers@liverpool.ac.uk.
authors: Patrick A
authors: PA
authors: Eyers
authors: Stem Cell and Leukaemia Proteomics Laboratory, University of Manchester, Manchester M20 3LJ, UK. stefan.meyer@manchester.ac.uk.|Paediatric and Adolescent Oncology, Royal Manchester Children's and Christie Hospital, University of Manchester, Manchester M13 9WL, UK. stefan.meyer@manchester.ac.uk.
authors: Stefan
authors: S
authors: Meyer
authors: School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland. t.mccarthy@ucc.ie.
authors: Tommie V
authors: TV
authors: McCarthy
authors: Paul O'Gorman Leukemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0ZD, UK. karen.keeshan@glasgow.ac.uk.
authors: Karen
authors: K
authors: Keeshan
mesh_terms: D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D054875:Ubiquitination / Q000235:genetics / Q000502:physiology; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C489044:TRIB2 protein, human; C517009:CDC25C protein, human; D054637:Dual-Specificity Phosphatases; D020687:cdc25 Phosphatases; D046988:Proteasome Endopeptidase Complex
keywords: CDC25B; CDC25C; TRIB2; cell cycle; degradation; dual-specificity phosphatase; pseudokinase; ubiquitin proteasome