title: The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines.
abstract: Unlike the other MAP3Ks, MEKK1 (encoded by Map3k1) contains a PHD motif. To understand the role of this motif, we have created a knockin mutant of mouse Map3k1 (Map3k1(m) (PHD)) with an inactive PHD motif. Map3k1(m) (PHD) ES cells demonstrate that the MEKK1 PHD controls p38 and JNK activation during TGF-β, EGF and microtubule disruption signalling, but does not affect MAPK responses to hyperosmotic stress. Protein microarray profiling identified the adaptor TAB1 as a PHD substrate, and TGF-β- or EGF-stimulated Map3k1(m) (PHD) ES cells exhibit defective non-canonical ubiquitination of MEKK1 and TAB1. The MEKK1 PHD binds and mediates the transfer of Lys63-linked poly-Ub, using the conjugating enzyme UBE2N, onto TAB1 to regulate TAK1 and MAPK activation by TGF-β and EGF. Both the MEKK1 PHD and TAB1 are critical for ES-cell differentiation and tumourigenesis. Map3k1(m) (PHD) (/+) mice exhibit aberrant cardiac tissue, B-cell development, testis and T-cell signalling.
authors.affiliation: Department of Medicine, Imperial College London, London, UK.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Charlaftis
authors.affiliation: Department of Medicine, Imperial College London, London, UK.
authors.forename: Tesha
authors.initials: T
authors.lastname: Suddason
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego School of Medicine, San Diego, CA, USA.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Medicine, Imperial College London, London, UK.
authors.forename: Saba
authors.initials: S
authors.lastname: Anwar
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego School of Medicine, San Diego, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: Department of Medicine, Imperial College London, London, UK ewen.gallagher@ntlworld.com.
authors.forename: Ewen
authors.initials: E
authors.lastname: Gallagher
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D025821:Polyubiquitin / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C531463:Tab1 protein, mouse; D016212:Transforming Growth Factor beta; D025821:Polyubiquitin; D004815:Epidermal Growth Factor; D048051:p38 Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D048670:MAP Kinase Kinase 4
keywords: differentiation; signalling; stem cell; tumourigenesis; ubiquitin