The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines

• Nikolaos Charlaftis ^[1] ; Tesha Suddason ^[1] ; Xuefeng Wu ^[2] ; Saba Anwar ^[1] ; Michael Karin ^[2] ; Ewen Gallagher ^[1]
  1. [1] Imperial College London

     Imperial College London

     Reino Unido

     
  2. [2] 2 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine San Diego, CA, USA
• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 33, Nº. 21, 2014, págs. 2581-2596
• Idioma: inglés
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• Resumen

  • 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 (Map3k1mPHD) with an inactive PHD motif. Map3k1mPHD 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 Map3k1mPHD 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. Map3k1mPHD/+ mice exhibit aberrant cardiac tissue, B-cell development, testis and T-cell signalling.