2. Academic Validation
  3. The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines

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

  • EMBO J. 2014 Nov 3;33(21):2581-96. doi: 10.15252/embj.201488351.
Nikolaos Charlaftis 1,  Tesha Suddason 1,  Xuefeng Wu 2,  Saba Anwar 1,  Michael Karin 2,  Ewen Gallagher 3
Affiliations

Affiliations

  • 1 Department of Medicine, Imperial College London, London, UK.
  • 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.
  • 3 Department of Medicine, Imperial College London, London, UK [email protected].
PMID: 25260751 DOI: 10.15252/embj.201488351
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.

Keywords

differentiation; signalling; stem cell; tumourigenesis; ubiquitin.

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