RGD Reference Report - The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines. - Rat Genome Database

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

Authors: Charlaftis, N  Suddason, T  Wu, X  Anwar, S  Karin, M  Gallagher, E 
Citation: Charlaftis N, etal., EMBO J. 2014 Nov 3;33(21):2581-96. doi: 10.15252/embj.201488351. Epub 2014 Sep 26.
RGD ID: 10047302
Pubmed: PMID:25260751   (View Abstract at PubMed)
PMCID: PMC4282369   (View Article at PubMed Central)
DOI: DOI:10.15252/embj.201488351   (Journal Full-text)

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-beta, 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-beta- 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-beta 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.

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein binding enablesIPIUniProtKB:P6108810047302PMID:25260751IntAct 
protein binding enablesIPIUniProtKB:Q1293310047302PMID:25260751IntAct 

Objects Annotated

Genes (Rattus norvegicus)
Map3k1  (mitogen-activated protein kinase kinase kinase 1)


Additional Information