| First Author | Charlaftis N | Year | 2014 |
| Journal | EMBO J | Volume | 33 |
| Issue | 21 | Pages | 2581-96 |
| PubMed ID | 25260751 | Mgi Jnum | J:215973 |
| Mgi Id | MGI:5607447 | Doi | 10.15252/embj.201488351 |
| Citation | Charlaftis N, et al. (2014) The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines. EMBO J 33(21):2581-96 |
| abstractText | 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. |
