Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.25 (MEKK1)
 1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Members of the mitogen-activated protein kinase kinase kinase (MAP3K) family are crucial for the Toll-like receptor (TLR) signaling and cellular stress responses. However, the molecular mechanisms underlying the TLR- and cellular stress-mediated MAP3K activation remain largely unknown. In this study, we identified a key regulatory phosphorylation site, serine 519 and serine 526, in MAP3K MEKK2 and MEKK3, respectively. Mutation of this serine to an alanine severely impaired MEKK2/3 activation. We generated an anti-p-MEKK2/3 antibody and used this antibody to demonstrate that lipopolysaccharide induced MEKK2 and MEKK3 phosphorylation on their regulatory serine. We found that the serine phosphorylation was crucial for TLR-induced interleukin 6 production and this process is regulated by TRAF6, a key adaptor molecule for the TLR pathway. We further demonstrated that many, but not all, MAPK agonists induced the regulatory serine phosphorylation, suggesting an involvement of different MAP3Ks in activation of the MAPK cascades leading to different cellular responses. In conclusion, this study reveals a novel molecular mechanism for MEKK2/3 activation by the TLR and cellular stress pathways.
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PMID:Identification of MEKK2/3 serine phosphorylation site targeted by the Toll-like receptor and stress pathways. 1636 41

We investigated the physiological role of endogenous MAPK-activating death domain-containing protein (MADD), a splice variant of the IG20 gene, that can interact with TNFR1 in tumor necrosis factor-alpha (TNFalpha)-induced activation of NF-kappaB, MAPK, ERK1/2, JNK, and p38. Using exon-specific short hairpin RNAs expressing lentiviruses, we knocked down the expression of all IG20 splice variants or MADD, which is overexpressed in cancer cells. Abrogation of MADD expression rendered cells highly susceptible to TNFalpha-induced apoptosis in the absence of cycloheximide. It also resulted in a dramatic loss in TNFalpha-induced activation of MAPK without any apparent effect on NF-kappaB activation. This observation was substantiated by an accompanying loss in the activation of p90RSK, a key downstream target of MAPK, whereas the NF-kappaB-regulated interleukin 6 levels remained unaffected. Endogenous MADD knockdown, however, did not affect epidermal growth factor-induced MAPK activation thereby demonstrating the specific requirement of MADD for TNF receptor-mediated MAPK activation. Re-expression of short hairpin RNA-resistant MADD in the absence of endogenous IG20 expression rescued the cells from TNFalpha-induced apoptosis. The requirement for MADD was highly specific for TNFalpha-induced activation of MAPK but not the related JNK and p38 kinases. Loss of MADD expression resulted in reduced Grb2 and Sos1/2 recruitment to the TNFR1 complex and decreased Ras and MEKK1/2 activation. These results demonstrate the essential role of MADD in protecting cancer cells from TNFalpha-induced apoptosis by specifically activating MAPKs through Grb2 and Sos1/2 recruitment, and its potential as a novel cancer therapeutic target.
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PMID:MADD, a splice variant of IG20, is indispensable for MAPK activation and protection against apoptosis upon tumor necrosis factor-alpha treatment. 1928 68