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)

The stress-responsive p38 and JNK MAPK pathways regulate cell cycle and apoptosis. A human MAPKKK, MTK1 (= MEKK4), mediates activation of both p38 and JNK in response to environmental stresses. Using a yeast two-hybrid method, three related proteins, GADD45alpha (= GADD45), GADD45, (= MyD118), and GADD45gamma, were identified that bound to an N-terminal domain of MTK1. These proteins activated MTK1 kinase activity, both in vivo and in vitro. The GADD45-like genes are induced by environmental stresses, including MMS, UV, and gamma irradiation. Expression of the GADD45-like genes induces p38/JNK activation and apoptosis, which can be partially suppressed by coexpression of a dominant inhibitory MTK1 mutant protein. We propose that the GADD45-like proteins mediate activation of the p38/JNK pathway, via MTK1/ MEKK4, in response to environmental stresses.
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PMID:A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. 982 4

The stress-inducible molecules GADD45beta and GADD45gamma have been implicated in regulating IFNgamma production in CD4 T cells. However, how GADD45 proteins function has been controversial. MEKK4 is a MAP kinase kinase kinase that interacts with GADD45 in vitro. Here we generated MEKK4-deficient mice to define the function and regulation of this pathway. CD4 T cells from MEKK4-/- mice have reduced p38 activity and defective IFNgamma synthesis. Expression of GADD45beta or GADD45gamma promotes IFNgamma production in MEKK4+/+ T cells, but not in MEKK4-/- cells or in cells treated with a p38 inhibitor. Thus, MEKK4 mediates the action of GADD45beta and GADD45gamma on p38 activation and IFNgamma production. During Th1 differentiation, the GADD45beta/GADD45gamma/MEKK4 pathway appears to integrate upstream signals transduced by both T cell receptor and IL12/STAT4, leading to augmented IFNgamma production in a process independent of STAT4.
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PMID:GADD45beta/GADD45gamma and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNgamma production in T cells. 1504 49