Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity
Authors
Yang, DiTournier, Cathy
Wysk, Mark Allen
Lu, Hong-Tao
Xu, Jie
Davis, Roger J.
Flavell, Richard A.
Document Type
Journal ArticlePublication Date
1997-04-01Keywords
Animals; Calcium-Calmodulin-Dependent Protein Kinases; inhibitors; Embryonic and Fetal Development; Enzyme Activation; *Genes, Lethal; Heterozygote; Homozygote; JNK Mitogen-Activated Protein Kinases; *MAP Kinase Kinase 4; Mice; Mice, Knockout; *Mitogen-Activated Protein Kinase Kinases; *Mitogen-Activated Protein Kinases; Protein-Serine-Threonine Kinases; Protein-Tyrosine Kinases; Transcription Factor AP-1Life Sciences
Medicine and Health Sciences
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Show full item recordAbstract
MKK4 is a member of the mitogen-activated protein kinase kinase group of dual specificity protein kinases that functions as an activator of the c-Jun NH2-terminal kinase (JNK) in vitro. To examine the function of MKK4 in vivo, we investigated the effect of targeted disruption of the MKK4 gene. Crosses of heterozygous MKK4 (+/-) mice demonstrated that homozygous knockout (-/-) animals die before embryonic day 14, indicating that the MKK4 gene is required for viability. The role of MKK4 in JNK activation was examined by investigation of cultured MKK4 (+/+) and MKK4 (-/-) cells. Disruption of the MKK4 gene blocked JNK activation caused by: (i) the mitogen-activated protein kinase kinase kinase MEKK1, and (ii) treatment with anisomycin or heat shock. In contrast, JNK activation caused by other forms of environmental stress (UV-C radiation and osmotic shock) was partially inhibited in MKK4 (-/-) cells. Regulated AP-1 transcriptional activity, a target of the JNK signal transduction pathway, was also selectively blocked in MKK4 (-/-) cells. Complementation studies demonstrated that the defective AP-1 transcriptional activity was restored by transfection of MKK4 (-/-) cells with an MKK4 expression vector. These data establish that MKK4 is a JNK activator in vivo and demonstrate that MKK4 is an essential component of the JNK signal transduction pathway.Source
Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3004-9.
DOI
10.1073/pnas.94.7.3004Permanent Link to this Item
http://hdl.handle.net/20.500.14038/34085PubMed ID
9096336Related Resources
ae974a485f413a2113503eed53cd6c53
10.1073/pnas.94.7.3004
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Molecular determinants that mediate selective activation of p38 MAP kinase isoformsEnslen, Herve; Brancho, Deborah Marie; Davis, Roger J. (2000-03-16)The p38 mitogen-activated protein kinase (MAPK) group is represented by four isoforms in mammals (p38alpha, p38beta2, p38gamma and p38delta). These p38 MAPK isoforms appear to mediate distinct functions in vivo due, in part, to differences in substrate phosphorylation by individual p38 MAPKs and also to selective activation by MAPK kinases (MAPKKs). Here we report the identification of two factors that contribute to the specificity of p38 MAPK activation. One mechanism of specificity is the selective formation of functional complexes between MAPKK and different p38 MAPKs. The formation of these complexes requires the presence of a MAPK docking site in the N-terminus of the MAPKK. The second mechanism that confers signaling specificity is the selective recognition of the activation loop (T-loop) of p38 MAPK isoforms. Together, these processes provide a mechanism that enables the selective activation of p38 MAPK in response to activated MAPKK.
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