A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stress-induced activation of the p38 and JNK pathways

• Published in: The EMBO journal Vol. 16; no. 16; pp. 4973 - 4982
• Main Authors: Takekawa, Mutsuhiro, Posas, Francesc, Saito, Haruo
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 15-08-1997
• Subjects: Amino Acid Sequence; Animals; Anisomycin - pharmacology; Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cloning, Molecular; COS Cells; Enzyme Activation; Gene Expression Regulation; Genetic Complementation Test; HeLa Cells; Humans; JNK Mitogen-Activated Protein Kinases; MAP kinase; MAP Kinase Kinase 3; MAP Kinase Kinase 4; MAP Kinase Kinase 6; MAP Kinase Kinase Kinase 4; MAP Kinase Kinase Kinases; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Molecular Sequence Data; Osmotic Pressure; p38 Mitogen-Activated Protein Kinases; Phosphorylation; protein kinase; Protein Kinases - chemistry; Protein Kinases - genetics; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - chemistry; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - metabolism; RNA, Messenger - analysis; Sequence Homology; signal transduction; stress response; Ultraviolet Rays
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/16.16.4973

A human homolog of the yeast Ssk2 and Ssk22 mitogen‐activated protein kinase kinase kinases (MAPKKK) was cloned by functional complementation of the osmosensitivity of the yeast ssk2Δ ssk22Δ sho1Δ triple mutant. This kinase, termed MTK1 (MAP Three Kinase 1), is 1607 amino acids long and is structurally highly similar to the yeast Ssk2 and Ssk22 MAPKKKs. In mammalian cells (COS‐7 and HeLa), MTK1 overexpression stimulated both the p38 and JNK MAP kinase pathways, but not the ERK pathway. MTK1 overexpression also activated the MKK3, MKK6 and SEK1 MAPKKs, but not the MEK1 MAPKK. Furthermore, MTK1 phosphorylated and activated MKK6 and SEK1 in vitro. Overexpression of a dominant‐negative MTK1 mutant [MTK1(K/R)] strongly inhibited the activation of the p38 pathway by environmental stresses (osmotic shock, UV and anisomycin), but not the p38 activation by the cytokine TNF‐α. The dominant‐negative MTK1(K/R) had no effect on the activation of the JNK pathway or the ERK pathway. These results indicate that MTK1 is a major mediator of environmental stresses that activate the p38 MAPK pathway, and is also a minor mediator of the JNK pathway.