Negative regulation of MEKK1/2 signaling by serine-threonine kinase 38 (STK38).
Mitogen-activated protein kinases (MAPKs) are activated through the kinase cascades of MAPK, MAPK kinase (MAPKK) and MAPKK kinase (MAPKKK). MAPKKKs phosphorylate and activate their downstream MAPKKs, which in turn phosphorylate and activate their downstream MAPKs. MAPKKK proteins relay upstream signals through the MAPK cascades to induce cellular responses. However, the molecular mechanisms by which given MAPKKKs are regulated remain largely unknown. Here, we found that serine-threonine protein kinase 38, STK38, physically interacts with the MAPKKKs MEKK1 and MEKK2 (MEKK1/2). The carboxy terminus, including the catalytic domain, but not the amino terminus of MEKK1/2 was necessary for the interaction with STK38. STK38 inhibited MEKK1/2 activation without preventing MEKK1/2 binding to its substrate, SEK1. Importantly, STK38 suppressed the autophosphorylation of MEKK2 without interfering with MEKK2 dimer formation, and converted MEKK2 from its phosphorylated to its nonphosphorylated form. The negative regulation of MEKK1/2 was not due to its phosphorylation by STK38. On the other hand, stk38 short hairpin RNA enhanced sorbitol-induced activation of MEKK2 and phosphorylation of the downstream MAPKKs, MKK3/6. Taken together, our results indicate that STK38 negatively regulates the activation of MEKK1/2 by direct interaction with the catalytic domain of MEKK1/2, suggesting a novel mechanism of MEKK1/2 regulation.
Enomoto
A
A
Section of Radiation Biology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. aenomoto@m.u-tokyo.ac.jp
Kido
N
N
Ito
M
M
Morita
A
A
Matsumoto
Y
Y
Takamatsu
N
N
Hosoi
Y
Y
Miyagawa
K
K
D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D019281:Dimerization; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D007202:Indicators and Reagents / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048730:MAP Kinase Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D013012:Sorbitol / Q000494:pharmacology
D007202:Indicators and Reagents; D034741:RNA, Small Interfering; D013012:Sorbitol; D017346:Protein Serine-Threonine Kinases; C491614:STK38 protein, human; D048728:MAP Kinase Kinase Kinase 1; D048730:MAP Kinase Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases; C482576:MAP3K1 protein, human; C482618:MAP3K2 protein, human; D048670:MAP Kinase Kinase 4