Negative regulation of MEKK1/2 signaling by Serine-Threonine kinase 38 (STK38)

A. Enomoto, N. Kido, M. Ito, A. Morita, Y. Matsumoto, N. Takamatsu, Y. Hosoi, K. Miyagawa

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1930-1938
Number of pages9
JournalOncogene
Volume27
Issue number13
DOIs
Publication statusPublished - 2008 Mar 20
Externally publishedYes

Keywords

  • MAPKKK
  • MEKK1
  • MEKK2
  • STK38
  • Signal transduction

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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  • Cite this

    Enomoto, A., Kido, N., Ito, M., Morita, A., Matsumoto, Y., Takamatsu, N., Hosoi, Y., & Miyagawa, K. (2008). Negative regulation of MEKK1/2 signaling by Serine-Threonine kinase 38 (STK38). Oncogene, 27(13), 1930-1938. https://doi.org/10.1038/sj.onc.1210828