Mirk protein kinase is activated by MKK3 and functions as a transcriptional activator of HNF1α

Seunghwan Lim, Kideok Jin, Eileen Friedman

Research output: Contribution to journalArticlepeer-review

Abstract

Mirk/Dyrk1B is an arginine-directed serine/threonine protein kinase that is expressed at low levels in most normal tissues but at elevated levels in many tumor cell lines and in normal skeletal muscle. Colon carcinoma cell lines stably overexpressing Mirk proliferated in serum-free medium, but the mechanism of Mirk action is unknown. DCoHm (dimerization cofactor of hepatocyte nuclear factor la (HNF1α) from muscle), a novel gene of the DCoH family with 78% amino acid identity to DCoH, was identified as a Mirk-binding protein by yeast two-hybrid analysis and cloned. Mirk co-immunoprecipitated with DCoHm and bound to DCoHm in glutathione S-transferase pull-down assays. DCoH stabilizes HNF1α as a dimer and enhances its transcriptional activity on the β-fibrinogen promoter reporter, and DCoHm had similar activity. Mirk enhanced HNF1α transcriptional activity in a dose-dependent manner, whereas two kinase-inactive Mirk mutants and a Mirk N-terminal deletion mutant did not. Mirk, DCoHm, and HNF1α formed a complex. Mirk bound to a specific region within the CREB-binding protein-binding region of HNF1α and phosphorylated HNF1α at a site adjacent to the Mirk-binding region. Conversely, the HNF1α binding domain was located within the first five conserved kinase subdomains of Mirk. Mirk co-immunoprecipitated with the MAPK kinase MKK3, an upstream activator of p38. MKK3 enhanced Mirk kinase activity and the transcriptional activation of HNF1α by Mirk, suggesting that Mirk, like p38, is activated by certain environmental stress agents. The Mirk-binding protein DCoH has been shown to be selectively expressed in colon carcinomas but not in normal tissue. Mirk may function as an HNF1α transcriptional activator in response to an MKK3-mediated stress signal, and the selective expression of DCoH could restrict the Mirk response to carcinoma cells.

Original languageEnglish (US)
Pages (from-to)25040-25046
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number28
DOIs
StatePublished - Jul 12 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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