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Serine/threonine kinase Mirk/Dyrk1B is an inhibitor of epithelial cell migration and is negatively regulated by the Met adaptor Ran-binding protein M.

Abstract
Minibrain-related kinase (Mirk)/Dyrk1B is an arginine-directed serine/threonine kinase that is active in skeletal muscle development but is also expressed in various carcinomas. In the current study, the Met adaptor protein Ran-binding protein M (RanBPM) was identified as a Mirk-binding protein by yeast two-hybrid analysis. The Mirk-RanBPM association was confirmed by glutathione S-transferase pull-down assays, co-immunoprecipitation studies, and in vivo cross-linking. Met plays an important role in tumor cell invasion and cell migration. RanBPM has been reported to bind to the tyrosine kinase domain of the hepatocyte growth factor (HGF) receptor Met, enhance Met downstream signaling, and enhance HGF-induced A704 kidney carcinoma cell invasion (Wang, D., Li, Z., Messing, E. M., and Wu, G. (2002) J. Biol. Chem. 277, 36216-36222). We made a stable Mirk-inducible subline from nontransformed Mv1Lu lung epithelial cells and now demonstrate that induction of Mirk inhibited the migration of these cells in wounding experiments and inhibited their invasion through polycarbonate Transwell filters. Furthermore the ability of Mirk to inhibit Mv1Lu cell migration was attenuated when cells were exposed to HGF or to elevated levels of transiently expressed RanBPM. RanBPM inhibited the kinase activity of Mirk/Dyrk1B and Dyrk1A. In addition, RanBPM and HGF inhibited the function of Mirk as a transcriptional coactivator. Our findings suggest that Mirk plays a role in modulating cell migration through opposing the action of the Met signaling cascade adaptor protein RanBPM.
AuthorsYonglong Zou, Seunghwan Lim, Kangmoon Lee, Xiaobing Deng, Eileen Friedman
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 49 Pg. 49573-81 (Dec 05 2003) ISSN: 0021-9258 [Print] United States
PMID14500717 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • Nuclear Proteins
  • Ran binding protein 9
  • Trans-Activators
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • ran GTP-Binding Protein
Topics
  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Cell Movement (physiology)
  • Cytoskeletal Proteins
  • Epithelial Cells (cytology)
  • Humans
  • Nuclear Proteins (physiology)
  • Protein Serine-Threonine Kinases (physiology)
  • Protein-Tyrosine Kinases (physiology)
  • Trans-Activators (physiology)
  • Transcription, Genetic (physiology)
  • Two-Hybrid System Techniques
  • ran GTP-Binding Protein (physiology)

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