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.