Regulatory protein kinases are involved in various cellular processes such as proliferation, differentiation, and apoptosis. Using cDNA differential display, we identified MOK, a member of the mitogen-activated protein kinase superfamily, as one of the genes induced by a caudal-related homeobox transcription factor, Cdx2. Analysis of the 5'-flanking region of the MOK gene led to the identification of primary Cdx2 responsive element, and an electrophoretic mobility shift assay indicated that Cdx2 binds to that element. The interaction of Cdx2 with the MOK promoter region was further confirmed in vivo by chromatin immunoprecipitation assays. The expression of MOK mRNA and protein was limited to the crypt epithelial cells of the mouse intestine. We also determined the MOK activity associated with the growth arrest and induction of differentiation by sodium butyrate or Cdx2 expression in the human colon cancer cell line HT-29. Taken together, these data indicate that MOK is a direct target gene for Cdx2, and that MOK may be involved in growth arrest and differentiation in the intestinal epithelium.