A portion of the catalytic domain of a novel tyrosine kinase was cloned from mouse intestinal crypt cells, in a screen designed to identify kinases that may play a role in the regeneration of the intestinal epithelium (E Siyanova, MS Serfas, IA Mazo and AL Tyner, Oncogene 9, 2053-2057). We have cloned a cDNA encoding this kinase, termed sik for src-related intestinal kinase. The sik cDNA encodes a 451 amino acid protein that shares 80% identity with the recently cloned human tyrosine kinase, brk. Sequences found in src family kinases, such as SH2 and SH3 domains and a putative regulatory tyrosine at the carboxy terminus are found in the sik kinase. In contrast, sik lacks a myristylation site. The protein encoded by the sik cDNA has tyrosine kinase activity when expressed in E. coli. We have determined that sik is expressed only in epithelial tissues, including the skin and lining of the alimentary canal, and using in situ hybridization we show that expression of sik mRNA is restricted to the cell layers immediately above the proliferative cell zone in these epithelia. The sik mRNA is first detected at day 15.5 of gestation in the mouse embryo, where it is expressed in the newly forming granular layer of the skin. The restricted expression of sik to differentiating cells of rapidly renewing epithelia suggests that sik may play a specialized role in these tissues.