FYN TYROSINE KINASE IS INVOLVED IN KERATINOCYTE DIFFERENTIATION CONTROL

Induction of tyrosine phosphorylation is an early and specific event w hich is required for mouse keratinocyte differentiation to occur, in r esponse to both calcium and TPA (12-O-tetradecanoylphorbol-13-acetate) . We report here that there is an increase of tyrosine kinase activity immunoprecipitable with anti-phospho tyrosine antibodies specifically in response to calcium-and a number of other divalent cations-within 2 min of exposure. Such an activity does not correspond to any of the known tyrosine kinases that were tested. A second tyrosine kinase acti vity is induced in response to both calcium and TPA, and has been iden tified as fyn, a nonreceptor tyrosine kinase of the src family. fyn ac tivation is induced in keratinocytes within 6 hr of calcium exposure, but already within 2 min of TPA treatment. Cortactin, a p80-85 substra te of src- and fyn-related kinases that localizes with actin at cell a dhesion sites, is increasingly tyrosine phosphorylated in calcium- and TPA-induced differentiation, with a time course which parallels that of fyn activation. Keratinocytes with a specific disruption of the fyn , but not yes kinase gene show no induction of phosphorylation of p80- 85 proteins, and are significantly altered in their differentiation re sponse both in vitro and in vivo. Thus, at least two tyrosine kinase a ctivities are induced in keratinocyte differentiation, one of which ha s been identified as fyn and shown to be specifically involved in this process.