V. Vasioukhin et Al. Tyner, A ROLE FOR THE EPITHELIAL-CELL-SPECIFIC TYROSINE KINASE SIK DURING KERATINOCYTE DIFFERENTIATION, Proceedings of the National Academy of Sciences of the United Statesof America, 94(26), 1997, pp. 14477-14482
Sik, the mouse homologue of the breast tumor kinase Brk, is expressed
in differentiating cells of the gastrointestinal tract and skin. We ex
amined expression and activity of Sik in primary mouse keratinocytes a
nd a mouse embryonic keratinocyte cell line (EMK). Calcium-induced dif
ferentiation of these cells has been shown to be accompanied by the ac
tivation of tyrosine kinases and rapid phosphorylation of a 65-kDa GTP
ase-activating protein (GAP)-associated protein (GAP-A.p65). We demons
trate that Sik is activated within 2 min after calcium addition in pri
mary keratinocytes and EMK cells. In EMK cells, Sik binds GAP-A.p65, a
nd this interaction is mediated by the Sik Src homology 2 domain. Alth
ough Sik directly complexes with GAP-A.p65, overexpression of wild-typ
e or kinase defective Sik in EMK cells does not lead to detectable cha
nges in GAP-A.p65 phosphorylation. These data suggest that Sik is not
responsible for phosphorylation of GAP-A.p65. GAP-A.p65 may act as an
adapter protein, bringing Sik into proximity of an unidentified substr
ate. Overexpression of Sik in EMK cells results in increased expressio
n of filaggrin during differentiation, supporting a role for Sik in di
fferentiation.