Induction of tyrosine phosphorylation occurs as an early and specific event in keratinocyte differentiation. A set of tyrosine-phosphorylated
substrates which transduce mitogenic signals by tyrosine kinases has previously been identified. We show here that of these
substrates, the Ras GTPase-activating protein, GAP, is specifically affected during calcium-induced keratinocyte differentiation.
As
... [Show full abstract] early as 10 min after calcium addition to cultured primary mouse keratinocytes, GAP associates with tyrosine-phosphorylated
proteins and translocates to the membrane. In addition, a GAP-associated protein of approximately 62 kDa (p62) becomes rapidly
and heavily tyrosine phosphorylated in both membrane and cytosolic fractions. This protein corresponds to the major tyrosine-phosphorylated
protein that is induced in differentiating keratinocytes as early as 5 min after calcium addition. p62 phosphorylation was
not observed after exposure of these cells to epidermal growth factor, phorbol ester, or transforming growth factor beta.
In contrast, PLC gamma and P13K were tyrosine phosphorylated after epidermal growth factor, but not calcium, stimulation.
Thus, changes of Ras GAP and an associated p62 protein occur as early and specific events in keratinocyte differentiation
and appear to involve a calcium-induced tyrosine kinase.