The insulin receptor and the insulin-like growth factor-1 receptor are widely expressed tyrosine kinases that mediate insulin and insulin-like growth factor-1 signaling. Both receptors are expressed in many cells in which insulin stimulation does not result in an increase in glucose transport, and the distinct role of the insulin receptor in these tissues, is not known. We have studied the regulation of insulin receptor and insulin-like growth factor-1 receptor in the differentiation of cultured murine keratinocytes. Both receptors are expressed in skin keratinocytes and their expression was unchanged in all stages of calcium-induced differentiation. Insulin binding to skin keratinocytes, however, increased during calcium-induced differentiation, whereas insulin-like growth factor-1 binding decreased. Ligand-induced autophosphorylation was also changed during differentiation. In proliferating keratinocytes both receptors became phosphorylated upon ligand binding, insulin-like growth factor-1 receptor to a greater extent. Terminal differentiation resulted in a decrease in insulin receptor autophosphorylation, whereas insulin-like growth factor-1 receptor autophosphorylation was abolished. There was no change in the cellular localization of the proteins, their intrinsic activity, or their internal structure. Finally, due to the change in the receptor's activity during keratinocyte differentiation, the role of insulin and insulin-like growth factor-1 in the differentiation process was examined. The expected increase in the expression of keratins 1 and 10 during calcium-induced differentiation was facilitated in the presence of insulin, whereas this induction was inhibited in the presence of insulin-like growth factor-1. In conclusion, these results demonstrate that insulin and insulin-like growth factor-1 signaling pathways are differentially involved in skin differentiation, suggesting that abnormal insulin signaling, as occurs in diabetes, may lead to skin pathology.
