PKCδ activation: A divergence point in the signaling of insulin and IGF-1-induced proliferation of skin keratinocytes

Shlomzion Shen, Addy Alt, Efrat Wertheimer, Marina Gartsbein, Toshio Kuroki, Motoi Ohba, Liora Braiman, Sanford R. Sampson, Tamar Tennenbaum

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


Insulin and insulin-like growth factor-1 (IGF-1) are members of the family of the insulin family of growth factors, which activate similar cellular downstream pathways. In this study, we analyzed the effects of insulin and IGF-1 on the proliferation of murine skin keratinocytes in an attempt to determine whether these hormones trigger the same signaling pathways. Increasing doses of insulin and IGF-1 promote keratinocyte proliferation in an additive manner. We identified downstream pathways specifically involved in insulin signaling that are known to play a role in skin physiology; these include activation of the Na+/K+ pump and protein kinase C (PKC). Insulin, but not IGF-1, stimulated Na+/K+ pump activity. Furthermore, ouabain, a specific Na+/K+ pump inhibitor, abolished the proliferative effect of insulin but not that of IGF-1. Insulin and IGF-1 also differentially regulated PKC activation. Insulin, but not IGF-1, specifically activated and translocated the PKCδ isoform to the membrane fraction. There was no effect on PKC isoforms α, η, ε, and ζ, which are expressed in skin. PKCδ overexpression increased keratinocyte proliferation and Na+/K+ pump activity to a degree similar to that induced by insulin but had no affect on IGF-1-induced proliferation. Furthermore, a dominant negative form of PKCδ abolished the effects of insulin on both proliferation and Na+/K+ pump activity but did not abrogate induction of keratinocyte proliferation induced by other growth factors. These data indicate that though insulin or IGF-1 stimulation induce keratinocyte proliferation, only insulin action is specifically mediated via PKCδ and involves activation of the Na+/K+ pump.

Original languageEnglish
Pages (from-to)255-264
Number of pages10
Issue number2
StatePublished - Feb 2001


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