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First published online 17 January 2006
doi: 10.1242/jcs.02744

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The role of protein kinase C activation and STAT3 Ser727 phosphorylation in insulin-induced keratinocyte proliferation

¹ Faculty of Life Sciences, Bar Ilan University, Ramat-Gan, 52900 Israel
² Department of Dermatology, Ehime University School of Medicine, Onsen-gun, Ehime 791-0295, Japan
³ Osaka University Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka 545-8585, Japan
⁴ Gifu University, Yanagido 1-1, Gifu 501-1193, Japan

^* Author for correspondence (e-mail: tennet{at}mail.biu.ac.il)

Accepted 3 October 2005

Activation of the STAT family of transcription factors is regulated by cytokines and growth factors. STAT tyrosine and serine phosphorylation are linked to the transcriptional activation and function of STAT. We have previously described a unique pathway inducing keratinocyte proliferation, which is mediated by insulin stimulation and depends on protein kinase C (PKC). In this study, we assessed STAT3 activation downstream of this pathway and characterized the role of PKC activation in STAT3 tyrosine and serine phosphorylation and keratinocyte proliferation. Following insulin stimulation, STAT3 interacted with PKC but not with any other PKC isoform expressed in skin. Activated forms of PKC and STAT3 were essential for insulin-induced PKC-STAT3 activation in keratinocyte proliferation. Abrogation of PKC activity inhibited insulin-induced STAT3 phosphorylation, PKC-STAT3 association and nuclear translocation. In addition, overexpression of STAT3 tyrosine mutant eliminated insulin-induced PKC activation and keratinocyte proliferation. Finally, overexpression of a STAT3 serine mutant abrogated insulin-induced STAT3 serine phosphorylation and STAT3-induced keratinocyte proliferation, whereas STAT3 tyrosine phosphorylation was induced and nuclear localization remained intact. This study indicates that PKC activation is a primary regulator of STAT3 serine phosphorylation and that PKC is essential in directing insulin-induced signaling in keratinocyte proliferation.

Key words: STAT3, PKC, Tyrosine phosphorylation, Serine phosphorylation, Keratinocyte, Proliferation

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