Abstract
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 delta (PKCdelta). In this study, we assessed STAT3 activation downstream of this pathway and characterized the role of PKCdelta activation in STAT3 tyrosine and serine phosphorylation and keratinocyte proliferation. Following insulin stimulation, STAT3 interacted with PKCdelta but not with any other PKC isoform expressed in skin. Activated forms of PKCdelta and STAT3 were essential for insulin-induced PKCdelta-STAT3 activation in keratinocyte proliferation. Abrogation of PKCdelta activity inhibited insulin-induced STAT3 phosphorylation, PKCdelta-STAT3 association and nuclear translocation. In addition, overexpression of STAT3 tyrosine mutant eliminated insulin-induced PKCdelta 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 PKCdelta activation is a primary regulator of STAT3 serine phosphorylation and that PKCdelta is essential in directing insulin-induced signaling in keratinocyte proliferation.
Highlights
STATs are cytoplasmic proteins that function as transcriptional activators
The role of STAT3 in signaling of keratinocyte proliferation In previous studies, we identified a unique pathway involved in mediating insulin action in keratinocytes
This pathway uses the activation of protein kinase C (PKC)␦ as a crucial signaling factor downstream of insulin to induce keratinocyte proliferation
Summary
STATs (signal transducers and activators of transcription) are cytoplasmic proteins that function as transcriptional activators. Seven STAT family members have been identified including: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6 (Akira, 1999; Akira, 2000; Horvath, 2000; Levy and Darnell, 2002). The use of isoform-specific transgenic knockout mouse models defined discreet physiological roles for each of the STAT family members. Among the seven known STAT proteins, STAT3 is unique. The importance of STAT3 for specific organ development was confirmed by experiments in which STAT3 expression was conditionally ablated in defined organs (Bromberg and Darnell, 2000; Sano et al, 2000; Takeda et al, 1997; Wen and Darnell, 1997). STAT3 has a specialized role in skin development. In the absence of STAT3 expression, both skin remodeling and hair cycle progression are severely disrupted (Sano et al, 1999; Sano et al, 2000)
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