The role of protein kinase C δ activation and STAT3 Ser727 phosphorylation in insulin-induced keratinocyte proliferation
The role of protein kinase C δ activation and STAT3 Ser727 phosphorylation in insulin-induced keratinocyte proliferation
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DOI：
10.1242/jcs.02744
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发表时间：
2006-02-01
影响因子：
4
通讯作者：
Tennenbaum, T
中科院分区：
文献类型：
--
作者：
Gartsbein, M;Alt, A;Tennenbaum, T
STAT家族转录因子的激活受细胞因子和生长因子调节。STAT酪氨酸和丝氨酸磷酸化与STAT的转录激活和功能有关。我们以前描述了一个独特的途径诱导角质形成细胞增殖，这是由胰岛素刺激介导的，并依赖于蛋白激酶C8（PKC δ）。在这项研究中，我们评估了该途径下游的STAT 3激活，并表征了PKC δ激活在STAT 3酪氨酸和丝氨酸磷酸化以及角质形成细胞增殖中的作用。胰岛素刺激后，STAT 3与PKC delta相互作用，但不与皮肤中表达的任何其他PKC亚型相互作用。PKC δ和STAT 3的活化形式对于角质形成细胞增殖中胰岛素诱导的PKC δ-STAT 3活化是必需的。PKC δ活性的消除抑制胰岛素诱导的STAT 3磷酸化、PKC δ-STAT 3缔合和核转位。此外，STAT 3酪氨酸突变体的过表达消除了胰岛素诱导的PKCS活化和角质形成细胞增殖。最后，过表达的STAT 3丝氨酸突变废除胰岛素诱导的STAT 3丝氨酸磷酸化和STAT 3诱导的角质形成细胞增殖，而STAT 3酪氨酸磷酸化诱导和核定位保持完整。这项研究表明PKCS激活是STAT 3丝氨酸磷酸化的主要调节因子，并且PKC delta在引导角质形成细胞增殖中胰岛素诱导的信号传导中至关重要。
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 8 (PKC delta). In this study, we assessed STAT3 activation downstream of this pathway and characterized the role of PKC delta activation in STAT3 tyrosine and serine phosphorylation and keratinocyte proliferation. Following insulin stimulation, STAT3 interacted with PKC delta but not with any other PKC isoform expressed in skin. Activated forms of PKC delta and STAT3 were essential for insulin-induced PKC delta-STAT3 activation in keratinocyte proliferation. Abrogation of PKC delta activity inhibited insulin-induced STAT3 phosphorylation, PKC delta-STAT3 association and nuclear translocation. In addition, overexpression of STAT3 tyrosine mutant eliminated insulin-induced PKCS 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 PKCS activation is a primary regulator of STAT3 serine phosphorylation and that PKC delta is essential in directing insulin-induced signaling in keratinocyte proliferation.