Extracellular UDP-Glucose Activates P2Y14 Receptor and Induces Signal Transducer and Activator of Transcription 3 (STAT3) Tyr705 Phosphorylation and Binding to Hyaluronan Synthase 2 (HAS2) Promoter, Stimulating Hyaluronan Synthesis of Keratinocytes
Extracellular UDP-Glucose Activates P2Y14 Receptor and Induces Signal Transducer and Activator of Transcription 3 (STAT3) Tyr705 Phosphorylation and Binding to Hyaluronan Synthase 2 (HAS2) Promoter, Stimulating Hyaluronan Synthesis of Keratinocytes
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DOI：
10.1074/jbc.m114.551804
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发表时间：
2014-06-27
影响因子：
4.8
通讯作者：
Tammi, Markku I.
中科院分区：
文献类型：
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作者：
Jokela, Tiina A.;Karna, Riikka;Tammi, Markku I.
透明质酸是表皮中的一种主要基质分子，经常在促进角质形成细胞增殖和迁移的刺激下增加。我们发现角质形成细胞可以释放少量的UDP-糖，并且在角质形成细胞培养中加入UDP-葡萄糖(UDP-GLC)可以特异性地、快速地诱导透明质酸合成酶2(HAS2)，并增加透明质酸的合成。HAS2的上调与JAK2和ERK1/2的激活以及转录因子STAT3的特异性Tyr(705)磷酸化有关。JAK2、STAT3或G(I)偶联受体的抑制阻断了UDP-GLC对HAS2表达的诱导，后者的抑制表明该信号是由UDP-糖受体P2Y(14)触发的。染色质免疫沉淀显示在HAS2诱导时Tyr(P)(705)-STAT3的启动子结合增加。有趣的是，同时，Ser(P)(727)-STAT3与其在HAS2启动子中的反应元件区域的结合没有改变或减少。UDP-GLC还刺激角质形成细胞迁移、增殖和IL-8的表达，支持UDP-GLC是表皮炎症的信号，促进透明质酸合成是其不可或缺的一部分。
Hyaluronan, a major matrix molecule in epidermis, is often increased by stimuli that enhance keratinocyte proliferation and migration. We found that small amounts of UDP-sugars were released from keratinocytes and that UDP-glucose (UDP-Glc) added into keratinocyte cultures induced a specific, rapid induction of hyaluronan synthase 2 (HAS2), and an increase of hyaluronan synthesis. The up-regulation of HAS2 was associated with JAK2 and ERK1/2 activation, and specific Tyr(705) phosphorylation of transcription factor STAT3. Inhibition of JAK2, STAT3, or G(i)-coupled receptors blocked the induction of HAS2 expression by UDP-Glc, the latter inhibitor suggesting that the signaling was triggered by the UDP-sugar receptor P2Y(14). Chromatin immunoprecipitations demonstrated increased promoter binding of Tyr(P)(705)-STAT3 at the time of HAS2 induction. Interestingly, at the same time Ser(P)(727)-STAT3 binding to its response element regions in the HAS2 promoter was unchanged or decreased. UDP-Glc also stimulated keratinocyte migration, proliferation, and IL-8 expression, supporting a notion that UDP-Glc signals for epidermal inflammation, enhanced hyaluronan synthesis as an integral part of it.