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首页> 外文期刊>Cellular Signalling >Anti-apoptotic action of Wnt5a in dermal fibroblasts is mediated by the PKA signaling pathways
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Anti-apoptotic action of Wnt5a in dermal fibroblasts is mediated by the PKA signaling pathways

机译：Wnt5a在皮肤成纤维细胞中的抗凋亡作用是由PKA信号通路介导的

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Wnts are secreted glycoproteins that control diverse biological processes, such as proliferation, differentiation, and apoptosis. We here found that Wnt5a inhibited apoptosis induced by serum deprivation in primary-cultured human dermal fibroblasts. Anti-apoptotic activity of Wnt5a was not inhibited by a dickkopf-1 (DKK), which blocks the canonical Wnt pathway. On the other hand, loss of function of protein kinase A (PKA), induced by treatment with PKA inhibitors, siRNA-mediated knocking down of endogenous PKA catalytic subunits, or enforced expression of dominant-negative PKA inhibited the Wnt5a anti-apoptotic activity, indicating the involvement of PKA in the Wnt5a anti-apoptotic activity. In agreement, phosphorylation levels of a cAMP response element binding protein (CREB), a representative downstream effector of PKA, the activation of which is known to lead to the pro-survival effects, was elevated by Wnt5a. In addition, Wnt5a increased the nuclear beta-catenin level and treatment with imatinib or ionomycin, either of which blocks the beta-catenin pathway, reduced the anti-apoptotic activity of Wnt5a, together suggesting the simultaneous involvement of the beta-catenin-mediated pathway in the Wnt5a anti-apoptotic activity. Based on another finding indicating that Wnt5a upregulated PKA-mediated phosphorylation of glycogen synthase kinase-3 beta (GSK-3 beta) at serine 9 that caused inactivation of GSK-3 beta and subsequently resulted in activation of the beta-catenin pathway, we have speculated that the Wnt5a anti-apoptotic activity may be partially mediated by PKA-mediated phosphorylation of GSK-3 beta and subsequent activation of the beta-catenin pathway. (c) 2008 Elsevier Inc. All rights reserved.
机译：Wnt是分泌的糖蛋白，可控制多种生物过程，例如增殖，分化和凋亡。我们在这里发现Wnt5a抑制了原代培养的人真皮成纤维细胞中血清剥夺诱导的凋亡。 Dintkopf-1（DKK）不会抑制Wnt5a的抗凋亡活性，该蛋白会阻止经典的Wnt途径。另一方面，通过使用PKA抑制剂治疗，siRNA介导的内源PKA催化亚基的敲低或显性负PKA的强制表达诱导的蛋白激酶A（PKA）功能丧失，抑制了Wnt5a的抗凋亡活性，提示PKA参与Wnt5a抗凋亡活性。一致的是，Wnt5a提高了cAMP反应元件结合蛋白（CREB）的磷酸化水平，CREB是PKA的代表性下游效应物，其激活已知会导致促存活作用。此外，Wnt5a增加了核β-catenin的水平，并用伊马替尼或离子霉素治疗，两者均阻断了β-catenin途径，降低了Wnt5a的抗凋亡活性，这表明β-catenin介导的途径同时参与在Wnt5a中具有抗凋亡活性。基于另一个发现，该发现表明Wnt5a在丝氨酸9上调了PKA介导的糖原合酶激酶3 beta（GSK-3 beta）的磷酸化，导致GSK-3 beta失活，进而导致β-catenin途径活化，推测Wnt5a抗凋亡活性可能部分由PKA介导的GSK-3β磷酸化和随后的β-catenin途径激活介导。 （c）2008 Elsevier Inc.保留所有权利。

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