Lysophosphatidic acid interacts with transforming growth factor-beta signaling to mediate keratinocyte growth arrest and chemotaxis.
Lysophosphatidic acid interacts with transforming growth factor-beta signaling to mediate keratinocyte growth arrest and chemotaxis.
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DOI：
10.1111/j.0022-202x.2004.23458.x
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发表时间：
2004-11
期刊：
影响因子：
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通讯作者：
B. Sauer;R. Vogler;K. Zimmermann;M. Fujii;M. Anzano;M. Schäfer-Korting;A. Roberts;B. Kleuser
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文献类型：
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作者：
B. Sauer;R. Vogler;K. Zimmermann;M. Fujii;M. Anzano;M. Schäfer-Korting;A. Roberts;B. Kleuser
溶血磷脂酸（LPA，1-酰基甘油-3-磷酸）在多种生物反应中发挥着重要作用，包括细胞增殖、分化、存活、迁移和肿瘤细胞侵袭。 LPA 最重要的来源是血小板，在凝血酶激活后从血小板中释放出来，并且被认为是这种溶血磷脂在皮肤伤口闭合中的基本功能。因此，我们研究了 LPA 对角质形成细胞生物反应的作用。虽然 LPA 能有效增强角质细胞迁移，但它会强烈诱导增殖表皮细胞的生长停滞。因此，LPA 具有与转化生长因子-β (TGF-β) 类似的作用，TGF-β 也是由受伤部位脱颗粒的血小板释放的。与 LPA 相比，TGF-β 的细胞内信号转导事件已被明确识别，并表明 Smad3 参与该细胞因子诱导的角质形成细胞的趋化性和细胞生长停滞。在这里，我们表明，LPA 虽然不会改变 TGF-β 的释放，但却能够激活 Smad3，并导致与 Smad4 的异聚化以及复合物与其特定 DNA 启动子元件的结合。 LPA 完全不能诱导 Smad3 缺陷细胞的趋化性，而生长抑制至少部分减弱。这些发现表明 Smad3 在 LPA 刺激的角质形成细胞的多种生物学特性中发挥着重要作用。
Lysophosphatidic acid (LPA, 1-acyl-glycerol-3-phosphate) plays an important role in diverse biological responses including cell proliferation, differentiation, survival, migration, and tumor cell invasion. The most prominent source of LPA is platelets from which it is released after thrombin activation and is assumed to be an essential function of this lysophospholipid in cutaneous wound closure. Therefore, we examined the role of LPA on biological responses of keratinocytes. Although LPA potently enhances keratinocyte migration, it strongly induces growth arrest of proliferating epidermal cells. Thus, LPA possesses analogous actions to transforming growth factor-beta (TGF-beta), which is also released from degranulating platelets at wounded sites. In contrast to LPA, the intracellular signaling events of TGF-beta have been clearly identified and indicate that Smad3 is involved in chemotaxis and cell growth arrest of keratinocytes induced by this cytokine. Here we show that LPA, although it does not alter TGF-beta release is capable to activate Smad3 and results in a heteromerization with Smad4 and binding of the complex to its specific DNA-promoter elements. LPA completely fails to induce chemotaxis in Smad3-deficient cells, whereas growth inhibition is at least in part reduced. These findings indicate an essential role of Smad3 in diverse biological properties of LPA-stimulated keratinocytes.