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首页> 外文期刊>Molecular and Cellular Biology >Transactivation of platelet-derived growth factor receptor alpha by the GTPase-deficient activated mutant of Galpha12.
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Transactivation of platelet-derived growth factor receptor alpha by the GTPase-deficient activated mutant of Galpha12.

机译：GTP酶缺陷激活的Galpha12突变体对血小板衍生生长因子受体α的反式激活。

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摘要

The GTPase-deficient, activated mutant of Galpha12 (Galpha12Q229L, or Galpha12QL) induces neoplastic growth and oncogenic transformation of NIH 3T3 cells. Using microarray analysis, we have previously identified a role for platelet-derived growth factor receptor alpha (PDGFRalpha) in Galpha12-mediated cell growth (R. N. Kumar et al., Cell Biochem. Biophys. 41:63-73, 2004). In the present study, we report that Galpha12QL stimulates the functional expression of PDGFRalpha and demonstrate that the expression of PDGFRalpha by Galpha12QL is dependent on the small GTPase Rho. Our results indicate that it is cell type independent as the transient expression of Galpha12QL or the activation of Galpha12-coupled receptors stimulates the expression of PDGFRalpha in NIH 3T3 as well as in human astrocytoma 1321N1 cells. Furthermore, we demonstrate the presence of an autocrine loop involving PDGF-A and PDGFRalpha in Galpha12QL-transformed cells. Analysis of the functional consequences of the Galpha12-PDGFRalpha signaling axis indicates that Galpha12 stimulates the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway through PDGFR. In addition, we show that Galpha12QL stimulates the phosphorylation of forkhead transcription factor FKHRL1 via AKT in a PDGFRalpha- and PI3K-dependent manner. Since AKT promotes cell growth by blocking the transcription of antiproliferative genes through the inhibitory phosphorylation of forkhead transcription factors, our results describe for the first time a PDGFRalpha-dependent signaling pathway involving PI3K-AKT-FKHRL1, regulated by Galpha12QL in promoting cell growth. Consistent with this view, we demonstrate that the expression of a dominant negative mutant of PDGFRalpha attenuated Galpha12-mediated neoplastic transformation of NIH 3T3 cells.
机译：GTP酶缺陷的Galpha12激活突变体（Galpha12Q229L或Galpha12QL）诱导NIH 3T3细胞的肿瘤生长和致癌转化。使用微阵列分析，我们之前已经确定了血小板衍生生长因子受体α（PDGFRalpha）在Galpha12介导的细胞生长中的作用（R. N. Kumar等人，Cell Biochem。生物物理学。41:63-73, 2004).在本研究中，我们报道了 Galpha12QL 刺激 PDGFRalpha 的功能表达，并证明 Galpha12QL 对 PDGFRalpha 的表达依赖于小 GTP 酶 Rho。我们的结果表明，它是细胞类型无关的，因为 Galpha12QL 的瞬时表达或 Galpha12 偶联受体的激活刺激 NIH 3T3 以及人星形细胞瘤 1321N1 细胞中 PDGFRalpha 的表达。此外，我们证明了在 Galpha12QL 转化的细胞中存在涉及 PDGF-A 和 PDGFRalpha 的自分泌环。对 Galpha12-PDGFRalpha 信号转导轴功能后果的分析表明，Galpha12 通过 PDGFR 刺激磷脂酰肌醇 3-激酶 （PI3K）-AKT 信号通路。此外，我们发现 Galpha12QL 以 PDGFRalpha 和 PI3K 依赖性方式通过 AKT 刺激叉头转录因子 FKHRL1 的磷酸化。由于AKT通过叉头转录因子的抑制性磷酸化阻断抗增殖基因的转录来促进细胞生长，因此我们的结果首次描述了涉及PI3K-AKT-FKHRL1的PDGFRα依赖性信号通路，该通路受Galpha12QL调控，促进细胞生长。与这一观点一致，我们证明 PDGFRα 显性阴性突变体的表达减弱了 Galpha12 介导的 NIH 3T3 细胞的肿瘤转化。

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