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首页> 外文期刊>Molecular and Cellular Biology >Bradykinin B2 Receptor-Mediated Mitogen-Activated Protein Kinase Activation in COS-7 Cells Requires Dual Signaling via Both Protein Kinase C Pathway and Epidermal Growth Factor Receptor Transactivation
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Bradykinin B2 Receptor-Mediated Mitogen-Activated Protein Kinase Activation in COS-7 Cells Requires Dual Signaling via Both Protein Kinase C Pathway and Epidermal Growth Factor Receptor Transactivation

机译：缓激肽B2受体介导的COS-7细胞中丝裂原激活的蛋白激酶激活需要通过蛋白激酶C途径和表皮生长因子受体反式激活的双重信号

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The signaling routes linking G-protein-coupled receptors to mitogen-activated protein kinase (MAPK) may involve tyrosine kinases, phosphoinositide 3-kinase γ (PI3Kγ), and protein kinase C (PKC). To characterize the mitogenic pathway of bradykinin (BK), COS-7 cells were transiently cotransfected with the human bradykinin B2receptor and hemagglutinin-tagged MAPK. We demonstrate that BK-induced activation of MAPK is mediated via the α subunits of a Gq/11 protein. Both activation of Raf-1 and activation of MAPK in response to BK were blocked by inhibitors of PKC as well as of the epidermal growth factor (EGF) receptor. Furthermore, in PKC-depleted COS-7 cells, the effect of BK on MAPK was clearly reduced. Inhibition of PI3-Kγ or Src kinase failed to diminish MAPK activation by BK. BK-induced translocation and overexpression of PKC isoforms as well as coexpression of inactive or constitutively active mutants of different PKC isozymes provided evidence for a role of the diacylglycerol-sensitive PKCs α and ? in BK signaling toward MAPK. In addition to PKC activation, BK also induced tyrosine phosphorylation of EGF receptor (transactivation) in COS-7 cells. Inhibition of PKC did not alter BK-induced transactivation, and blockade of EGF receptor did not affect BK-stimulated phosphatidylinositol turnover or BK-induced PKC translocation, suggesting that PKC acts neither upstream nor downstream of the EGF receptor. Comparison of the kinetics of PKC activation and EGF receptor transactivation in response to BK also suggests simultaneous rather than consecutive signaling. We conclude that in COS-7 cells, BK activates MAPK via a permanent dual signaling pathway involving the independent activation of the PKC isoforms α and ? and transactivation of the EGF receptor. The two branches of this pathway may converge at the level of the Ras-Raf complex.
机译：将G蛋白偶联受体连接到丝裂原活化蛋白激酶（MAPK）的信号传导途径可能涉及酪氨酸激酶，磷酸肌醇3激酶γ（PI3Kγ）和蛋白激酶C（PKC）。为了表征缓激肽（BK）的促有丝分裂途径，将COS-7细胞与人缓激肽B 2 受体和血凝素标记的MAPK瞬时共转染。我们证明BK诱导的MAPK激活是通过G q / 11 蛋白的α亚基介导的。 Raf-1激活和响应BK的MAPK激活均被PKC抑制剂和表皮生长因子（EGF）受体阻断。此外，在PKC耗尽的COS-7细胞中，BK对MAPK的作用明显降低。 PI3-Kγ或Src激酶的抑制未能减少BK激活MAPK的作用。 BK诱导的PKC同工型的易位和过度表达以及不同PKC同工酶的无活性或组成型活性突变体的共表达为二酰基甘油敏感性PKCα和α的作用提供了证据。在BK信号转导MAPK。除PKC激活外，BK还诱导COS-7细胞中EGF受体的酪氨酸磷酸化（反式激活）。抑制PKC不会改变BK诱导的反式激活，对EGF受体的阻断也不会影响BK刺激的磷脂酰肌醇的转换或BK诱导的PKC易位，这表明PKC既不作用于EGF受体的上游，也不作用于下游。响应BK的PKC激活和EGF受体反式激活的动力学比较也表明是同时而不是连续的信号传导。我们得出结论，在COS-7细胞中，BK通过涉及PKC亚型α和β的独立激活的永久双重信号通路激活MAPK。和EGF受体的反式激活。该途径的两个分支可能会在Ras-Raf复合体的水平会聚。

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