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首页> 外文期刊>Cellular Signalling >P2Y(12) receptor signalling towards PKB proceeds through IGF-I receptor cross-talk and requires activation of Src, Pyk2 and Rap1
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P2Y(12) receptor signalling towards PKB proceeds through IGF-I receptor cross-talk and requires activation of Src, Pyk2 and Rap1

机译：向PKB的P2Y（12）受体信号通过IGF-I受体串扰进行并需要激活Src，Pyk2和Rap1

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摘要

Previously it was shown that stimulation of the P2Y(12) receptor activates PKB signalling in C6 glioma cells (K. Van Kolen and H. Slegers, J. Neurochem. 89, 442.]. In the present study, the mechanisms involved in this response were further elucidated. In cells transfected with the G beta gamma-scavenger beta-ARK1/GRK2 or Rap1GAII, stimulation with 2MeSADP failed to enhance PKB phosphorylation demonstrating that the signalling proceeds through G beta gamma-subunits and Rap1. Moreover, Rap1-GTP pull-down assays revealed that P2Y12 receptor stimulation induced a rapid activation of Rap1. Treatment of cells with the Ca2+ chelator BAPTA-AM and inhibition of Src and PLD2 with PP2 or 1-butanol, respectively, abrogated P2Y12 receptor-mediated activation of Rap1 and PKB. In addition inhibition of PKC zeta decreased basal and 2MeSADP-stimulated phosphorylation of PKB indicating a role for this PKC isoform in PKB signalling. Although the increased PKB phosphorylation was abolished in the presence of the IGF-I receptor tyrosine kinase inhibitor AG 1024, 2MeSADP did not significantly increase receptor phosphorylation. Nevertheless, phosphorylation of a 120 kDa IGF-I receptor-associated protein was observed. The latter protein was identified by MALDI-TOF/TOF-MS as the proline-rich tyrosine kinase 2 (Pyk2) that co-operates with Src in a PLD2-dependent manner. Consistent with the signalling towards Rap1 and PKB, activation of Pyk2 was abrogated by Ca2+ chelation, inhibition of PLD2 and IGF-I receptor tyrosine kinase activity. In conclusion, the data reveal a novel type of cross-talk between P2Y(12), and IGF-I receptors that proceeds through G beta gamma-, Ca2+-and PLD2-dependent activation of the Pyk2/Src pathway resulting in GTP-loading of Rap1 required for an increased PKB phosphorylation. (c) 2005 Elsevier Inc. All rights reserved.
机译：以前显示刺激P2Y（12）受体可激活C6胶质瘤细胞中的PKB信号传导（K. Van Kolen和H.Slegers，J. Neurochem。89，442.]。在本研究中，参与该机制的机制在转染了Gβγ-清除剂β-ARK1/ GRK2或Rap1GAII的细胞中，用2MeSADP刺激不能增强PKB磷酸化，表明信号通过Gβγ-亚基和Rap1进行。下拉测定法显示P2Y12受体刺激可诱导Rap1的快速活化，分别用Ca2 +螯合剂BAPTA-AM处理细胞和分别用PP2或1-丁醇抑制Src和PLD2，可废除P2Y12受体介导的Rap1和Rap1活化。此外，对PKC zeta的抑制降低了基础和2MeSADP刺激的PKB磷酸化，表明该PKC同工型在PKB信号传导中的作用尽管存在时消除了增加的PKB磷酸化在IGF-1受体酪氨酸激酶抑制剂AG 1024中，2MeSADP没有显着增加受体磷酸化。然而，观察到120kDa IGF-1受体相关蛋白的磷酸化。后者被MALDI-TOF / TOF-MS鉴定为富含脯氨酸的酪氨酸激酶2（Pyk2），可与Src以PLD2依赖性方式协同作用。与针对Rap1和PKB的信号传导一致，Pyk2的激活被Ca2 +螯合，PLD2和IGF-1受体酪氨酸激酶活性的抑制所废除。总之，数据揭示了P2Y（12）与IGF-I受体之间的新型串扰，这种相互作用是通过Pyk2 / Src途径的G betaγ-，Ca2 +-和PLD2依赖性激活而进行的，从而导致GTP负载Pap磷酸化所需的Rap1片段数。 （c）2005 Elsevier Inc.保留所有权利。

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