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首页> 外文期刊>Molecular and Cellular Biology >Phosphorylation of tyrosine 720 in the platelet-derived growth factor alpha receptor is required for binding of Grb2 and SHP-2 but not for activation of Ras or cell proliferation.
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Phosphorylation of tyrosine 720 in the platelet-derived growth factor alpha receptor is required for binding of Grb2 and SHP-2 but not for activation of Ras or cell proliferation.

机译：血小板衍生的生长因子α受体中酪氨酸720的磷酸化对于Grb2和SHP-2的结合是必需的，但对于Ras的激活或细胞增殖则不是。

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Following binding of platelet-derived growth factor (PDGF), the PDGF alpha receptor (alphaPDGFR) becomes tyrosine phosphorylated and associates with a number of signal transduction molecules, including phospholipase Cgamma-1 (PLCgamma-1), phosphatidylinositol 3-kinase (PI3K), the phosphotyrosine phosphatase SHP-2, Grb2, and Src. Here, we present data identifying a novel phosphorylation site in the kinase insert domain of the alphaPDGFR at tyrosine (Y) 720. We replaced this residue with phenylalanine and expressed the mutated receptor (F720) in Patch fibroblasts that do not express the alphaPDGFR. Characterization of the F720 mutant indicated that binding of two proteins, SHP-2 and Grb2, was severely impaired, whereas PLCgamma-1 and PI3K associated to wild-type levels. In addition, mutating Y720 to phenylalanine dramatically reduced PDGF-dependent tyrosine phosphorylation of SHP-2. Since Y720 was required for recruitment of two proteins, we investigated the mechanism by which these two proteins associated with the alphaPDGFR. SHP-2 bound the alphaPDGFR directly, whereas Grb2 associated indirectly, most probably via SHP-2, as Grb2 and SHP-2 coimmunoprecipitated when SHP-2 was tyrosine phosphorylated. We also compared the ability of the wild-type and F720 alphaPDGFRs to mediate a number of downstream events. Preventing the alphaPDGFR from recruiting SHP-2 and Grb2 did not compromise PDGF-AA-induced activation of Ras, initiation of DNA synthesis, or growth of cells in soft agar. We conclude that phosphorylation of the alphaPDGFR at Y720 is required for association of SHP-2 and Grb2 and tyrosine phosphorylation of SHP-2; however, these events are not required for the alphaPDGFR to activate Ras or initiate a proliferative response. In addition, these findings reveal that while SHP-2 binds to both of the receptors, it binds in different locations: to the carboxy terminus of the betaPDGFR but to the kinase insert of the alphaPDGFR.
机译：结合血小板衍生生长因子（PDGF）后，PDGFα受体（alphaPDGFR）酪氨酸被磷酸化并与许多信号转导分子缔合，包括磷脂酶Cgamma-1（PLCgamma-1），磷脂酰肌醇3-激酶（PI3K） ，磷酸酪氨酸磷酸酶SHP-2，Grb2和Src。在这里，我们提供的数据确定了酪氨酸（Y）720在alphaPDGFR的激酶插入域中的一个新的磷酸化位点。我们用苯丙氨酸取代了这个残基，并在不表达alphaPDGFR的斑块成纤维细胞中表达了突变受体（F720）。 F720突变体的表征表明，两个蛋白质SHP-2和Grb2的结合受到严重损害，而PLCgamma-1和PI3K与野生型水平相关。此外，将Y720突变为苯丙氨酸可显着降低SHP-2的PDGF依赖性酪氨酸磷酸化。由于Y720是募集两种蛋白质所必需的，因此我们研究了这两种蛋白质与alphaPDGFR相关的机制。 SHP-2直接结合alphaPDGFR，而Grb2最可能通过SHP-2间接结合，因为当SHP-2酪氨酸磷酸化时，Grb2和SHP-2共免疫沉淀。我们还比较了野生型和F720 alphaPDGFRs介导许多下游事件的能力。防止alphaPDGFR募集SHP-2和Grb2不会损害PDGF-AA诱导的Ras活化，DNA合成的起始或软琼脂中细胞的生长。我们得出结论，SHP-2和Grb2的缔合和SHP-2的酪氨酸磷酸化需要Y720处的alphaPDGFR磷酸化。但是，alphaPDGFR激活Ras或引发增殖反应并不是必需的。此外，这些发现表明，尽管SHP-2与两个受体都结合，但它在不同的位置结合：与βPDGFR的羧基末端结合，但与αPDGFR的激酶插入片段结合。

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