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首页> 外文期刊>Molecular and Cellular Biology >Mitogenic signalling and substrate specificity of the Flk2/Flt3 receptor tyrosine kinase in fibroblasts and interleukin 3-dependent hematopoietic cells.
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Mitogenic signalling and substrate specificity of the Flk2/Flt3 receptor tyrosine kinase in fibroblasts and interleukin 3-dependent hematopoietic cells.

机译：Flk2 / Flt3受体酪氨酸激酶在成纤维细胞和白介素3依赖的造血细胞中的促有丝分裂信号和底物特异性。

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Flk2/Flt3 is a recently identified receptor tyrosine kinase expressed in brain, placenta, testis, and primitive hematopoietic cells. The mitogenic signalling potential and biochemical properties of Flk2/Flt3 have been analyzed by using a chimeric receptor composed of the extracellular domain of the human colony-stimulating factor 1 receptor and the transmembrane and cytoplasmic domains of murine Flk2/Flt3. We demonstrate that colony-stimulating factor 1 stimulation of the Flk2/Flt3 kinase in transfected NIH 3T3 fibroblasts leads to a transformed phenotype and generates a full proliferative response in the absence of other growth factors. In transfected interleukin 3 (IL-3)-dependent Ba/F3 lymphoid cells, activation of the chimeric receptor can abrogate IL-3 requirement and sustain long-term proliferation. We show that phospholipase C-gamma 1, Ras GTPase-activating protein, the p85 subunit of phosphatidylinositol 3'-kinase, Shc, Grb2, Vav, Fyn, and Src are components of the Flk2/Flt3 signal transduction pathway. In addition, we demonstrate that phospholipase C-gamma 1, the p85 subunit of phosphatidylinositol 3'-kinase, Shc, Grb2, and Src family tyrosine kinases, but not Ras GTPase-activating protein, Vav, or Nck, physically associate with the Flk2/Flt3 cytoplasmic domain. Cell-type-specific differences in tyrosine phosphorylation of p85 and Shc are observed. A comparative analysis of the Flk2/Flt3 signal cascade with those of the endogenous platelet-derived growth factor and IL-3 receptors indicates that Flk2/Flt3 displays specific substrate preferences. Furthermore, tyrosine phosphorylation of p85 and Shc is similarly affected by totally different growth factors in the same cellular background.
机译：Flk2 / Flt3是最近在脑，胎盘，睾丸和原始造血细胞中表达的受体酪氨酸激酶。 Flk2 / Flt3的有丝分裂信号转导潜力和生化特性已通过使用由人类集落刺激因子1受体的胞外域和鼠Flk2 / Flt3的跨膜和胞质域组成的嵌合受体进行了分析。我们证明，在转染的NIH 3T3成纤维细胞中Flk2 / Flt3激酶的集落刺激因子1刺激导致转化表型，并在没有其他生长因子的情况下产生完整的增殖反应。在转染的白介素3（IL-3）依赖性Ba / F3淋巴样细胞中，嵌合受体的激活可以消除IL-3的需求并维持长期增殖。我们显示磷脂酶C-γ1，Ras GTPase激活蛋白，磷脂酰肌醇3'-激酶，Shc，Grb2，Vav，Fyn和Src的p85亚基是Flk2 / Flt3信号转导途径的组成部分。此外，我们证明磷脂酶C-γ1（磷脂酰肌醇3'-激酶的p85亚基，Shc，Grb2和Src家族的酪氨酸激酶，而不是Ras GTPase激活蛋白，Vav或Nck与Flk2物理缔合） / Flt3细胞质结构域。观察到p85和Shc酪氨酸磷酸化的细胞类型特异性差异。对Flk2 / Flt3信号级联与内源性血小板衍生生长因子和IL-3受体的信号级联的比较分析表明，Flk2 / Flt3显示特定的底物偏好。此外，p85和Shc的酪氨酸磷酸化在相同的细胞背景下同样受到完全不同的生长因子的影响。

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