Hanazono Y, Odai H, Sasaki K, Iwamatsu A, Yazaki Y, Hirai H
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Acta Haematol. 1996;95(3-4):236-42. doi: 10.1159/000203884.
Grb2/Ash is composed of one SH2 and two SH3 domains and functions as an adapter linking tyrosine kinase receptors and Ras in fibroblasts. We have investigated the nature of proteins interacting with Grb2/Ash in hematopoietic cells. The product of the vav proto-oncogene (Vav) is expressed exclusively in hematopoietic cells and has guanine nucleotide exchange activity. Here we report that granulocyte/macrophage-colony- stimulating factor (GM-CSF), interleukin-3, and erythropoietin (Epo) induce rapid and transient tyrosine phosphorylation of Vav and that Vav is constitutively associated with the SH3 domain of Grb2/Ash in a human leukemia cell line UT-7. These data implicate Vav in a signaling pathway leading to activation of Ras or Ras-related proteins in hematopoietic cells. Furthermore, we have shown that the proto-oncogene c-cbl product (c-Cbl) is also tyrosine-phosphorylated by stimulation with GM-CSF or Epo and is constitutively associated with the SH3 domain of Grb2/Ash in UT-7. However, we could not find the homologous regions with guanine nucleotide exchange factors or GTPase-activating proteins in the c-cbl gene. Therefore, Grb2/Ash might also transduce a signal that is different from the signal leading to the small-G protein regulation.
Grb2/Ash由一个SH2结构域和两个SH3结构域组成，在成纤维细胞中作为连接酪氨酸激酶受体和Ras的衔接蛋白发挥作用。我们研究了造血细胞中与Grb2/Ash相互作用的蛋白质的性质。原癌基因vav（Vav）的产物仅在造血细胞中表达，并具有鸟嘌呤核苷酸交换活性。在此我们报告，粒细胞/巨噬细胞集落刺激因子（GM-CSF）、白细胞介素-3和促红细胞生成素（Epo）可诱导Vav快速且短暂的酪氨酸磷酸化，并且在人白血病细胞系UT-7中，Vav与Grb2/Ash的SH3结构域持续相关。这些数据表明Vav参与了造血细胞中导致Ras或Ras相关蛋白激活的信号通路。此外，我们还表明，原癌基因c-cbl产物（c-Cbl）也可被GM-CSF或Epo刺激酪氨酸磷酸化，并在UT-7中与Grb2/Ash的SH3结构域持续相关。然而，我们在c-cbl基因中未发现与鸟嘌呤核苷酸交换因子或GTP酶激活蛋白同源的区域。因此，Grb2/Ash可能还转导了一种不同于导致小G蛋白调节的信号。
