Arbet-Engels C, Tartare-Deckert S, Eckhart W
Molecular Biology and Virology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
J Biol Chem. 1999 Feb 26;274(9):5422-8. doi: 10.1074/jbc.274.9.5422.
Increased expression of the insulin-like growth factor-I receptor (IGF-IR) protein-tyrosine kinase occurs in several kinds of cancer and induces neoplastic transformation in fibroblast cell lines. The transformed phenotype can be reversed by interfering with the function of the IGF-IR. The IGF-IR is required for transformation by a number of viral and cellular oncoproteins, including SV40 large T antigen, Ras, Raf, and Src. The IGF-IR is a substrate for Src in vitro and is phosphorylated in v-Src-transformed cells. We observed that the IGF-IR and IR associated with the C-terminal Src kinase (CSK) following ligand stimulation. We found that the SH2 domain of CSK binds to the tyrosine-phosphorylated form of IGF-IR and IR. We determined the tyrosine residues in the IGF-IR and in the IR responsible for this interaction. We also observed that fibroblasts stimulated with IGF-I or insulin showed a rapid and transient decrease in c-Src tyrosine kinase activity. The results suggest that c-Src and CSK are involved in IGF-IR and IR signaling and that the interaction of CSK with the IGF-IR may play a role in the decrease in c-Src activity following IGF-I stimulation.
胰岛素样生长因子-I受体（IGF-IR）蛋白酪氨酸激酶的表达增加出现在多种癌症中，并在成纤维细胞系中诱导肿瘤转化。通过干扰IGF-IR的功能，可使转化表型逆转。IGF-IR是多种病毒和细胞癌蛋白（包括SV40大T抗原、Ras、Raf和Src）实现转化所必需的。在体外，IGF-IR是Src的底物，且在v-Src转化的细胞中会发生磷酸化。我们观察到，在配体刺激后，IGF-IR和胰岛素受体（IR）与C末端Src激酶（CSK）相关联。我们发现CSK的SH2结构域与酪氨酸磷酸化形式的IGF-IR和IR结合。我们确定了IGF-IR和IR中负责这种相互作用的酪氨酸残基。我们还观察到，用IGF-I或胰岛素刺激的成纤维细胞显示c-Src酪氨酸激酶活性迅速且短暂下降。结果表明，c-Src和CSK参与了IGF-IR和IR信号传导，并且CSK与IGF-IR的相互作用可能在IGF-I刺激后c-Src活性下降中发挥作用。
