Li B, Subleski M, Fusaki N, Yamamoto T, Copeland T, Princler G L, Kung H, Kamata T
Biological Carcinogenesis and Development Program, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702-1201, USA.
Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):1001-5. doi: 10.1073/pnas.93.3.1001.
mSOS, a guanine nucleotide exchange factor, is a positive regulator of Ras. Fyn tyrosine protein kinase is a potential mediator in T-cell antigen receptor signal transduction in subsets of T cells. We investigated the functional and physical interaction between mSOS and Fyn in T-cell hybridoma cells. Stimulation of the T-cell antigen receptor induced the activation of guanine nucleotide exchange activity in mSOS immunoprecipitates. Overexpression of Fyn mutants with an activated kinase mutation and with a Src homology 2 deletion mutation resulted in a stimulation and suppression of the mSOS activity, respectively. The complex formations of Fyn-Shc, Shc-Grb2, and Grb2-mSOS were detected in the activated Fyn-transformed cells, whereas the SH2 deletion mutant of Fyn failed to form a complex with mSOS. Moreover, tyrosine phosphorylation of Shc was induced by the overexpression of the activated Fyn. These findings support the idea that Fyn activates the activity of mSOS bound to Grb2 through tyrosine phosphorylation of Shc. Unlike the current prevailing model, Fyn-induced activation of Ras might involve the stimulation of the catalytic guanine nucleotide exchange activity of mSOS.
mSOS是一种鸟嘌呤核苷酸交换因子，是Ras的正向调节因子。Fyn酪氨酸蛋白激酶是T细胞亚群中T细胞抗原受体信号转导的潜在介质。我们研究了T细胞杂交瘤细胞中mSOS与Fyn之间的功能和物理相互作用。T细胞抗原受体的刺激诱导了mSOS免疫沉淀物中鸟嘌呤核苷酸交换活性的激活。具有激活激酶突变和Src同源2缺失突变的Fyn突变体的过表达分别导致mSOS活性的刺激和抑制。在激活的Fyn转化细胞中检测到Fyn-Shc、Shc-Grb2和Grb2-mSOS的复合物形成，而Fyn的SH2缺失突变体未能与mSOS形成复合物。此外，激活的Fyn的过表达诱导了Shc的酪氨酸磷酸化。这些发现支持了Fyn通过Shc的酪氨酸磷酸化激活与Grb2结合的mSOS活性的观点。与当前流行的模型不同，Fyn诱导的Ras激活可能涉及对mSOS催化鸟嘌呤核苷酸交换活性的刺激。
