Migliaccio E, Mele S, Salcini A E, Pelicci G, Lai K M, Superti-Furga G, Pawson T, Di Fiore P P, Lanfrancone L, Pelicci P G
European Institute of Oncology, Department of Experimental Oncology, Milan, Italy.
EMBO J. 1997 Feb 17;16(4):706-16. doi: 10.1093/emboj/16.4.706.
Shc proteins are targets of activated tyrosine kinases and are implicated in the transmission of activation signals to Ras. The p46shc and p52shc isoforms share a C-terminal SH2 domain, a proline- and glycine-rich region (collagen homologous region 1; CH1) and a N-terminal PTB domain. We have isolated cDNAs encoding for a third Shc isoform, p66shc. The predicted amino acid sequence of p66shc overlaps that of p52shc and contains a unique N-terminal region which is also rich in glycines and prolines (CH2). p52shc/p46shc is found in every cell type with invariant reciprocal relationship, whereas p66shc expression varies from cell type to cell type. p66shc differs from p52shc/p46shc in its inability to transform mouse fibroblasts in vitro. Like p52shc/p46shc, p66shc is tyrosine-phosphorylated upon epidermal growth factor (EGF) stimulation, binds to activated EGF receptors (EGFRs) and forms stable complexes with Grb2. However, unlike p52shc/p46shc it does not increase EGF activation of MAP kinases, but inhibits fos promoter activation. The isolated CH2 domain retains the inhibitory effect of p66shc on the fos promoter. p52shc/p46shc and p66shc, therefore, appear to exert different effects on the EGFR-MAP kinase and other signalling pathways that control fos promoter activity. Regulation of p66shc expression might, therefore, influence the cellular response to growth factors.
Shc蛋白是活化酪氨酸激酶的作用靶点，参与激活信号向Ras的传递。p46shc和p52shc亚型共享一个C端SH2结构域、一个富含脯氨酸和甘氨酸的区域（胶原同源区域1；CH1）以及一个N端PTB结构域。我们分离出了编码第三种Shc亚型p66shc的cDNA。p66shc的预测氨基酸序列与p52shc的序列重叠，并且含有一个独特的N端区域，该区域也富含甘氨酸和脯氨酸（CH2）。在每种细胞类型中都能发现p52shc/p46shc，二者呈恒定的相互关系，而p66shc的表达在不同细胞类型中有所差异。p66shc与p52shc/p46shc的不同之处在于它在体外无法转化小鼠成纤维细胞。与p52shc/p46shc一样，p66shc在表皮生长因子（EGF）刺激下会发生酪氨酸磷酸化，与活化的EGF受体（EGFRs）结合，并与Grb2形成稳定的复合物。然而，与p52shc/p46shc不同的是，它不会增强EGF对丝裂原活化蛋白激酶（MAP激酶）的激活作用，反而会抑制fos启动子的激活。分离出的CH2结构域保留了p66shc对fos启动子的抑制作用。因此，p52shc/p46shc和p66shc似乎对EGFR-MAP激酶以及其他控制fos启动子活性的信号通路发挥不同的作用。所以，p66shc表达的调控可能会影响细胞对生长因子的反应。
