Opposite effects of the p52(shc)/p46(shc) and p66(shc) splicing isoforms on the EGF receptor-MAP kinase-fos signalling pathway

被引:354
作者
Migliaccio, E
Mele, S
Salcini, AE
Pelicci, G
Lai, KMV
SupertiFurga, G
Pawson, T
DiFiore, P
Lanfrancone, L
Pelicci, PG
机构
[1] EUROPEAN INST ONCOL,DEPT EXPT ONCOL,I-20141 MILAN,ITALY
[2] UNIV PERUGIA,IST MED INTERNA & SCI ONCOL,I-06100 PERUGIA,ITALY
[3] MT SINAI HOSP,SAMUEL LUNENFELD RES INST,DIV MOL & DEV BIOL,TORONTO,ON M5G 1X5,CANADA
[4] EMBL,HEIDELBERG,GERMANY
[5] IST MICROBIOL,BARI,ITALY
关键词
fos; p52(shc); p46(shc); p66(shc); phosphorylation; SH2; proteins;
D O I
10.1093/emboj/16.4.706
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 She 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.
引用
收藏
页码:706 / 716
页数:11
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