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Titolo:
A CONSERVED AMINO-TERMINAL SHC DOMAIN BINDS TO PHOSPHOTYROSINE MOTIFSIN ACTIVATED RECEPTORS AND PHOSPHOPEPTIDES
Autore:
VANDERGEER P; WILEY S; LAI VKM; OLIVIER JP; GISH GD; STEPHENS R; KAPLAN D; SHOELSON S; PAWSON T;
Indirizzi:
MT SINAI HOSP,SAMUEL LUNENFELD RES INST,PROGRAM MOLEC BIOL & CANC,600UNIV AVE TORONTO ON M5G 1X5 CANADA MT SINAI HOSP,SAMUEL LUNENFELD RES INST,PROGRAM MOLEC BIOL & CANC TORONTO ON M5G 1X5 CANADA NCI,FREDERICK CANC RES & DEV CTR,ABL BASIC RES PROGRAM FREDERICK MD 21702 BRIGHAM & WOMENS HOSP,JOSLIN DIABET CTR BOSTON MA 02115 BRIGHAM & WOMENS HOSP,DEPT MED BOSTON MA 02115 HARVARD UNIV,SCH MED BOSTON MA 02115
Titolo Testata:
Current biology
fascicolo: 4, volume: 5, anno: 1995,
pagine: 404 - 412
SICI:
0960-9822(1995)5:4<404:ACASDB>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROTEIN-TYROSINE KINASES; GUANINE-NUCLEOTIDE EXCHANGE; GROWTH-FACTOR RECEPTORS; SIGNAL TRANSDUCTION; V-SRC; TRANSFORMING PROTEIN; ADAPTER PROTEIN; HIGH-AFFINITY; EGF RECEPTOR; GRB2;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
52
Recensione:
Indirizzi per estratti:
Citazione:
P. Vandergeer et al., "A CONSERVED AMINO-TERMINAL SHC DOMAIN BINDS TO PHOSPHOTYROSINE MOTIFSIN ACTIVATED RECEPTORS AND PHOSPHOPEPTIDES", Current biology, 5(4), 1995, pp. 404-412

Abstract

Background: Signal transduction by growth factor receptor protein-tyrosine kinases is generally initiated by autophosphorylation on tyrosine residues following ligand binding. Phosphotyrosines within activatedreceptors form binding sites for the Src homology 2 (SH2) domains of cytoplasmic signalling proteins. One such protein, Shc, is tyrosine phosphorylated in response to a large number of growth factors and cytokines. Phosphorylation of Shc on tyrosine residue Y317 allows binding to the SH2 domain of Grb2, and hence stimulation of the Ras pathway. Shc is therefore implicated as an adaptor protein able to couple normal and oncogenic protein-tyrosine kinases to Ras activation. Shc itself contains an SH2 domain at its carboxyl terminus, but the function of the amino-terminal half of the protein is unknown. Results: We have found that the Shc amino-terminal region binds to a number of tyrosine-phosphorylated proteins in v-src-transformed cells. This domain also bound directly to the activated epidermal growth factor (EGF) receptor. A phosphotyrosine (pY)-containing peptide modeled after the Shc-binding site in polyoma middle T antigen (LLSNPTpYSVMRSK) was able to compete efficiently with the activated EGF receptor for binding to the Shc amino terminus. This competition was dependent on phosphorylation of the tyrosine residue within the peptide, and was abrogated by deletion of the leucine residue at position -5. The Shc amino-terminal domain alsobound to the autophosphorylated nerve growth factor receptor (Trk), but bound significantly less well to a mutant receptor in which tyrosine Y490 in the receptor's Shc-binding site had been substituted by phenylalanine. Conclusion: These data implicate the amino-terminal region of Shc in binding to activated receptors and other tyrosine-phosphorylated proteins. Binding appears to be specific for phosphorylated tyrosine residues within the sequence NPXpY, which is conserved in many Shc-binding sites. The Shc amino-terminal region bears only very limited sequence identity to known SH2 domains, suggesting that it represents a new class of phosphotyrosine-binding modules. Consistent with this view, the amino-terminal Shc domain is highly conserved in a DrosophilaShc homologue. Binding of Shc to activated receptors through its amino terminus could leave the carboxy-terminal SH2 domain free for other interactions. In this way, Shc may Function as an adaptor protein to bring two tyrosine-phosphorylated proteins together.

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Documento generato il 27/11/20 alle ore 13:07:18