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J Biol Chem. 1994 May 27;269(21):15337-43.

Direct interaction between Shc and the platelet-derived growth factor beta-receptor.

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  • 1Ludwig Institute for Cancer Research, Biomedical Center, Uppsala, Sweden.

Abstract

The Src homology 2 (SH2) domain-containing Shc proteins p52shc and p46shc become phosphorylated upon activation of several tyrosine kinases and are implicated in mitogenic signal transduction. Ligand stimulation of the platelet-derived growth factor (PDGF) beta-receptor leads to autophosphorylation of tyrosine residues, which is known to mediate interactions with several SH2 domain-containing signaling molecules. In this study, we have characterized the interaction between the PDGF beta-receptor and Shc. PDGF beta-receptor coprecipitation in Shc immunoprecipitates was dependent on stimulation with PDGF-BB. The Shc SH2 domain expressed as a bacterial fusion protein bound the autophosphorylated PDGF beta-receptor. Moreover, the Shc SH2 domain could bind the autophosphorylated purified baculovirus-expressed PDGF beta-receptor intracellular domain, which indicates a direct association of Shc with the PDGF beta-receptor. Activation of the PDGF beta-receptor induced the preferential phosphorylation of p52shc. Tyrosine-phosphorylated Shc, in turn, formed a complex with the signaling molecule Grb2. Synthetic peptide analysis revealed that certain autophosphorylation sites in the PDGF beta-receptor (Tyr-579, Tyr-740, Tyr-751, and Tyr-771) were able to mediate the specific binding of the Shc SH2 domain as well as intact Shc proteins. A mutant PDGF beta-receptor in which Tyr-579 was replaced with phenylalanine showed 40% impaired association of Shc in vivo, but phosphorylation of Shc proteins was not affected. We conclude that multiple autophosphorylation sites in the PDGF beta-receptor are responsible for the binding of Shc. This is in contrast to previously characterized interactions between the PDGF beta-receptor and SH2 domain-containing proteins, which generally involve one high affinity binding site in the receptor.

PMID:
8195171
[PubMed - indexed for MEDLINE]
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