Two signaling molecules share a phosphotyrosine-containing binding site in the platelet-derived growth factor receptor

R. Nishimura, W. Li, A. Kashishian, A. Mondino, M. Zhou, J. Cooper, J. Schlessinger

Research output: Contribution to journalArticle

146 Citations (Scopus)

Abstract

Autophosphorylation sites of growth factor receptors with tyrosine kinase activity function as specific binding sites for Src homology 2 (SH2) domains of signaling molecules. This interaction appears to be a crucial step in a mechanism by which receptor tyrosine kinases relay signals to downstream signaling pathways. Nek is a widely expressed protein consisting exclusively of SH2 and SH3 domains, the overexpression of which causes cell transformation. It has been shown that various growth factors stimulate the phosphorylation of Nek and its association with autophosphorylated growth factor receptors. A panel of platelet-derived growth factor (PDGF) receptor mutations at tyrosine residues has been used to identify the Nek binding site. Here we show that mutation at Tyr-751 of the PDGF β-receptor eliminates Nek binding both in vitro and in living cells. Moreover, the Y751F PDGF receptor mutant failed to mediate PDGF-stimulated phosphorylation of Nck in intact cells. A phosphorylated Tyr-751 is also required for binding of phosphatidylinositol-3 kinase to the PDGF receptor. Hence, the SH2 domains of p85 and Nck share a binding site in the PDGF receptor. Competition experiments with different phosphopeptides derived from the PDGF receptor suggest that binding of Nek and p85 is influenced by different residues around Tyr-751. Thus, a single tyrosine autophosphorylation site is able to link the PDGF receptor to two distinct SH2 domain-containing signaling molecules.

Original languageEnglish
Pages (from-to)6889-6896
Number of pages8
JournalMolecular and Cellular Biology
Volume13
Issue number11
Publication statusPublished - Nov 1993

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Platelet-Derived Growth Factor Receptors
Phosphotyrosine
src Homology Domains
Binding Sites
Growth Factor Receptors
Tyrosine
Phosphorylation
Phosphatidylinositol 3-Kinase
Phosphopeptides
Mutation
Platelet-Derived Growth Factor
Receptor Protein-Tyrosine Kinases
Protein-Tyrosine Kinases
Intercellular Signaling Peptides and Proteins

ASJC Scopus subject areas

  • Cell Biology
  • Genetics
  • Molecular Biology

Cite this

Nishimura, R., Li, W., Kashishian, A., Mondino, A., Zhou, M., Cooper, J., & Schlessinger, J. (1993). Two signaling molecules share a phosphotyrosine-containing binding site in the platelet-derived growth factor receptor. Molecular and Cellular Biology, 13(11), 6889-6896.

Two signaling molecules share a phosphotyrosine-containing binding site in the platelet-derived growth factor receptor. / Nishimura, R.; Li, W.; Kashishian, A.; Mondino, A.; Zhou, M.; Cooper, J.; Schlessinger, J.

In: Molecular and Cellular Biology, Vol. 13, No. 11, 11.1993, p. 6889-6896.

Research output: Contribution to journalArticle

Nishimura, R, Li, W, Kashishian, A, Mondino, A, Zhou, M, Cooper, J & Schlessinger, J 1993, 'Two signaling molecules share a phosphotyrosine-containing binding site in the platelet-derived growth factor receptor', Molecular and Cellular Biology, vol. 13, no. 11, pp. 6889-6896.
Nishimura, R. ; Li, W. ; Kashishian, A. ; Mondino, A. ; Zhou, M. ; Cooper, J. ; Schlessinger, J. / Two signaling molecules share a phosphotyrosine-containing binding site in the platelet-derived growth factor receptor. In: Molecular and Cellular Biology. 1993 ; Vol. 13, No. 11. pp. 6889-6896.
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