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Demonstration of functionally different interactions between phospholipase C-gamma and the two types of platelet-derived growth factor receptors

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Author

  • Anders Eriksson
  • Eeva Nånberg
  • Lars Rönnstrand
  • Ulla Engström
  • Ulf Hellman
  • Eva Rupp
  • Graham Carpenter
  • Carl-Henrik Heldin
  • Lena Claesson-Welsh

Summary, in English

Phosphorylated tyrosine residues in receptor tyrosine kinases serve as binding sites for signal transduction molecules. We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). The capacities of the Y988F and Y1018F mutant PDGF alpha-receptors, expressed in porcine aortic endothelial cells, to bind PLC-gamma are 60 and 5% of that of the wild-type receptor, respectively. Phosphorylated but not unphosphorylated peptides containing Tyr-1018 are able to compete with the intact receptor for binding to immobilized PLC-gamma SH2 domains; a phosphorylated Tyr-988 peptide competes 10 times less efficiently. The complex between PLC-gamma and the PDGF alpha-receptor is more stable than that of PLC-gamma and the PDGF beta-receptor. However, PDGF stimulation results in a smaller fraction of tyrosine-phosphorylated PLC-gamma and a smaller accumulation of inositol trisphosphate in cells expressing the alpha-receptor as compared with cells expressing the beta-receptor. We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF alpha-receptor carboxyl-terminal tail bind PLC-gamma, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-gamma.

Publishing year

1995

Language

English

Pages

7773-7781

Publication/Series

Journal of Biological Chemistry

Volume

270

Issue

13

Document type

Journal article

Publisher

American Society for Biochemistry and Molecular Biology

Topic

  • Medicinal Chemistry

Keywords

  • Platelet-Derived Growth Factor/*metabolism Recombinant Proteins/pharmacology Sequence Homology
  • Platelet-Derived Growth Factor alpha Receptor
  • Platelet-Derived Growth Factor beta Receptors
  • Site-Directed Oligodeoxyribonucleotides Peptide Fragments/chemistry/isolation & purification Phospholipases/*metabolism Phosphopeptides/pharmacology Phosphorylation Phosphotyrosine Platelet-Derived Growth Factor/pharmacology Point Mutation Receptor Protein-Tyrosine Kinases/metabolism Receptor
  • Vascular/*metabolism Isoenzymes/*metabolism Kinetics Molecular Sequence Data Mutagenesis
  • Amino Acid Sequence Animals Aorta Base Sequence Binding
  • Competitive Cell Division Endothelium
  • Amino Acid Swine Thymidine/metabolism Tyrosine/analogs & derivatives/metabolism

Status

Published

ISBN/ISSN/Other

  • ISSN: 1083-351X