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Increased mitogenicity of an alphabeta heterodimeric PDGF receptor complex correlates with lack of RasGAP binding

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Author

Summary, in English

The different platelet-derived growth factor (PDGF) isoforms cause activation of their alpha and beta protein tyrosine kinase receptors through dimerization. Homodimerization as well as heterodimerization of receptors occur. It has been shown previously that the heterodimeric receptor complex mediates a stronger mitogenic response than either of the homodimeric complexes. In this report, we show that in cells expressing both PDGF alpha- and beta-receptors, stimulation with PDGF-AB, which leads to preferential heterodimer formation, leads to a very low degree of phosphorylation of Tyr771 in the beta-receptor. In contrast, Tyr771 is phosphorylated in a homodimeric complex of beta-receptors. Phosphorylated Tyr771 is a binding site for RasGAP; an analogous site is not present in the alpha-receptor, which lacks the ability to associate with RasGAP. The lowered phosphorylation of Tyr771 in the heterodimeric receptor complex correlates with lowered association with RasGAP, as well as with a more efficient activation of Ras and MAP kinase, which is consistent with the increased mitogenicity elicited by PDGF-AB, compared to PDGF-AA or PDGF-BB.

Publishing year

1999

Language

English

Pages

2481-2488

Publication/Series

Oncogene

Volume

18

Issue

15

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Medicinal Chemistry

Keywords

  • Platelet-Derived Growth Factor alpha Receptor
  • Platelet-Derived Growth Factor beta Receptors
  • ras Mitogens/metabolism Molecular Sequence Data Mutation Phosphorylation Platelet-Derived Growth Factor/metabolism/pharmacology Protein Isoforms Proteins/*metabolism Receptor
  • Amino Acid Sequence Animals Binding Sites Calcium-Calmodulin-Dependent Protein Kinases/drug effects/metabolism Cell Line Dimerization Endothelium
  • Vascular/cytology/drug effects/metabolism Enzyme Activation GTPase-Activating Proteins Genes
  • Platelet-Derived Growth Factor/chemistry/genetics/*metabolism Swine Tyrosine/metabolism ras GTPase-Activating Proteins

Status

Published

ISBN/ISSN/Other

  • ISSN: 1476-5594