Full activation of the platelet-derived growth factor β-receptor kinase involves multiple events

Ruth M. Baxter, John Paul Secrist, Richard R. Vaillancourt, Andrius Kazlauskas

Research output: Contribution to journalArticle

92 Scopus citations

Abstract

Activation of receptor tyrosine kinases is thought to involve ligand- induced dimerization, which promotes receptor transphosphorylation and thereby increases the receptor's phosphotransferase activity. We used two platelet-derived growth factor β-receptor (β-PDGFR) mutants to identify events that are required for full engagement (autophosphorylation and activation of the kinase activity) of the β-PDGFR kinase. The F79/81 receptor (Tyr to Phe substitution at 579 and 581 in the juxtamembrane domain of the receptor) was capable of only very modest ligand-dependent autophosphorylation and also failed to associate with numerous SH2 domain- containing proteins. Furthermore, stimulation with platelet-derived growth factor (PDGF) did not increase the kinase activity of the F79/81 mutant toward exogenous substrates. However, the F79/81 receptor had basal kinase activity and could be artificially stimulated by incubation with ATP. Because the low kinase activity of the F857 mutant (Tyr to Phe substitution at 857 in the putative activation loop) could not be increased by incubation with ATP, failure to phosphorylate Tyr-857 may be the reason why the F79/81 mutant has low kinase activity. Surprisingly, the F857 mutant underwent efficient PDGF- dependent autophosphorylation. Thus the PDGF-dependent increase in the kinase activity of the receptor is not required for autophosphorylation. We conclude that full activation of the β-PDGFR kinase requires at least two, apparently distinct events.

Original languageEnglish (US)
Pages (from-to)17050-17055
Number of pages6
JournalJournal of Biological Chemistry
Volume273
Issue number27
DOIs
StatePublished - Jul 3 1998

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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