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Tyr-716 in the platelet-derived growth factor beta-receptor kinase insert is involved in GRB2 binding and Ras activation

Författare

  • AK Arvidsson
  • E Rupp
  • E Nånberg
  • J Downward
  • Lars Rönnstrand
  • S Wennström
  • J Schlessinger
  • Carl-Henrik Heldin
  • Lena Claesson-Welsh

Summary, in English

Ligand stimulation of the platelet-derived growth factor (PDGF) beta-receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation of the intracellular part of the receptor. The autophosphorylated tyrosine residues mediate interactions with downstream signal transduction molecules and thereby initiate different signalling pathways. A pathway leading to activation of the GTP-binding protein Ras involves the adaptor molecule GRB2. Here we show that Tyr-716, a novel autophosphorylation site in the PDGF beta-receptor kinase insert, mediates direct binding of GRB2 in vitro and in vivo. In a panel of mutant PDGF beta-receptors, in which Tyr-716 and the previously known autophosphorylation sites were individually mutated, only PDGFR beta Y716F failed to bind GRB2. Furthermore, a synthetic phosphorylated peptide containing Tyr-716 bound GRB2, and this peptide specifically interrupted the interaction between GRB2 and the wild-type receptor. In addition, the Y716(P) peptide significantly decreased the amount of GTP bound to Ras in response to PDGF in permeabilized fibroblasts as well as in porcine aortic endothelial cells expressing transfected PDGF beta-receptors. The mutant PDGFR beta Y716F still mediated activation of mitogen-activated protein kinases and an increased DNA synthesis in response to PDGF, indicating that multiple signal transduction pathways transduce mitogenic signals from the activated PDGF beta-receptor.

Publiceringsår

1994

Språk

Engelska

Sidor

6715-6726

Publikation/Tidskrift/Serie

Molecular and Cellular Biology

Volym

14

Issue

10

Dokumenttyp

Artikel i tidskrift

Förlag

American Society for Microbiology

Ämne

  • Medicinal Chemistry

Nyckelord

  • Platelet-Derived Growth Factor/genetics/*metabolismSequence AnalysisSignal TransductionStructure-Activity Relationship
  • *Adaptor Proteins
  • CulturedDNA Mutational AnalysisGRB2 Adaptor ProteinGuanosine Triphosphate/metabolismHumansLigandsMolecular Sequence DataPeptide Fragments/metabolismPhosphorylationPlatelet-Derived Growth Factor/*metabolismProtein BindingProteins/*metabolismProto-Oncogene Proteins p21(ras)/*metabolismReceptor Protein-Tyrosine Kinases/genetics/*metabolismReceptors
  • Signal TransducingAmino Acid SequenceAnimalsBase SequenceCell DivisionCells

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 0270-7306