Structural determinants in the platelet-derived growth factor alpha-receptor implicated in modulation of chemotaxis

Research output: Contribution to journalArticle

Abstract

Activation of the platelet-derived growth factor (PDGF) beta-receptor leads to cell growth and chemotaxis. The PDGF alpha-receptor also mediates a mitogenic signal, but fails to induce cell migration in certain cell types. To examine this difference in signal transduction, a series of point-mutated PDGF alpha-receptors were analyzed. Porcine aortic endothelial cells expressing mutant PDGF alpha-receptors, in which tyrosine residues 768, 993, or 1018 were changed to phenylalanine residues migrated toward PDGF, whereas wild-type alpha-receptors and mutant alpha-receptors changed at tyrosine residues 720, 944, or 988 failed to migrate. All mutant receptors were mitogenically active and their capacity to activate phosphatidylinositol 3'-kinase and phospholipase C-gamma was not different from that of the wild-type receptor. Tyr-768 was found to be phosphorylated in PDGF-stimulated cells; in the Y768F mutant, there was a considerable increase in phosphorylation of Ser-767. Tyr-993 was not phosphorylated, but mutation of this tyrosine residue to a phenylalanine residue resulted in increased efficiency of phosphorylation on Tyr-988. Tyr-1018 is known to be an autophosphorylation site. Phosphorylated Tyr-768 and Tyr-1018 may bind signal transduction molecules involved in negative modulation of the chemotactic signaling capacity, whereas phosphorylated Tyr-988 may mediate increased chemotaxis. Thus our data indicate that the PDGF alpha-receptor has an intrinsic ability to transduce a chemotactic signal, and that this signal is counteracted by overriding negative signals.

Details

Authors
  • Koutaro Yokote
  • Seijiro Mori
  • Agneta Siegbahn
  • Lars Rönnstrand
  • Christer Wernstedt
  • Carl-Henrik Heldin
  • Lena Claesson-Welsh
External organisations
  • External Organization - Unknown
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medicinal Chemistry

Keywords

  • Amino Acid Sequence Animals Aorta Base Sequence Cell Line *Chemotaxis/drug effects Endothelium, Vascular/*physiology Enzyme Activation Humans Inositol Phosphates/metabolism Isoenzymes/metabolism Kinetics Molecular Sequence Data Mutagenesis, Site-Directed Oligodeoxyribonucleotides Peptide Fragments/chemistry/isolation & purification Phenylalanine Phosphatidylinositol 3-Kinases Phosphopeptides/chemistry/isolation & purification Phosphotransferases (Alcohol Group Acceptor)/metabolism Platelet-Derived Growth Factor/*pharmacology *Point Mutation Receptor, Platelet-Derived Growth Factor alpha Receptors, Platelet-Derived Growth Factor/biosynthesis/*chemistry/*physiology Recombinant Proteins/biosynthesis/chemistry/metabolism Signal Transduction Swine Transfection Type C Phospholipases/metabolism Tyrosine
Original languageEnglish
Pages (from-to)5101-5111
JournalJournal of Biological Chemistry
Volume271
Issue number9
Publication statusPublished - 1996
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Clinical Chemistry (013016010)