Advanced

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

Yokote, Koutaro; Mori, Seijiro; Siegbahn, Agneta; Rönnstrand, Lars LU ; Wernstedt, Christer; Heldin, Carl-Henrik and Claesson-Welsh, Lena (1996) In Journal of Biological Chemistry 271(9). p.5101-5111
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
@article{4e749139-ad7c-4a1f-94ac-9ea26d53ed2b,
  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.},
  author       = {Yokote, Koutaro and Mori, Seijiro and Siegbahn, Agneta and Rönnstrand, Lars and Wernstedt, Christer and Heldin, Carl-Henrik and Claesson-Welsh, Lena},
  issn         = {1083-351X},
  keyword      = {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},
  language     = {eng},
  number       = {9},
  pages        = {5101--5111},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Structural determinants in the platelet-derived growth factor alpha-receptor implicated in modulation of chemotaxis},
  volume       = {271},
  year         = {1996},
}