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

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 ; Mori, Seijiro ; Siegbahn, Agneta ; Rönnstrand, Lars ; Wernstedt, Christer ; Heldin, Carl-Henrik and Claesson-Welsh, Lena
• publishing date: 1996
• type: Contribution to journal
• publication status: published
• subject: 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
• in: Journal of Biological Chemistry
• volume: 271
• issue: 9
• pages: 5101 - 5111
• publisher: American Society for Biochemistry and Molecular Biology
• ISSN: 1083-351X
• language: English
• LU publication?: no
• additional info: 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)
• id: 4e749139-ad7c-4a1f-94ac-9ea26d53ed2b (old id 1783946)
• date added to LUP: 2016-04-04 08:03:56
• date last changed: 2019-05-22 02:18:32