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Increased mitogenicity of an alphabeta heterodimeric PDGF receptor complex correlates with lack of RasGAP binding

Ekman, Simon; Thuresson, Eva Rupp; Heldin, Carl-Henrik and Rönnstrand, Lars LU (1999) In Oncogene 18(15). p.2481-2488
Abstract
The different platelet-derived growth factor (PDGF) isoforms cause activation of their alpha and beta protein tyrosine kinase receptors through dimerization. Homodimerization as well as heterodimerization of receptors occur. It has been shown previously that the heterodimeric receptor complex mediates a stronger mitogenic response than either of the homodimeric complexes. In this report, we show that in cells expressing both PDGF alpha- and beta-receptors, stimulation with PDGF-AB, which leads to preferential heterodimer formation, leads to a very low degree of phosphorylation of Tyr771 in the beta-receptor. In contrast, Tyr771 is phosphorylated in a homodimeric complex of beta-receptors. Phosphorylated Tyr771 is a binding site for RasGAP;... (More)
The different platelet-derived growth factor (PDGF) isoforms cause activation of their alpha and beta protein tyrosine kinase receptors through dimerization. Homodimerization as well as heterodimerization of receptors occur. It has been shown previously that the heterodimeric receptor complex mediates a stronger mitogenic response than either of the homodimeric complexes. In this report, we show that in cells expressing both PDGF alpha- and beta-receptors, stimulation with PDGF-AB, which leads to preferential heterodimer formation, leads to a very low degree of phosphorylation of Tyr771 in the beta-receptor. In contrast, Tyr771 is phosphorylated in a homodimeric complex of beta-receptors. Phosphorylated Tyr771 is a binding site for RasGAP; an analogous site is not present in the alpha-receptor, which lacks the ability to associate with RasGAP. The lowered phosphorylation of Tyr771 in the heterodimeric receptor complex correlates with lowered association with RasGAP, as well as with a more efficient activation of Ras and MAP kinase, which is consistent with the increased mitogenicity elicited by PDGF-AB, compared to PDGF-AA or PDGF-BB. (Less)
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@article{fc89579d-5743-4e12-a2e7-702127d84f1d,
  abstract     = {The different platelet-derived growth factor (PDGF) isoforms cause activation of their alpha and beta protein tyrosine kinase receptors through dimerization. Homodimerization as well as heterodimerization of receptors occur. It has been shown previously that the heterodimeric receptor complex mediates a stronger mitogenic response than either of the homodimeric complexes. In this report, we show that in cells expressing both PDGF alpha- and beta-receptors, stimulation with PDGF-AB, which leads to preferential heterodimer formation, leads to a very low degree of phosphorylation of Tyr771 in the beta-receptor. In contrast, Tyr771 is phosphorylated in a homodimeric complex of beta-receptors. Phosphorylated Tyr771 is a binding site for RasGAP; an analogous site is not present in the alpha-receptor, which lacks the ability to associate with RasGAP. The lowered phosphorylation of Tyr771 in the heterodimeric receptor complex correlates with lowered association with RasGAP, as well as with a more efficient activation of Ras and MAP kinase, which is consistent with the increased mitogenicity elicited by PDGF-AB, compared to PDGF-AA or PDGF-BB.},
  author       = {Ekman, Simon and Thuresson, Eva Rupp and Heldin, Carl-Henrik and Rönnstrand, Lars},
  issn         = {1476-5594},
  keyword      = {Platelet-Derived Growth Factor alpha
Receptor,Platelet-Derived Growth Factor beta
Receptors,ras
Mitogens/metabolism
Molecular Sequence Data
Mutation
Phosphorylation
Platelet-Derived Growth Factor/metabolism/pharmacology
Protein Isoforms
Proteins/*metabolism
Receptor,Amino Acid Sequence
Animals
Binding Sites
Calcium-Calmodulin-Dependent Protein Kinases/drug effects/metabolism
Cell Line
Dimerization
Endothelium,Vascular/cytology/drug effects/metabolism
Enzyme Activation
GTPase-Activating Proteins
Genes,Platelet-Derived Growth Factor/chemistry/genetics/*metabolism
Swine
Tyrosine/metabolism
ras GTPase-Activating Proteins},
  language     = {eng},
  number       = {15},
  pages        = {2481--2488},
  publisher    = {Nature Publishing Group},
  series       = {Oncogene},
  title        = {Increased mitogenicity of an alphabeta heterodimeric PDGF receptor complex correlates with lack of RasGAP binding},
  volume       = {18},
  year         = {1999},
}