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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 orcid (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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; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
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
in
Oncogene
volume
18
issue
15
pages
2481 - 2488
publisher
Nature Publishing Group
ISSN
1476-5594
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
fc89579d-5743-4e12-a2e7-702127d84f1d (old id 1782708)
date added to LUP
2016-04-04 08:36:31
date last changed
2019-05-22 02:18:31
@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}},
  keywords     = {{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}},
}