Increased mitogenicity of an alphabeta heterodimeric PDGF receptor complex correlates with lack of RasGAP binding.
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.
Ekman
S
S
Ludwig Institute for Cancer Research, Biomedical Center, Uppsala, Sweden.
Thuresson
E R
ER
Heldin
C H
CH
Rönnstrand
L
L
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D019281:Dimerization; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins; D011905:Genes, ras; D008934:Mitogens / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D020033:Protein Isoforms; D011506:Proteins / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013552:Swine; D014443:Tyrosine / Q000378:metabolism; D020703:ras GTPase-Activating Proteins
D020690:GTPase-Activating Proteins; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D020033:Protein Isoforms; D011506:Proteins; D020703:ras GTPase-Activating Proteins; D014443:Tyrosine; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases