Oncogenic activation of the alphaPDGFR defines a domain that negatively regulates receptor dimerization.
The alpha platelet derived growth factor receptor (alphaPDGFR) extracellular Immunoglobulin (Ig) like domains 1-3 contain major determinants for ligand interaction. We now report that a deletion of Ig-like loop 3, but not Ig-like loop 1 or 2, of the alphaPDGFR causes ligand-independent transformation in NIH3T3 cells. Biochemical analyses of alphaPDGFR mutants lacking Ig-like loop 3 indicate that cellular transformation is mediated by ligand-independent activation of the alphaPDGFR tyrosine kinase activity as determined by receptor autophosphorylation both in vivo and in vitro. Moreover, cross-linking analysis of alphaPDGFR mutants expressed ectopically in NIH3T3 cells indicate that deletion within extracellular domain 3 leads to ligand-independent receptor dimerization. All of these findings suggest that the Ig-like loop 3 of the alphaPDGFR contains the major determinants which inhibit receptor dimerization in the quiescent cells and that the ligand binding induces receptor activation by neutralizing the inhibitory effect of this domain.
Uren
A
A
Laboratory of Cellular and Molecular Biology, National Cancer Institute (37-1E24), National Institutes of Health, Bethesda, Maryland 20892, USA.
Yu
J C
JC
Karcaaltincaba
M
M
Pierce
J H
JH
Heidaran
M A
MA
D016475:3T3 Cells; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019281:Dimerization; D004789:Enzyme Activation; D000939:Epitopes / Q000235:genetics* / Q000378:metabolism; D005822:Genetic Vectors; D007136:Immunoglobulins / Q000235:genetics*; D051379:Mice; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D014162:Transfection
D000939:Epitopes; D007136:Immunoglobulins; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor