Oncogenic activation of the alpha PDGFR defines a domain that negatively regulates receptor dimerization

The alpha platelet derived growth factor receptor (alpha PDGFR) 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 alpha PDGFR causes ligandindependent transformation in NIH3T3 cells. Biochemical analyses of alpha PDGFR mutants lacking Ig-like loop 3 indicate that cellular transformation is mediated by ligand-independent activation of the alpha PDGFR tyrosine kinase activity as determined by receptor autophosphorylation both in vivo and in vitro. Moreover, crosslinking analysis of alpha PDGFR 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 alpha PDGFR 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.