Platelet-derived growth factor (PDGF) receptor activation in cell transformation and human malignancy.
We demonstrate that the v-sis-transformed NIH/3T3 fibroblasts exhibit tyrosine-phosphorylation of both intracellular and cell surface forms of the alpha and beta platelet-derived growth factor (PDGF) receptors (PDGFRs). Cell proliferation was partially inhibited by PDGF-neutralizing antibody, but was completely blocked by the drug suramin. Suramin treatment markedly reduced tyrosine-phosphorylated cell surface PDGFRs, but had no effect on the tyrosine-phosphorylated intracellular receptor species. These findings indicate that v-sis-activated PDGFRs must attain a cell surface localization to functionally couple with the mitogenic-signaling pathway. Additionally, we were able to demonstrate a functional autocrine loop involving PDGF in human tumor cell lines. Exposure to suramin resulted in diminished receptor autophosphorylation and/or upregulation of the PDGFRs. A subset of the tumor cell lines possessing a PDGF autocrine pathway exhibited a significant reduction in proliferation after exposure to suramin. These findings indicate that a PDGF autocrine loop contributes to the uncontrolled proliferative drive in some human malignancies.
Fleming
T P
TP
Department of Ophthalmology and Visual Science, Washington University School of Medicine, St. Louis, Missouri 63110.
Matsui
T
T
Aaronson
S A
SA
D000818:Animals; D000906:Antibodies; D002455:Cell Division; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D005347:Fibroblasts; D006801:Humans; D051379:Mice; D019000:Phosphotyrosine; D010982:Platelet-Derived Growth Factor / Q000276:immunology; D017479:Receptors, Platelet-Derived Growth Factor / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D013498:Suramin / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000906:Antibodies; D010982:Platelet-Derived Growth Factor; D019000:Phosphotyrosine; D014443:Tyrosine; D013498:Suramin; D017479:Receptors, Platelet-Derived Growth Factor