Autocrine mechanism for v-sis transformation requires cell surface localization of internally activated growth factor receptors.
v-sis represents a prototype for the class of oncogenes that encode growth factors. Whether its platelet-derived growth factor (PDGF)-like product functionally activates its receptors within the cell or at the cell surface has potential implications in efforts to intervene with the v-sis-transformed phenotype. We demonstrate that intracellular as well as cell surface forms of two PDGF receptor gene products are tyrosine phosphorylated in v-sis transformants. In a chemically defined medium in which cell growth was dependent on v-sis expression, proliferation was partially inhibited by PDGF neutralizing antibody but completely blocked by suramin. Suramin treatment resulted in a marked reduction in tyrosine phosphorylated cell surface PDGF receptors but had no effect on the level of tyrosine phosphorylation of intracellular receptor species. All of these findings demonstrate that the v-sis-encoded mitogen can bind and activate its receptors internally but that activated receptors must achieve a cell surface location in order to functionally couple with intracellular mitogenic signaling pathways.
Fleming
T P
TP
Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, MD 20892.
Matsui
T
T
Molloy
C J
CJ
Robbins
K C
KC
Aaronson
S A
SA
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D007700:Kinetics; D051379:Mice; D020575:Oncogene Proteins v-sis; D009857:Oncogenes; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D015682:Retroviridae Proteins, Oncogenic / Q000502:physiology*; D013498:Suramin / Q000494:pharmacology; D015291:Transforming Growth Factors / Q000502:physiology*
D020575:Oncogene Proteins v-sis; D010982:Platelet-Derived Growth Factor; D015682:Retroviridae Proteins, Oncogenic; D013498:Suramin; D015291:Transforming Growth Factors