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Autocrine mechanism for v-sis transformation requires cell surface localization of internally activated growth factor
T P Fleming1, T Matsui, C J Molloy
1Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, MD 20892.
Abstract:
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.
Insights
The v-sis oncogene product activates platelet-derived growth factor (PDGF) receptors internally. Activated receptors must reach the cell surface to trigger proliferation, offering therapeutic intervention points.
Area of Science:
- Oncogenomics
- Cell Signaling
- Molecular Biology
Background:
- v-sis is a prototype oncogene encoding a growth factor.
- Understanding v-sis-driven cell transformation is key for cancer intervention.
- The location of platelet-derived growth factor (PDGF) receptor activation by v-sis is critical.
Purpose of the Study:
- To investigate whether v-sis-like growth factors activate PDGF receptors intracellularly or at the cell surface.
- To explore therapeutic strategies targeting the v-sis-transformed phenotype.
Main Methods:
- Utilized v-sis transformed cells in a chemically defined medium.
- Assessed tyrosine phosphorylation of PDGF receptor gene products (intracellular and cell surface).
- Administered PDGF neutralizing antibody and suramin to evaluate proliferation and receptor activity.
Main Results:
- Intracellular and cell surface PDGF receptors showed tyrosine phosphorylation in v-sis transformants.
- PDGF neutralizing antibody partially inhibited proliferation; suramin completely blocked it.
- Suramin reduced cell surface PDGF receptor phosphorylation but not intracellular levels.
Conclusions:
- The v-sis-encoded mitogen can bind and activate PDGF receptors internally.
- Activated PDGF receptors require cell surface localization to couple with intracellular mitogenic signaling pathways.
- This localization dependency presents a target for intervening with v-sis-induced cell proliferation.