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A PDGF receptor domain essential for mitogenesis but not for many other responses to PDGF
1Department of Medicine, University of California, San Francisco 94143-0724.
Abstract:
The receptors for mesenchymal growth factors contain tyrosine kinase coding sequences and exhibit ligand-activated tyrosine kinase activity. A variety of mutations of the epidermal growth factor, insulin and platelet-derived growth factor (PDGF) (manuscript in preparation) receptors that have resulted in a loss of tyrosine kinase activity have produced a concomitant loss of growth factor-stimulated DNA synthesis. Comparison of amino acid sequences of tyrosine kinases shows that these regions in the PDGF receptors in mouse and human contain an insert of unknown function. We have deleted this region, and expressed the altered form of the receptor in fibroblasts which lack PDGF receptors. This had no effect on a number of responses to PDGF, but cells bearing the mutant receptor did not proliferate or synthesize DNA in response to PDGF. This demonstrates that the insert is essential in PDGF-induced mitogenesis, and that PDGF stimulation of the mutant receptor tyrosine kinase and phosphatidylinositol turnover are not sufficient to elicit a mitogenic response to PDGF.
Insights
A specific region in platelet-derived growth factor (PDGF) receptors is crucial for cell growth and DNA synthesis. Removing this insert prevents PDGF-induced mitogenesis, even when receptor kinase activity is present.
Area of Science:
- Molecular Biology
- Cell Signaling
- Biochemistry
Background:
- Receptors for mesenchymal growth factors possess tyrosine kinase activity.
- Mutations affecting tyrosine kinase activity often abolish growth factor-stimulated DNA synthesis.
Purpose of the Study:
- To investigate the function of an amino acid sequence insert in platelet-derived growth factor (PDGF) receptors.
- To determine the role of this insert in PDGF-induced mitogenesis.
Main Methods:
- Deletion of a specific insert region in PDGF receptors.
- Expression of the altered PDGF receptor in fibroblasts lacking endogenous receptors.
- Assessing various cellular responses to PDGF stimulation in cells expressing the mutant receptor.
Main Results:
- Deletion of the insert region did not affect all PDGF responses.
- Cells expressing the mutant PDGF receptor failed to proliferate or synthesize DNA in response to PDGF.
- The insert is essential for PDGF-induced mitogenesis.
Conclusions:
- The identified insert in PDGF receptors is critical for PDGF-induced cell proliferation and DNA synthesis.
- PDGF receptor tyrosine kinase activity and phosphatidylinositol turnover are insufficient for mitogenesis without this insert.