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The role of lipid-derived second messengers in cell growth and transformation
L Cantley1, L Fleischman, M Whitman
1Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts 02111.
Abstract:
Recent information on the structure of growth factor receptors and oncogenes has advanced our understanding of the biochemical mechanism of growth control. Several peptide growth factor receptors have now been purified and, with a few notable exceptions, they fall into a family of homologous proteins with growth factor-stimulated protein-tyrosine kinase (PTK) activity. Mutations in the genes encoding for both the growth factors and the growth factor receptors of this family have been shown to cause cell transformation. Thus, PTKs have been implicated both in normal growth control and in cell transformation. The critical targets for these PTKs have not been determined. Several but not all growth factors stimulate production of the phosphatidylinositol (PI)-derived second messengers, diacylglycerol and inositol-1,4,5-trisphosphate. By purifying and characterizing the enzymes involved in PI turnover we are attempting to determine how this system is regulated by growth factors and oncogene products. We have found that fibroblasts contain two distinct PI kinases, and that one of these enzymes can be precipitated with antibodies against phosphotyrosine only after addition of platelet-derived growth factor. The relevance of the PI turnover pathway in propagation of growth signals is discussed.
Insights
Protein-tyrosine kinases (PTKs) regulate cell growth and transformation. This study investigates phosphatidylinositol (PI) kinases, identifying a PTK-associated PI kinase regulated by platelet-derived growth factor.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Signaling
Background:
- Growth factor receptors and oncogenes are crucial for cell growth control.
- Many growth factor receptors possess protein-tyrosine kinase (PTK) activity and are implicated in cell transformation.
- The precise targets of PTKs remain largely undetermined.
Purpose of the Study:
- To investigate the role of phosphatidylinositol (PI) turnover in signal propagation from growth factors and oncogenes.
- To purify and characterize enzymes involved in PI turnover.
- To understand how growth factors and oncogene products regulate the PI turnover system.
Main Methods:
- Purification and characterization of enzymes involved in PI turnover.
- Use of antibodies against phosphotyrosine for protein precipitation.
- Stimulation of fibroblasts with platelet-derived growth factor.
Main Results:
- Fibroblasts possess two distinct PI kinases.
- One PI kinase is precipitated with anti-phosphotyrosine antibodies only after platelet-derived growth factor stimulation.
- This suggests a link between PTK activity and PI kinase regulation.
Conclusions:
- The phosphatidylinositol (PI) turnover pathway is relevant for propagating growth signals.
- Growth factors and oncogene products may regulate cellular processes through PI kinases.
- Further research is needed to elucidate the precise mechanisms of PTK-mediated PI metabolism.