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Phosphatidylinositol 3' kinase: one of the effectors of Ras
P Rodriguez-Viciana1, B M Marte, P H Warne
1Imperial Cancer Research Fund, London, U.K.
Abstract:
Ras proteins are proto-oncogene products that are critical components of signalling pathways leading from cell surface receptors to control of cellular proliferation, morphology and differentiation. the ability of Ras to activate the MAP kinase pathway through interaction with the serine/threonine kinase Raf is now well established. However, recent work has shown that Ras can also interact directly with the catalytic subunit of phosphatidylinositol 3' kinase and is involved in control of the lipid kinase in intact cells. A model is presented in which both tyrosine phosphoprotein interaction with the regulatory p85 subunit and Ras. GTP interaction with the catalytic p110 subunit is required to achieve optimal activation of phosphatidylinositol 3'kinase in response to extracellular stimuli. The ability of Ras to regulate phosphatidylinositol 3' kinase may be important both in Ras control of cellular morphology through the actin cytoskeleton and also in Ras control of DNA synthesis.
Insights
Ras proteins, key signaling molecules, directly regulate phosphatidylinositol 3-kinase (PI3K). This interaction is crucial for controlling cell shape and DNA synthesis, expanding our understanding of Ras function.
Area of Science:
- Molecular Biology
- Cell Signaling
- Oncogenes
Background:
- Ras proteins are proto-oncogenes vital for cell signaling pathways.
- Ras activation of MAP kinase pathway via Raf is established.
- Emerging evidence links Ras to phosphatidylinositol 3-kinase (PI3K) regulation.
Purpose of the Study:
- To elucidate the mechanism of Ras interaction with PI3K.
- To model the optimal activation of PI3K by Ras in response to stimuli.
- To explore the role of Ras-PI3K signaling in cellular morphology and DNA synthesis.
Main Methods:
- Investigated Ras interaction with the catalytic p110 subunit of PI3K.
- Examined the role of tyrosine phosphoprotein interaction with the p85 subunit.
- Proposed a model for optimal PI3K activation involving Ras.GTP and p85 subunit.
Main Results:
- Ras.GTP directly interacts with the catalytic p110 subunit of PI3K.
- Optimal PI3K activation requires both tyrosine phosphoprotein interaction with p85 and Ras.GTP with p110.
- Ras regulation of PI3K is implicated in controlling cellular morphology and DNA synthesis.
Conclusions:
- Ras directly modulates PI3K activity, extending its known signaling roles.
- Ras-PI3K pathway is critical for cellular responses like actin cytoskeleton organization and DNA replication.
- This highlights a new mechanism for Ras in controlling fundamental cellular processes.