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[Isoprenylated proteins and cell proliferation: regulators and effectors of Ras proteins]
1INSERM U-248, Institut Curie, Paris. gunzburg@curie.fr
Abstract:
Ras proteins play a central role in the control of cellular proliferation. They are 189 amino acid monomeric GTP-binding proteins that cycle between an inactive GDP-bound and the active GTP-bound state, and carry a slow intrinsic GTPase activity. Ras proteins are activated by growth promoting signals incoming from receptor tyrosine kinases via SH2 domain and SH3 domain containing adapter proteins and the Ras exchange factor Sos, as well as from serpentine receptors via the beta gamma subunits of heterotrimeric G proteins and the Ras exchange factor Ras-GRF (or Cdc25). Proteins that can stimulate the GTPase activity of Ras (GAPs) ensure that following mitogenic stimulations, they return to their inactive GDP-bound state; amongst these proteins are p120-GAP, neurofibomin (the product of the susceptibility gene to type I neurofibromatosis), as well as the inositol 1,3,4,5-tetrakisphosphate-dependent GAPIP4BF. Several effectors have been identified that mediate the biological effects of Ras. The serine/threonine kinase Raf-1, as well as the closely related protein B-Raf, elicit the ERK cascade of MAP kinases. Phosphatidylinositol-3-OH kinase is involved in the activation of the Rac/Rho family proteins that play a role in the control of actin polymerisation, as well as in growth control, RalGDS, RGL and Rlf, are responsible for the activation of the Ras-related protein Ral. Recent evidence, using effector domain mutants of Ras, demonstrates that these pathways cooperate to elicit the growth promoting effects of Ras proteins.
Insights
Ras proteins are key regulators of cell growth, cycling between active and inactive states. Multiple signaling pathways cooperate to control cellular proliferation through Ras protein activation and regulation.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Context:
- Ras proteins are monomeric GTP-binding proteins crucial for regulating cellular proliferation.
- They are activated by growth signals from receptor tyrosine kinases and serpentine receptors.
- Ras GTPase-activating proteins (GAPs) like p120-GAP and neurofibomin regulate Ras activity.
Purpose:
- To elucidate the mechanisms by which Ras proteins control cellular proliferation.
- To identify and describe the signaling pathways and effectors mediating Ras biological functions.
- To investigate the cooperative roles of Ras-mediated pathways in promoting cell growth.
Summary:
- Ras proteins (189 amino acids) bind GTP to become active, initiating signaling cascades.
- Activation occurs via receptor tyrosine kinases and G proteins, involving adapter proteins and exchange factors like Sos and Ras-GRF.
- Effectors such as Raf kinases, phosphatidylinositol-3-OH kinase, and RalGDS mediate Ras functions, including the ERK/MAPK pathway and actin polymerization.
- GAPs, including p120-GAP and neurofibomin, inactivate Ras by stimulating GTP hydrolysis.
- Cooperative action of these pathways, as shown by effector domain mutants, drives Ras-mediated cell growth.
Impact:
- Provides a comprehensive overview of Ras signaling networks in cell proliferation.
- Highlights the interplay between different Ras effectors in mediating growth signals.
- Establishes the cooperative nature of Ras pathways in promoting cellular growth, relevant to cancer biology.