Relevance of the kinetic equilibrium of forces to the control of the cell cycle by Ras proteins

In higher organisms, the replacement of GDP bound to Ras proteins with GTR under the participation of an exchange factor, is an important step in the initiation of cell division. Ras-GTP activates kinases and other effectors, which pass signals to the cell nucleus and to the cytoskeleton. The active state of Ras is terminated by hydrolysis of the bound GTP with the assistance of an activating protein (GAP). Knowledge of these regulatory events is based on extensive experimental data, but many aspects of their interpretation are still controversial. It is assumed here that a significant part of the free energy released when two partners associate is stored in a 'kinetic equilibrium of forces' (KEF), and used to facilitate the separation from a third partner. The activation of the Raf kinase is explained primarily in terms of an allosteric effect of Ras-GTP on the phosphate transfer in the catalytic region of the kinase. A mechanism is proposed for the modification of GAP by Ras-GTP, which is believed to be a prerequisite for the well-known crosstalk between the Ras- and Rho-dependent signalling pathways. The cell, by meeting the requirements for KEF, manages to reduce activation barriers, thus significantly accelerating the regulatory events and other complex biological reaction sequences.