text: GTPases are enzymes capable of binding and hydrolyzing guanosine triphosphate (GTP).  Small GTPases, such as Ran and Ras, can exist in either a GTP-bound form (active) or a GDP-bound form (inactive), and the conversion between these two forms grants them a switch-like behavior. As such, small GTPases are involved in multiple cellular events, including nuclear translocation and signaling. The transition between the active and inactive states is facilitated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs).
  Computational studies on the switching behavior of GTPases have revealed that the GTPase-GAP-GEF system displays ultrasensitivity. In their study, Lipshtat et al. simulated the effects of the levels of GEF and GAP activation on the Rap activation signaling network in response to signals from activated α2-adrenergic (α2R) receptors, which lead to degradation of the activated Rap GAP. They found that the switching behavior of Rap activation was ultrasensitive to changes in the concentration (i.e. amplitude) and the duration of the α2R signal, yielding Hill coefficients of nH=2.9 and nH=1.7, respectively (a Hill coefficient greater than nH=1 is characteristic of ultrasensitivity ). The authors confirmed this experimentally by treating neuroblasts with HU-210, which activates RAP through degradation of Rap GAP. Ultrasensitivity was observed both in a dose-dependent manner (nH=5±0.2), by treating cells with different HU-210 concentrations for a fixed time, and in a duration-dependent manner (nH=8.6±0.8), by treating cells with a fixed HU-210 concentration during varying times.
  By further studying system, the authors determined that (the degree of responsiveness and ultrasensitivity) was heavily dependent on two parameters: the initial ratio of , where the k's incorporate both the concentration of active GAP or GEF and their corresponding kinetic rates; and the signal impact, which is the product of the degradation rate of activated GAP and either the signal amplitude or the signal duration. The parameter  affects the steepness of the transition from the two states of the GTPase switch, with higher values (~10) leading to ultrasensitivity. The signal impact affects the switching point. Therefore, by depending on the ratio of concentrations rather than on individual concentrations, the switch-like behavior of the system can also be displayed outside of the zero-order regime.