GTPase-activating Protein - Regulation of GAPs

Regulation of GAPs

While GAPs serve to regulate the G proteins, there is also some level of regulation of the GAPs themselves. Many GAPs have allosteric sites which serve as interfaces with downstream targets of the particular path that they regulate. For example, RGS9-1, the GAP in the photoreceptors from above, interacts with cGMP phosphodiesterase (cGMP PDE), a downstream component of phototransduction in the retina. Upon binding with cGMP PDE, RGS9-1 GAP activity is enhanced. In other words, a downstream target of photoreceptor-induced signaling binds and activates the inhibitor of signaling, GAP. This positive regulatory binding of downstream targets to GAP serves as a negative feedback loop which eventually turns off the signaling that was originally activated. GAPs are regulated by targets of the G protein that they regulate.

There are also examples of negative regulatory mechanisms, where downstream targets of G protein signaling inhibit the GAPs. In G protein-gated potassium channels, phosphatidylinositol 3, 4, 5-triphosphate (PIP3) is a downstream target of G protein signaling. PIP3 binds and inhibits the RGS4 GAP. Such inhibition of GAP may perhaps “prime” the signaling pathway for activation. This creates a window of activity for the G proteins once activated because the GAP is temporarily inhibited. When the potassium channel is activated, Ca2+ gets released and binds calmodulin. Together, they displace PIP3 from GAP by binding competitively to the same site, and by doing so, they reactivate GAP to turn G protein signaling off. This particular process demonstrates both inhibition and activation of GAP by its regulators. There is cross-talk between GAP and other components of the signaling pathway that regulate the activity of GAP.

Interestingly enough, there have been some findings suggesting the possibility of crosstalk between GAPs. A recent study showed that the p120Ras GAP could bind the DLC1 Rho GAP at its catalytic domain. The binding of the Ras GAP to the Rho GAP inhibits the activity of the Rho GAP, thereby activating the Rho G protein. One GAP serves as a negative regulator of another GAP. The reasons for such cross-regulation across GAPs are as of yet unclear, but one possible hypothesis is that this cross-talk across GAPs attenuates the “off” signal of all the GAPs. Although the p120Ras GAP is active, therefore inhibiting that particular pathway, other cellular processes can still continue because it inhibits other GAPs. This may ensure that the whole system does not shut down from a single “off’ signal. GAP activity is highly dynamic, interacting with many other components of signaling pathways.