The 'invisible hand': regulation of RHO GTPases by RHOGDIs

Abstract

RHO-specific guanine nucleotide dissociation inhibitors (RHOGDIs) are a family of proteins that have key roles in the regulation of the RHO GTPases. RHOGDIs function as negative regulators of RHO GTPases, extracting them from membranes and preventing their activation. RHOGDIs maintain a stable soluble pool of inactive RHO GTPases in the cytoplasm. Binding to RHOGDIs protects RHO GTPases from degradation. The total levels of the major RHO GTPases are determined by the levels of RHOGDIs in the cell. RHO proteins that are not bound to RHOGDIs or associated with membranes are degraded. Through competition for binding to RHOGDIs, there is crosstalk between RHO GTPases. Changes in the expression of one leads to the displacement of the others from the RHOGDI and results in their degradation. RHOGDIs play a part in shuttling RHO GTPases between different cellular membranes and regulate the delivery and extraction of RHO GTPases to and from their sites of action. The interaction between RHOGDIs and RHO GTPases can be regulated by several different mechanisms. Some regulate the specific displacement of a single RHO GTPase from RHOGDI, whereas others displace all of the RHO GTPases equally. Changes in expression of RHOGDIs have been associated with different types of cancer.