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RhoGDI Signaling | GeneGlobe

RhoGDI Signaling


Pathway Description

The family of small GTPase proteins is comprised of Cdc42, Rac, and Rho. Proteins of this family function as molecular switches that regulate a multitude of biological processes including cell proliferation, apoptosis, differentiation, migration, cytoskeletal reorganization, and membrane trafficking. GTPases cycle between an inactive GDP-bound conformation and an active GTP-bound conformation. Cycling between the two conformations enables these proteins to act as binary switches. The tightly regulated GTP-binding/GTPase cycle requires the coordinated action of three regulatory proteins: 1) Guanine nucleotide exchance factors (GEF), which stimulate the GTP-GDP exchange reaction, 2) GTPase activating proteins (GAP), which stimulate the GTP-hydrolytic reaction, and 3) GDP-dissociation inhibitors (GDI), which antagonize the actions of both GEFs and GAPs. Only three RhoGDIs have been described to date, namely RhoGDIa, RhoGDIb and RhoGDIgamma.

GDI have three activities: 1) To keep the GDP-bound form of the small G-protein in the cytosol, 2) To transport its complexed small G-protein to its target membrane where the GDP-bound form is converted to the GTP-bound form, and 3) To translocate the small G-protein back to the cytosol. RhoGDIs interact preferentially with GDP-bound forms of proteins preventing spontaneous GEF-catalyzed release of the GDP nucleotide, thereby maintaining the GTPases in an inactive state. In addition, GDI control membrane localization of GTPases. Most members of the family of small GTPase proteins cycle between cytosol and membranes. Membrane association of proteins is mediated by the insertion of an isoprenyl moiety (situated at their C-terminus) into the lipid bilayer. Transfer of the isoprenoid moiety from the lipid bilayer to a binding pocket within the GDI directly results in the dissociation of the small GTPase/GDI complex from the membrane producing a soluble species.

GDI negatively regulate Rho-family GTPases. The inhibitory activity of GDI derives both from an ability to bind the carboxy-terminal isoprene of Rho GTPases and extract them from membranes, and from inhibition of GTPase cycling between the GTP- and GDP-bound states. These binding and inhibitory functions of GDI can be attributed to two structurally distinct regions of the protein. Although GDI is predominantly thought to be a negative regulator of the Rho family G-proteins, recent work suggests a potential positive role for GDI via its association with a protein complex containing ERM proteins and their membrane-binding partner CD44.