Disease relevance of Arhgdia

• Firstly, Rho GDIalpha -/- mice were initially viable but developed massive proteinuria mimicking nephrotic syndrome, leading to death due to renal failure within a year [1].
• Increased expression of Rho GDIalpha led to atrial arrhythmias and mild ventricular hypertrophy in adult mice (4-7 months) [2].
• The RhoA/RhoGDI complex, purified to greater than 98% at high yield from the yeast cytosolic fraction, could be stoichiometrically ADP-ribosylated by Clostridium botulinum C3 exoenzyme, contained stoichiometric GDP, and could be nucleotide exchanged fully with [3H]GDP or partially with GTP in the presence of submicromolar Mg2+ [3].

High impact information on Arhgdia

• An ERM dominant-negative mutant blocked the distal accumulation of CD43 and another known ERM binding protein, Rho-GDI [4].
• The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI [5].
• Release of Rho-GDI after membrane translocation allows Rac to bind to effectors [6].
• Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding [7].
• RhoGDI binding to GFP-Cdc42hs was not affected by substituting farnesylation for geranylgeranylation [7].

Biological context of Arhgdia

• Inhibition of Rho family GTPases by Rho GDP dissociation inhibitor disrupts cardiac morphogenesis and inhibits cardiomyocyte proliferation [8].
• 5. Homozygotes of the middle copy-number lines, in which Rho GDIalpha expression was increased four-fold over normal levels, were also embryonic lethal [8].
• Rho GDIalpha -/- mice showed several abnormal phenotypes [1].
• Secondly, Rho GDIalpha -/- male mice were infertile and showed impaired spermatogenesis with vacuolar degeneration of seminiferous tubules in their testes [1].
• Decreased phosphorylation of Rho-GTPase dissociation inhibitor (Rho GDI) was also observed in BCR/ABL-transfected cells [9].

Anatomical context of Arhgdia

• In this study, we report that combined disruption of both the Rho GDIalpha and Rho GDIbeta genes in mice resulted in reduction of marginal zone B cells in the spleen, retention of mature T cells in the thymic medulla, and a marked increase in eosinophil numbers [10].
• Rho GDIalpha and Rho GDIbeta thus play synergistic roles in lymphocyte migration and development by modulating activation cycle of the Rho proteins in a lymphoid organ-specific manner [10].
• The Rho GDI (GDP dissociation inhibitor) family, consisting of Rho GDIalpha, -beta, and -gamma, is a regulator that keeps the Rho family members in the cytosol as the GDP-bound inactive form and translocates the GDP-bound form from the membranes to the cytosol after the GTP-bound form accomplishes their functions [1].
• The mRNA expression patterns of Rho-GDIgamma and Rho-GDIalpha were almost identical in the brain with expression in the developing and mature cerebral cortex, striatum, and hippocampus [11].
• As a consequence, most Rac1b remains bound to the plasma membrane and is not sequestered by Rho-GDI in the cytoplasm [12].

Associations of Arhgdia with chemical compounds

• Intracellularly perfused recombinant Rho-GDI (an inhibitor of guanine nucleotide exchange specific for the Rho family) attenuated the inhibition of ICa,V by BK [13].
• Beta8 integrin binds Rho GDP dissociation inhibitor-1 and activates Rac1 to inhibit mesangial cell myofibroblast differentiation [14].
• Treatment of cells with a cell-permeable chimeric C3 toxin led to complete localization of modified Rho to the cytosolic fraction based on the complexation of ADP-ribosylated Rho with the guanine-nucleotide dissociation inhibitor-1 (GDI-1) [15].
• The modified complex turned out to be resistant to phosphatidylinositol 4,5-bisphosphate- and GTPgammaS-induced release of Rho from GDI-1 [15].
• In vivo stimulation of the NO/PKG signaling by treating rats with sildenafil increased RhoA level and RhoA phosphorylation, and enhanced its association to RhoGDI in the pulmonary artery, whereas opposite effects are induced by chronic inhibition of NO synthesis in N-omega-nitro-L-arginine-treated rats [16].

Physical interactions of Arhgdia

• An activating mutant of Rac1 that fails to interact with Rho GDP-dissociation inhibitor stimulates membrane ruffling in mammalian cells [17].
• Introduction of the RhoGDI binding-defective mutation R66A within a constitutively active Cdc42(F28L) background was accompanied by changes in cell shape and an accumulation of Cdc42 in the Golgi when these cells were compared to those expressing Cdc42(F28L) [18].
• Consistent with the latter finding, RhoGDI binding and actin remodeling were normal in Rce1- and Icmt-deficient cells [19].

Regulatory relationships of Arhgdia

• These results suggest that the signaling pathways of the Rho family members regulated by Rho GDIalpha play important roles in maintaining the structure and physiological function of at least kidneys and reproductive systems in adult mice [1].
• In this study, we set out to examine how the regulatory protein RhoGDI influences the cellular responses elicited by activated Cdc42 [18].

Other interactions of Arhgdia

• When co-transfected with Galpha(13)Q226L, the C-terminal domain of radixin synergistically stimulated the SRE activation; RhoGDI inhibited this effect [20].
• Coimmunoprecipitation studies of Rac2D57N with RhoGDI alpha and Tiam1 demonstrated increased binding of Rac2D57N to these upstream regulators of Rac signaling relative to the wild type [21].
• We describe a novel mutant of Rac1, R66E (Arg66-->Glu), that fails to bind RhoGDI [17].
• In intact cells and in cell lysates, glucosylation leads to a translocation of the majority of RhoA GTPase to the membranes whereas a minor fraction is monomeric in the cytosol without being complexed with the guanine nucleotide dissociation inhibitor (GDI-1) [22].
• Overexpression of either NF-kappaB inhibitory protein IkappaBalphaDeltaN (a degradation resistant mutant IkappaBalpha) or Rho-GDI blocked the strain-induced proliferation of C2C12 cells [23].

Analytical, diagnostic and therapeutic context of Arhgdia

• Microinjection of the GTP-bound G14V-RhoA/RhoGDI complex (but not the GDP form) into serum-starved Swiss 3T3 cells elicited formation of stress fibers and focal adhesions [3].
• Further analysis of this region by site-directed mutagenesis showed that a single change at residue 174 of LD4 to the corresponding residue of Rho GDI (i.e., Asp-174-->Ile) could impart nearly full (70%) Rho GDI activity on the LD4 molecule [24].

References