Disease relevance of Rho

• Recent studies have suggested that the proliferative effects of p21(ras) may depend on signaling outputs from the small Rho GTPases, Rac and Rho, but the physiologic importance of these interactions in an animal disease model has not been established [1].
• We showed previously that anti-RhoA small interfering RNA (siRNA) inhibited aggressive breast cancer more effectively than conventional blockers of Rho-mediated signaling pathways [2].
• Subretinal injection of recombinant adeno-associated virus (AAV) encoding a Prph2 transgene results in stable generation of outer segment structures and formation of new stacks of discs containing both perpherin-2 and rhodopsin, which in many cases are morphologically similar to normal outer segments [3].
• Mutations in the retinal degeneration, retinal degeneration slow(/peripherin) and rhodopsin genes cause photoreceptor degeneration in humans and mice [4].
• Here we report a novel signaling pathway activated by the Rho proteins that may be responsible for their biological activities, including cytoskeleton organization, transformation, apoptosis, and metastasis [5].

Psychiatry related information on Rho

• Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin [6].
• Furthermore, we demonstrate that crosstalk between the Ras and Rho GTPase families is involved in cAMP-dependent processing of amyloid precursor protein (APP), a key protein in Alzheimer's disease [7].
• Moreover, loss of OCRL1 RhoGAP and the resulting alteration in Rho pathways may contribute to mental retardation in Lowe syndrome, as illustrated in other forms of X-linked mental retardation [8].
• Owing to the suppressive effects of Rho-kinase inhibitors on the contractile activity of the vas deferens, the possibility that these compounds might impair ejaculation must be taken into account when considering them as potential agents in the treatment of erectile dysfunction [9].

High impact information on Rho

• Here we solve the crystal structure of a YpkA-Rac1 complex and find that YpkA possesses a Rac1 binding domain that mimics host guanidine nucleotide dissociation inhibitors (GDIs) of the Rho GTPases [10].
• Although the underlying mechanism is likely complex, we show that p120 affects NFkB activation and immune homeostasis in part through regulation of Rho GTPases [11].
• Snails, Swiss, and serum: the solution for Rac 'n' Rho [12].
• The activation state of Rho following IGF-1 signaling is determined by the tyrosine-phosphorylation status of p190-B RhoGAP and its resulting subcellular relocalization [13].
• In vitro, activation of Rho-kinase by Rho inhibits adipogenesis and is required for myogenesis [13].

Chemical compound and disease context of Rho

• We show that inhibition of Rho GTPases by Clostridium difficile toxin B prevents apoptotic cell phagocytosis and inhibits the accumulation of both F-actin and phosphotyrosine [14].
• Tiam1 (T-lymphoma invasion and metastasis 1) is one of the known guanine nucleotide (GDP/GTP) exchange factors (GEFs) for Rho GTPases (e.g., Rac1) and is expressed in breast tumor cells (e.g., SP-1 cell line) [15].
• The Rho signalling pathway is activated, for example, by bioactive sphingolipids such as sphingosine-1-phosphate (SPP) or by overexpression of Rho family members in tumorigenesis and metastases [16].
• Here we demonstrate that Bordetella dermonecrotizing toxin (DNT) catalyzes cross-linking of Rho with ubiquitous polyamines such as putrescine, spermidine and spermine [17].
• Clostridium novyi alpha-toxin-catalyzed incorporation of GlcNAc into Rho subfamily proteins [18].

Biological context of Rho

• Here, we examine the role of Vav and Rho GTPases in phagocytosis by using primary murine macrophages [19].
• Vav guanine nucleotide exchange factors (GEFs) have been implicated in cell adhesion by integrin and immune response receptors through the regulation of Rho GTPases [19].
• Regulation of innate immunity by Rho GTPases [20].
• Neurotrophins regulate Schwann cell migration by activating divergent signaling pathways dependent on Rho GTPases [21].
• Activated Rac(G12V), when ectopically expressed in BaF3 cells, rendered the cells resistant to apoptosis upon interleukin-3 deprivation, while activated mutants of Rho and Cdc42 displayed no significant anti-apoptotic effect [22].

Anatomical context of Rho

• The Rac/Rho-specific guanine nucleotide exchange factor, Vav-1, is a key component of the T-cell antigen receptor (TCR)-linked signaling machinery [23].
• Thus, Vav proteins play an essential role coupling beta2 to Rho GTPases and regulating multiple integrin-induced events important in leukocyte adhesion and phagocytosis [24].
• The Rho GTPases play an important role in transducing signals linking plasma membrane receptors to the organization of the cytoskeleton and also regulate gene transcription [25].
• Rac2 is a Rho GTPase that is expressed in cells of hematopoietic origin, including neutrophils and macrophages [26].
• We have assigned the mouse rhodopsin gene, Rho, to chromosome 6 using DNA from a set of mouse-hamster somatic hybrid cell lines and a partial cDNA clone for mouse opsin [27].

Associations of Rho with chemical compounds

• Requirements for Vav guanine nucleotide exchange factors and Rho GTPases in FcgammaR- and complement-mediated phagocytosis [19].
• Vav proteins are Rho family guanine nucleotide exchange factors that become tyrosine phosphorylated in response to adhesion [24].
• The activation of JNK by Galpha12Q229L was inhibited by dominant-negative RhoA(T19N), and botulinum C3 exoenzyme which specifically inactivates Rho [28].
• Ablation of RPE65 in Nrl(-/-) and Rho(-/-) mice led to the absence of 11-cis retinal, but increased the total retinoid content, with retinyl esters representing the most abundant retinoid species [29].
• A single nucleotide transition from G to A was found in the Rho gene that is predicted to result in a substitution of Tyr for Cys at position 110, in an intradiscal loop [30].

Physical interactions of Rho

• Furthermore, cells infected during the differentiation procedure with a lentiviral vector expressing green fluorescent protein (GFP) under the control of either the rhodopsin promoter or the interphotoreceptor retinoid-binding protein (IRBP) promoter, expressed GFP [31].
• Organization of the G protein-coupled receptors rhodopsin and opsin in native membranes [32].
• Our results show that the DRF proteins couple Rho and Src during signaling and the regulation of actin dynamics [33].
• The Rho subfamily GTP-binding protein Cdc42 mediates actin cytoskeletal rearrangements and cell cycle progression and is essential for Ras transformation [34].
• The Rho family of guanosine triphosphate (GTP)-binding proteins regulates cytoskeletal reorganization in all cells tested and Rac and Rho have both been shown to regulate melanocyte dendrite formation [35].

Enzymatic interactions of Rho

• This is the first demonstration of an endogenous Rho family member being phosphorylated in vivo and indicates that phosphorylation is an important mechanism to control the stability and function of this GTPase-deficient Rho protein [36].

Regulatory relationships of Rho

• The gene Rpe65 is specifically expressed in the PE and essential for the re-isomerization of all-trans retinol in the visual cycle and thus for the regeneration of rhodopsin after bleaching [37].
• It acts synergistically with Crx to regulate rhodopsin transcription [38].
• In vitro and in vivo analyses indicate that Tiam1 activates the Rho like GTPase Rac1 [39].
• We found that Cdc42 also downregulates Rho activity [40].
• We observed that the foci of transformed NIH 3T3 cells caused by Mas were similar to those caused by activated Rho and Rac proteins [41].

Other interactions of Rho

• Rpe65-/- mice lack rhodopsin, but not opsin apoprotein [42].
• Regulation of c-myc expression by PDGF through Rho GTPases [43].
• Dominant negative Rho most potently inhibited the focus forming activity, whereas Cdc42 was most effective in inhibiting the colony forming ability of NM1-expressing cells [44].
• Distinct role of phosphatidylinositol 3-kinase and Rho family GTPases in Vav3-induced cell transformation, cell motility, and morphological changes [45].
• Differential requirement for Rho family GTPases in an oncogenic insulin-like growth factor-I receptor-induced cell transformation [44].

Analytical, diagnostic and therapeutic context of Rho

• RESULTS: Compared with the WT mice, Rho kinase activity was higher in eNOS KO mice (37 +/- 8%, P < 0.05) as was SBP (33 +/- 4%, P < 0.05), basal renal perfusion pressure (31 +/- 4%, P < 0.05) and renal vascular resistance (35 +/- 4%, P < 0.05) [46].
• Here, we have determined by atomic force microscopy the organization of rhodopsin in native membranes obtained from wild-type mouse photoreceptors and opsin isolated from photoreceptors of Rpe65-/- mutant mice, which do not produce the chromophore 11-cis-retinal [32].
• We show by immunocytochemistry analysis that a subpopulation of differentiated cells was committed to the photoreceptor lineage given that these cells expressed the photoreceptor proteins recoverin, peripherin, and rhodopsin in a same ratio [31].
• Generation, characterization, and molecular cloning of the Noerg-1 mutation of rhodopsin in the mouse [30].
• Microinjection of a dominant negative Rac mutant altered stress fiber organization, whereas inhibition of Rho was ineffective [47].

References