Disease relevance of Rho

• RESULTS AND CONCLUSIONS: Inhibition of Rho proteins with Clostridium difficile toxin B or inhibition of Rho prenylation with GGTI attenuated PTH(1-34)- and PTH(3-34)-stimulated translocation of endogenous PKCalpha and IL-6 promoter activity [1].
• Extremely prolonged survival of phosphorylated forms of Rho may contribute to persistent misregulation of phototransduction processes in retinal degeneration in RCS rat [2].
• The heterozygous P23H transgenic rat is a model of autosomal dominant retinitis pigmentosa, in which a mutation in the rhodopsin gene leads to a rapid loss of rods and a more protracted loss of cones [3].
• Y-27632 consistently suppresses Rho-induced, p160ROCK-mediated formation of stress fibres in cultured cells and dramatically corrects hypertension in several hypertensive rat models [4].
• Using a binding assay to measure Rho activity, we detected increased levels of GTP Rho in PC12 and dorsal root ganglion (DRG) cell lysates after Nogo-66 stimulation [5].

Psychiatry related information on Rho

• Our finding, that Rho-kinase antagonism stimulates rat penile erection independently of nitric oxide, introduces a potential alternate avenue for the treatment of erectile dysfunction [6].
• These results suggest that Rho-kinase is sufficient to activate myosin II motor activity and contraction in REF-52 cells [7].
• RhoA/Rho kinase and nitric oxide modulate the agonist-induced pulmonary artery diameter response time [8].

High impact information on Rho

• Using pharmacologic antagonism (Y-27632, ref. 13, 18), we examined the role of Rho-kinase in cavernosal tone, based on the hypothesis that antagonism of Rho-kinase results in increased corpus cavernosum pressure, initiating the erectile response independently of nitric oxide [6].
• The calcium-sensitizing rho-A/Rho-kinase pathway may play a synergistic role in cavernosal vasoconstriction to maintain penile flaccidity [6].
• Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway [6].
• Transfection of MM1 cells with cDNA encoding a dominant active mutant of ROCK conferred invasive activity independently of serum and Rho [9].
• Cultured rat MM1 hepatoma cells migrate through a mesothelial cell monolayer in vitro in a serum-dependent, Rho-mediated manners [9].

Chemical compound and disease context of Rho

• A small GTPase Rho and one of its downstream effectors ROCK (Rho-associated coiled-coil forming protein kinase), play essential roles in these processes, as evidenced by suppression of migration and morphological change of MM1 cells by Clostridium botulinum C3 exoenzyme, an inhibitor of Rho, or by Y-27632, an inhibitor of ROCK [10].
• 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/ p21 signaling pathway: Implications for diabetic nephropathy [11].
• Here, we tested the hypothesis that RhoA/Rho-kinase contributes to diabetes-related erectile dysfunction and down-regulation of eNOS in the streptozotocin (STZ)-diabetic rat penis [12].
• For identification of Rab, Rac, Rho, Ral, Rap, and Arf proteins on two-dimensional polyacrylamide gels, we have expressed full-length cDNAs of members of these protein families with the T7 RNA polymerase-recombinant vaccinia virus expression system [13].
• Involvement of Rho-kinase in angiotensin II-induced hypertrophy of rat vascular smooth muscle cells [14].

Biological context of Rho

• Our results highlight a novel role for Rho GTPases in mediating the regulatory effects of GPCRs on STAT-dependent gene expression [15].
• In vitro studies demonstrated decreased levels of both Rho phosphorylation and dephosphorylation reactions in RCS retinas [2].
• Prolonged survival of the phosphorylated form of rhodopsin during dark adaptation of Royal College Surgeons rat [2].
• These results indicate that thrombin activates Rho in RASMCs and establish Rho as a critical mediator of thrombin receptor effects on DNA synthesis and cell migration in these cells [16].
• Transient cotransfection of 293T cells with expression plasmids for p160ROCK (Rho-associated coiled-coil-containing kinase) and v-Crk, but not SH2 or SH3 mutants of v-Crk, results in hyperactivation of p160ROCK [17].

Anatomical context of Rho

• Small GTPases of the Rho family play key roles in the formation of neuronal axons and dendrites by transducing signals from guidance cues, such as neurotrophins, to the actin cytoskeleton [18].
• To elucidate molecular mechanisms that regulate proliferation and migration of vascular smooth muscle cells, we determined whether signaling through the small G protein Rho is involved in thrombin- and phenylephrine-stimulated proliferation and migration of rat aortic smooth muscle cells (RASMCs) [16].
• Rho and Rho kinase mediate thrombin-stimulated vascular smooth muscle cell DNA synthesis and migration [16].
• Activation of Rho-dependent cell spreading and focal adhesion biogenesis by the v-Crk adaptor protein [17].
• Our results indicate that v-Crk activates the Rho-signaling pathway and serves as a scaffolding protein during the assembly of focal adhesions in PC12 cells [17].

Associations of Rho with chemical compounds

• The Rho kinase inhibitor Y27632 attenuated PTH(1-34)- and PTH(3-34)-stimulated PKCalpha translocation and IL-6 promoter activation [1].
• The C3 exoenzyme, which ADP-ribosylates and inactivates Rho, fully inhibited both thrombin-stimulated proliferation and migration but had no effect on inositol phosphate accumulation [16].
• Moreover, the level of phosphatidylinositol-4,5-bisphosphate is increased in v-CrkPC12 cells compared to the levels in mutant v-Crk-expressing cells or wild-type cells, consistent with PI(4)P5 kinase being a downstream target for Rho [17].
• Thrombin and SFLLRNP, but not phenylephrine, also increased membrane-associated Rho in intact RASMCs, consistent with selective activation of Rho by thrombin [16].
• Analysis of Rho-family GAP domain sequences for conserved arginine residues that might contribute to accelerate GTP hydrolysis revealed a single conserved arginine residue [19].

Physical interactions of Rho

• Alternatively, astrocytes were transfected with an expression vector encoding fusion proteins of enhanced green fluorescent protein with either the Rho-binding domain of Rhotekin, which blocks RhoA function, or the dominant-negative N19RhoA mutant [20].
• We found that p75 can directly bind the GTPases Ras and Rho and that the unstimulated p75 inactivates total cellular Ras through a differential influence on the dissociation of GDP and GTP from Ras and an exchange of bound Ras.GDP for free Ras.GTP [21].
• They become activated by interaction with Rho-type small GTP-binding proteins Rac and Cdc42 in the GTP-bound conformation, thereby relieving the inhibition of the regulatory domain (RD) on the catalytic domain (CD) [22].
• In conclusion, our results demonstrate CCKA receptor activation causes rapid tyrosine phosphorylation of p130(Cas) through PLC-dependent and -independent mechanisms that require the participation of the small GTP-binding protein Rho and the integrity of the actin cytoskeleton, but not the microtubule network [23].
• Suppression of the whole protein or expression of a mutant form lacking the Rho-binding activity results in dispersion of the Golgi apparatus [24].

Enzymatic interactions of Rho

• Here, we report that the collapsing response mediator protein-2 (CRMP-2) is phosphorylated by a Rho-kinase-dependent mechanism downstream of MAG or Nogo-66 [25].

Regulatory relationships of Rho

• Glucosamine treatment was shown to activate Rho [26].
• In addition, stimulation of EP3 receptors inhibited the AVP-induced Rho inactivation and the AVP-induced F-actin depolymerization [27].
• Additionally, JNK activation but not ERK activation was inhibited by the expression of C3 exoenzyme that inactivates small GTPase Rho [28].
• Actin cytoskeletal dynamics and Rho signaling are involved in regulation of cytokine-induced iNOS expression in BSMC [29].
• CONCLUSION: ET-1 induced contraction and migration of PSCs through ET receptors and activation of Rho-Rho kinase [30].

Other interactions of Rho

• Rho and Rho kinase are involved in parathyroid hormone-stimulated protein kinase C alpha translocation and IL-6 promoter activity in osteoblastic cells [1].
• The effect of ROS on cell morphology and motility probably results from modulation of activity of Rac1, Rho, and cofilin proteins playing a key role in regulation of actin dynamics [31].
• In addition, Y-27632, an inhibitor of the Rho effector p160ROCK/Rho kinase, decreased thrombin-stimulated DNA synthesis and migration [16].
• Thus, both Rho GTPase and calcium/calmodulin contribute to the control of cortical F-actin disassembly [32].
• A yeast two-hybrid analysis using the coiled-coil domain of neurabin revealed an interaction with Lfc, a Rho GEF [33].

Analytical, diagnostic and therapeutic context of Rho

• Luteolin influenced migration by modulating the activity of Rho GTPases, signal transducers involved in transendothelial migration [34].
• In cell culture (NIH-3T3, rat basophilic leukemia cells) toxin A inhibits Clostridium botulinum ADP-ribosyltransferase C3 (C3)-catalyzed ADP-ribosylation of the low molecular mass GTP-binding Rho proteins [35].
• METHODS: Aortic expressions of RhoA and Rho-kinase were analyzed in sham-operated and BDL rats by reverse-transcription polymerase chain reaction (RT-PCR) and immunoblots [36].
• The hemodynamic effect of the Rho-kinase inhibitor (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632) was determined in vivo by measuring changes in mean arterial pressure and systemic vascular resistance (SVR) (microspheres) [36].
• The absence of the involvement of Rho was further confirmed by the treatment with lysophosphatidic acid or microinjection with the constitutively activated form of RhoA, both of which induced the stress fiber formation without affecting the Golgi complex [37].

References