RhoE Binds to ROCK I and Inhibits Downstream Signaling

Riento, Kirsi; Guasch, Rosa M.; Garg, Ritu; Jin, Boquan; Ridley, Anne J.

doi:10.1128/mcb.23.12.4219-4229.2003

Cited by 272 publications

(295 citation statements)

References 51 publications

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“…Indeed, similar findings are reported for vascular smooth muscle cells where ROCK2, but not ROCK1, binds and phosphorylates MBS [34]. Moreover, the coiled-coil region of ROCK2 (amino acids 338-750) that interacts with MBS shares only 58% homology with the equivalent region in ROCK1 and this domain of ROCK1, but not ROCK2, reportedly binds to RhoE and PDK1 [35, 36] indicating protein-protein interaction specificity between the two paralogs. These findings demonstrate the limitations of generally classifying ROCK1 & 2 activity based solely on data collected from non-selective pharmacological inhibitors.…”

Section: Discussionsupporting

confidence: 65%

Rock1 & 2 Perform Overlapping and Unique Roles in Angiogenesis and Angiosarcoma Tumor Progression

Montalvo¹,

Spencer²,

Hackathorn³

et al. 2012

CMM

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The serine/threonine protein kinase paralogs ROCK1 & 2 have been implicated as essential modulators of angiogenesis; however their paralog-specific roles in endothelial function are unknown. shRNA knockdown of ROCK1 or 2 in endothelial cells resulted in a significant disruption of in vitro capillary network formation, cell polarization, and cell migration compared to cells harboring non-targeting control shRNA plasmids. Knockdowns led to alterations in cytoskeletal dynamics due to ROCK1 & 2-mediated reductions in actin isoform expression, and ROCK2-specific reduction in myosin phosphatase and cofilin phosphorylation. Knockdowns enhanced cell survival and led to ROCK1 & 2-mediated reduction in caspase 6 and 9 cleavage, and a ROCK2-specific reduction in caspase 3 cleavage. Microarray analysis of ROCK knockdown lines revealed overlapping and unique control of global transcription by the paralogs, and a reduction in the transcriptional regulation of just under 50% of VEGF responsive genes. Finally, paralog knockdown in xenograft angiosarcoma tumors resulted in a significant reduction in tumor formation. Our data reveals that ROCK1 & 2 exhibit overlapping and unique roles in normal and dysfunctional endothelial cells, that alterations in cytoskeletal dynamics are capable of overriding mitogen activated transcription, and that therapeutic targeting of ROCK signaling may have profound impacts for targeting angiogenesis.

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Section: Discussionsupporting

confidence: 65%

Rock1 & 2 Perform Overlapping and Unique Roles in Angiogenesis and Angiosarcoma Tumor Progression

Montalvo¹,

Spencer²,

Hackathorn³

et al. 2012

CMM

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“…In this case, Gem would antagonize Rho GTPase signaling at two levels, both down-regulating overall Rho signaling through recruitment of Gmip and specifically inhibiting ROK function via direct interaction. This would be similar to the ability of the Rnd3/RhoE GTPase to both inhibit ROK [67] and act to recruit and activate p190Rho-GAP [68]. Finally, it is important to note that both Rem and Rem2 have been reported to induce cytoskeletal reorganization [41,43,47,58].…”

Section: Rgk Regulation Of Cytoskeletal Dynamics: Modulation Of Rho-dmentioning

confidence: 66%

The RGK family of GTP-binding proteins: Regulators of voltage-dependent calcium channels and cytoskeleton remodeling

Correll¹,

Pang²,

Niedowicz³

et al. 2008

Cellular Signalling

100

136

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RGK proteins constitute a novel subfamily of small Ras-related proteins that function as potent inhibitors of voltage-dependent (VDCC) Ca 2+ channels and regulators of actin cytoskeletal dynamics. Within the larger Ras superfamily, RGK proteins have distinct regulatory and structural characteristics, including nonconservative amino acid substitutions within regions known to participate in nucleotide binding and hydrolysis and a C-terminal extension that contains conserved regulatory sites which control both subcellular localization and function. RGK GTPases interact with the VDCC β-subunit (Ca V β) and inhibit Rho/Rho kinase signaling to regulate VDCC activity and the cytoskeleton respectively. Binding of both calmodulin and 14-3-3 to RGK proteins, and regulation by phosphorylation controls cellular trafficking and the downstream signaling of RGK proteins, suggesting that a complex interplay between interacting protein factors and trafficking contribute to their regulation.

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“…In addition to transcriptional regulation, Rnd3 is also phosphorylated by ROCK1 and PKCα, promoting its stabilization and translocation between the membrane and cytosolic fractions 30, 31. Rnd3 overexpression can inhibit the RhoA‐ROCK signaling pathway by suppressing RhoA activity through a p190RhoGAP‐dependent pathway, as well as by binding to and inhibiting downstream ROCK I signaling 32, 33. This Rnd3‐mediated inhibition of RhoA has also been shown to enhance tight junction barrier function in mammary epithelial cells 34, 35.…”

Section: Introductionmentioning

confidence: 99%

Rnd3 as a Novel Target to Ameliorate Microvascular Leakage

Breslin

Daines

Doggett

et al. 2016

JAHA

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BackgroundMicrovascular leakage of plasma proteins is a hallmark of inflammation that leads to tissue dysfunction. There are no current therapeutic strategies to reduce microvascular permeability. The purpose of this study was to identify the role of Rnd3, an atypical Rho family GTPase, in the control of endothelial barrier integrity. The potential therapeutic benefit of Rnd3 protein delivery to ameliorate microvascular leakage was also investigated.Methods and ResultsUsing immunofluorescence microscopy, Rnd3 was observed primarily in cytoplasmic areas around the nuclei of human umbilical vein endothelial cells. Permeability to fluorescein isothiocyanate–albumin and transendothelial electrical resistance of human umbilical vein endothelial cell monolayers served as indices of barrier function, and RhoA, Rac1, and Cdc42 activities were determined using G‐LISA assays. Overexpression of Rnd3 significantly reduced the magnitude of thrombin‐induced barrier dysfunction, and abolished thrombin‐induced Rac1 inactivation. Depleting Rnd3 expression with siRNA significantly extended the time course of thrombin‐induced barrier dysfunction and Rac1 inactivation. Time‐lapse microscopy of human umbilical vein endothelial cells expressing GFP‐actin showed that co‐expression of mCherry‐Rnd3 attenuated thrombin‐induced reductions in local lamellipodia that accompany endothelial barrier dysfunction. Lastly, a novel Rnd3 protein delivery method reduced microvascular leakage in a rat model of hemorrhagic shock and resuscitation, assessed by both intravital microscopic observation of extravasation of fluorescein isothiocyanate–albumin from the mesenteric microcirculation, and direct determination of solute permeability in intact isolated venules.ConclusionsThe data suggest that Rnd3 can shift the balance of RhoA and Rac1 signaling in endothelial cells. In addition, our findings suggest the therapeutic, anti‐inflammatory potential of delivering Rnd3 to promote endothelial barrier recovery during inflammatory challenge.

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RhoE Binds to ROCK I and Inhibits Downstream Signaling

Cited by 272 publications

References 51 publications

Rock1 & 2 Perform Overlapping and Unique Roles in Angiogenesis and Angiosarcoma Tumor Progression

Rock1 & 2 Perform Overlapping and Unique Roles in Angiogenesis and Angiosarcoma Tumor Progression

The RGK family of GTP-binding proteins: Regulators of voltage-dependent calcium channels and cytoskeleton remodeling

Rnd3 as a Novel Target to Ameliorate Microvascular Leakage

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