Rnd Proteins Function as RhoA Antagonists by Activating p190 RhoGAP

Wennerberg, Krister; Forget, Marie-Annick; Ellerbroek, Shawn M.; Arthur, William T.; Burridge, Keith; Settleman, Jeffrey; Der, Channing J.; Hansen, Steen Ingemann

doi:10.1016/s0960-9822(03)00418-4

Cited by 216 publications

(252 citation statements)

References 45 publications

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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: 64%

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

Correll¹,

Pang²,

Niedowicz³

et al. 2008

Cellular Signalling

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

confidence: 64%

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

Correll¹,

Pang²,

Niedowicz³

et al. 2008

Cellular Signalling

136

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“…Knowing this, and that Rnd3 was shown to activate p190RhoGAP in COS7 and 3T3 cells,32 we originally predicted that overexpression of Rnd3 in HUVEC would suppress thrombin‐induced RhoA activation. However, our results indicated this was not the case (Figure 4) and therefore we did not pursue this or the interaction between Rnd3 and p190RhoGAP further.…”

Section: Discussionmentioning

confidence: 99%

“…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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“…In addition to RhoA, B, and C they also modify the atypical Rho family member RhoE/Rnd3 (Wilde et al 2001). RhoE and Rnd3 are constitutively active isoforms, which differ only in an addition of 15 amino acids in the N-terminus of Rnd3 and function as a RhoA antagonist (Foster et al 1996;Wennerberg et al 2003;Riento et al 2003). However, the modification of RhoE/Rnd3 has a very slow reaction velocity compared with the ADP-ribosylation of RhoA and the functional relevance is not clear so far.…”

Section: Introductionmentioning

confidence: 99%

C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins

Vogelsgesang

Pautsch

Aktories

2006

Naunyn-Schmied Arch Pharmacol

100

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The family of C3-like exoenzymes comprises seven bacterial ADP-ribosyltransferases of different origin. The common hallmark of these exoenzymes is the selective N-ADP-ribosylation of the low molecular mass GTPbinding proteins RhoA, B, and C and inhibition of signal pathways controlled by Rho GTPases. Therefore, C3-like exoenzymes were applied as pharmacological tools for analyses of cellular functions of Rho protein in numerous studies. Recent structural and functional analyses of C3-like exoenzymes provide detailed information on the molecular mechanisms and functional consequences of ADP-ribosylation catalyzed by these toxins. More recently additional non-enzymatic actions of C3-like ADP-ribosyltransferases have been identified showing that C3 transferases from Clostridium botulinum and Clostridium limosum form a GDI-like complex with the Ras-like low molecular mass GTPase Ral without ADP-ribosylation. These results add novel information on the molecular mode of action(s) of C3-like exoenzymes and are discussed in this review.

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Rnd Proteins Function as RhoA Antagonists by Activating p190 RhoGAP

Abstract: Our results identify p190 RhoGAPs as effectors of Rnd proteins and demonstrate a novel mechanism by which Rnd proteins function as antagonists of RhoA.

Cited by 216 publications

References 45 publications

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

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

C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins

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