Rho GTPases and their effector proteins

Bishop, Anne L.; Hall, Alan

doi:10.1042/bj3480241

Cited by 1,530 publications

(746 citation statements)

References 221 publications

(195 reference statements)

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“…Combined activation of Rac and Cdc42 leads to peripheral translocation of Rac/Cdc42 cytoskeletal effectors cortactin, Arp2/3, WAVE, Arc21, and N-WASP leading to enhancement of cortical actin cytoskeleton and increased width of intercellular adherens junctions essential for EC barrier maintenance [10,[60][61][62][63]. Activation of Rac/Cdc42 effector kinase PAK1 also contributes to activation of WAVE-Arp2/3 complex and initiates peripheral actin polymerization [62]. Moreover, recent findings demonstrate ability of cortactin to regulate intracellular adhesion and cell spreading via direct interactions with cadherin and β-catenin within adherens junctions [64].…”

Section: Discussionmentioning

confidence: 99%

Prostaglandins PGE2 and PGI2 promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation

Birukova

Zagranichnaya

et al. 2007

Experimental Cell Research

264

267

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Prostaglandin E 2 (PGE 2 ) and prostacyclin are lipid mediators produced by cyclooxygenase and implicated in the regulation of vascular function, wound repair, inflammatory processes, and acute lung injury. Although protective effects of these prostaglandins (PGs) are associated with stimulation of intracellular cAMP production, the crosstalk between cAMP-activated signal pathways in the regulation of endothelial cell (EC) permeability is not well understood. We studied involvement of cAMP-dependent kinase (PKA), cAMP-Epac-Rap1 pathway, and small GTPase Rac in the PGsinduced EC barrier protective effects and cytoskeletal remodeling. PGE 2 and PGI 2 synthetic analog beraprost increased transendothelial electrical resistance and decreased dextran permeability, enhanced peripheral F-actin rim and increased intercellular adherens junction areas reflecting EC barrier-protective response. Furthermore, beraprost dramatically attenuated thrombin-induced Rho activation, MLC phosphorylation and EC barrier dysfunction. In vivo, beraprost attenuated lung barrier dysfunction induced by high tidal volume mechanical ventilation. Both PGs caused cAMPmediated activation of PKA-, Epac/Rap1-and Tiam1/Vav2-dependent pathways of Rac1 activation and EC barrier regulation. Knockdown of Epac, Rap1, Rac-specific exchange factors Tiam1 and Vav2 using siRNA approach, or inhibition of PKA activity decreased Rac1 activation and PGinduced EC barrier enhancement. Thus, our results show that barrier-protective effects of PGE 2 and prostacyclin on pulmonary EC are mediated by PKA and Epac/Rap pathways, which converge on Rac activation and lead to enhancement of peripheral actin cytoskeleton and adherens junctions. These mechanisms may mediate protective effects of PGs against agonist-induced lung vascular barrier dysfunction in vitro and against mechanical stress-induced lung injury in vivo.

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Section: Discussionmentioning

confidence: 99%

Prostaglandins PGE2 and PGI2 promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation

Birukova

Zagranichnaya

et al. 2007

Experimental Cell Research

264

267

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“…Rho proteins are master regulators of the actin cytoskeleton (Burridge and Wennerberg 2004;Hall 1998). Moreover, they are involved in cell and smooth muscle contraction, phagocytosis, polarity, activation of transcription, cell cycle progression and cell transformation (Bishop and Hall 2000;Etienne-Manneville and Hall 2002;Jaffe and Hall 2002;Wennerberg and Der 2004). The signal transduction of Rho is terminated by intrinsic hydrolysis of Rho-GTP, which is catalyzed by GTPase activating proteins (GAPs).…”

Section: The Targets Of C3-like Exoenzymes Are Molecular Switchesmentioning

confidence: 99%

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

Vogelsgesang

Pautsch

Aktories

2006

Naunyn-Schmied Arch Pharmacol

102

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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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“…Rho-associated coiled-coil kinases (ROCKs) were initially identified as Rho GTPase effectors (Nakagawa et al, 1996;Ishizaki et al, 1997;Bishop and Hall, 2000). Two members of the ROCK family, ROCK1 (ROK␤) and ROCK2 (ROK␣), have been identified thus far (Nakagawa et al, 1996;Amano et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…ROCK kinases also influence activity of transcription factors (Kuwahara et al, 1999;Yanazume et al, 2002). ROCK kinases are involved in a wide spectrum of cell activities, including cytoskeleton organization, focal adhesion, cell division, cell migration, apoptosis, smooth muscle contraction, and cardiomyocyte hypertrophy (Kuwahara et al, 1999;Amano et al, 2000;Bishop and Hall, 2000;Sah et al, 2000;Aznar and Lacal, 2001;Pruitt and Der, 2001;Yanazume et al, 2002). Recent evidence also suggests that these kinases are involved in cardiac development (Wei et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Rho‐associated kinases play an essential role in cardiac morphogenesis and cardiomyocyte proliferation

Zhao

Rivkees

2002

Developmental Dynamics

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Rho-associated coiled-coil kinases (ROCKs), initially identified as effectors for Rho GTPases, play a role in cardiac cell physiology and are also expressed in the developing heart. However, their role in cardiac development is not known. To investigate the role of these kinases in cardiac development, we examined cardiac development in cultured murine embryos treated with the ROCK inhibitor Y27632. After inhibition of ROCK activity, we found disturbed cardiac chamber formation and trabeculation. To further examine the mechanisms by which ROCK blockade causes cardiac hypoplasia, we assessed programmed cell death and cell proliferation in the hearts. We found decreased cell proliferation in the Y27632-treated hearts, but no changes in programmed cell death. We further observed that ROCK inhibition decreased cardiac myocyte proliferation, suggesting that ROCK kinases regulate cardiomyocyte division. To identify factors involved in ROCK action in regulation of cardiac cell division, we examined expression of cell cycle proteins by using Western blot analysis. We found that ROCK blockade decreased expression of cell cycle proteins, cyclin D3, CDK6, and p27 KIP1 in the hearts and cardiomyocytes, which are required for initiation of cell cycle and G1/S phase transition. These observations show that ROCK kinases play a role in cardiac development and that ROCK kinases regulate cardiac cell proliferation and cell cycle protein expression. Developmental Dynamics 226:24 -32, 2003.

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Rho GTPases and their effector proteins

Cited by 1,530 publications

References 221 publications

Prostaglandins PGE2 and PGI2 promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation

Prostaglandins PGE2 and PGI2 promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation

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

Rho‐associated kinases play an essential role in cardiac morphogenesis and cardiomyocyte proliferation

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