靶向Rho通路的抗高血压治疗策略研究进展
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摘要
在过去几十年中,高血压的患病率呈逐年上升趋势。它不但增加左心室肥厚、心绞痛、心肌梗死和心力衰竭等心血管疾病的患病风险,还可能导致卒中(中风)、肾衰竭等相关后遗症。尽管目前有多种降压方案可供选择,但经过药物治疗后,只有半数患者可有效控制血压,这意味着需要进一步了解潜在的致病因素并寻求更有效的治疗方法。然而血压稳态非常复杂,涉及多个系统的综合控制,其中平滑肌收缩力和动脉阻力是重要因素。来自临床前动物模型和全基因组关联研究的有力证据表明,平滑肌收缩和血压稳态受小分子GTP酶RhoA及其下游靶点Rho激酶控制。本文总结了平滑肌细胞中对RhoA活性进行严格控制的信号通路及调节器的相关进展,并讨论了当前针对这些RhoA通路成分的高血压治疗策略。还讨论了RhoA通路中已知的等位基因变异,并介绍了这些遗传多态性对高血压遗传风险的影响及其临床表现。
In the past few decades,the prevalence of hypertension has steadily increased. Hypertention is known as a silent killer,which not only increases the risk of cardiovascular disease,but also can lead to stroke,heart attack,kidney failure and related sequelae. Although there are currently a variety of anti-hypertensive therapies available,only half of the patients have effective blood pressure(BP)control after medication treatment,which means a better understanding of potential pathogenic factors is needed for seeking more effective treatments. However,BP homeostasis is very complex and involves comprehensive control of multiple systems,in which smooth muscle contractility and arterial resistance are important factors. Strong evidence from pre-clinical animal model and genome-wide association studies have suggested that the smooth muscle contraction and BP homeostasis are controlled by the small molecule GTPase RhoA and its downstream target,Rho-associated coiled coil domain containing protein kineses(ROCK). In this review,we summarize research progress in the pathways and regulators that control RhoA activity in smooth muscle cells,and discuss current treatment strategies targeting these RhoA pathway components for treatment of hypertension. We also discuss known allelic variations in the RhoA pathway and introduce the effect of the polymorphism on the genetic risk of hypertension and its clinical manifestations.
In the past few decades,the prevalence of hypertension has steadily increased. Hypertention is known as a silent killer,which not only increases the risk of cardiovascular disease,but also can lead to stroke,heart attack,kidney failure and related sequelae. Although there are currently a variety of anti-hypertensive therapies available,only half of the patients have effective blood pressure(BP)control after medication treatment,which means a better understanding of potential pathogenic factors is needed for seeking more effective treatments. However,BP homeostasis is very complex and involves comprehensive control of multiple systems,in which smooth muscle contractility and arterial resistance are important factors. Strong evidence from pre-clinical animal model and genome-wide association studies have suggested that the smooth muscle contraction and BP homeostasis are controlled by the small molecule GTPase RhoA and its downstream target,Rho-associated coiled coil domain containing protein kineses(ROCK). In this review,we summarize research progress in the pathways and regulators that control RhoA activity in smooth muscle cells,and discuss current treatment strategies targeting these RhoA pathway components for treatment of hypertension. We also discuss known allelic variations in the RhoA pathway and introduce the effect of the polymorphism on the genetic risk of hypertension and its clinical manifestations.
引文
[1]Lim SS,Vos T,Flaxman AD,et al.A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions,1990-2010:a systematic analysis for the Global Burden of Disease Study 2010[J].Lancet,2012,380(9859):2224-2260.
[2]Hinderliter AL,Voora RA,Viera AJ.Implementing ABPM into clinical practice[J].Curr Hypertens Rep,2018,20(1):5.
[3]Yoon S,Fryar C,Carroll M.Hypertension prevalence and control among adults:United States,2011-2014[J].NCHS Data Brief,2015,220(220):1-8.
[4]Achelrod D,Wenzel U,Frey S.Systematic review and metaanalysis of the prevalence of resistant hypertension in treated hypertensive populations[J].Am J Hypertens,2015,28(3):355-361.
[5]Ehret GB,Ferreira T,Chasman DI,et al.The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals[J].Nat Genet,2016,48(10):1171-1184.
[6]Guilluy C,Bregeon J,Toumaniantz G,et al.The Rho exchange factor Arhgef1 mediates the effects of angiotensinⅡon vascular tone and blood pressure[J].Nat Med,2010,16(2):183-190.
[7]Loirand G.Rho Kinases in health and disease:from basic science to translational research[J].Pharmacol Rev,2015,67(4):1074-1095.
[8]Narumiya S,Thumkeo D.Rho Signaling research:history,current status and future directions[J].FEBS Lett,2018,592(11):1763-1776.
[9]Cowley AW.The genetic dissection of essential hypertension[J].Nat Rev Genet,2006,7(11):829-840.
[10]Budzyn K,Marley PD,Sobey CG.Targeting Rho and Rho-kinase in the treatment of cardiovascular disease[J].Trends Pharmacol Sci,2006,27(2):97-104.
[11]Loirand G,Pacaud P.The role of Rho protein signaling in hypertension[J].Nat Rev Cardiol,2010,7(11):637-647.
[12]Carlstrom M,Wilcox CS,Arendshorst WJ.Renal autoregulation in health and disease[J].Physiol Rev,2015,95(2):405-511.
[13]Homma K,Hayashi K,Wakino S,et al.Rho-kinase contributes to pressure-induced constriction of renal microvessels[J].Keio JMed,2014,63(1):1-12.
[14]Feng Y,LoGrasso PV,Defert O,et al.Rho kinase(ROCK)inhibitors and their therapeutic potential[J].J Med Chem,2016,59(6):2269-2300.
[15]Ibeawuchi SR,Agbor LN,Quelle FW,et al.Hypertension-causing mutations in Cullin3 protein impair RhoA protein ubiquitination and augment the association with substrate adaptors[J].JBiol Chem,2015,290(31):19208-19217.
[16]Levy D,Ehret GB,Rice K,et al.Genome-wide association study of blood pressure and hypertension[J].Nat Genet,2009,41(6):677-687.
[17]Lin Y,Lai X,Chen B,et al.Genetic variations in CYP17A1,CACNB2 and PLEKHA7 are associated with blood pressure and/or hypertension in She ethnic minority of China[J].Atherosclerosis,2011,219(2):709-714.
[18]Citi S,Pulimeno P,Paschoud S.Cingulin,paracingulin,and PLEKHA7:signaling and cytoskeletal adaptors at the apical junctional complex[J].Ann N Y Acad Sci,2012,1257(1):125-132.
[19]Endres BT,Priestley JR,Palygin O,et al.Mutation of Plekha7attenuates salt-sensitive hypertension in the rat[J].Proc Nat Acad Sci USA,2014,111(35):12817-12822.
[20]Liao YC,Liu PY,Lin HF,et al.Two functional polymorphisms of ROCK2 enhance arterial stiffening through inhibiting its activity and expression[J].J Mol Cell Cardiol,2015,79(2):180-186.
[21]Li C,He J,Chen J,et al.Genome-wide gene-sodium interaction analyses on blood pressure:the genetic epidemiology network of saltsensitivity study[J].Hypertension,2016,68(2):348-355.
[22]Kato N,Loh M,Takeuchi F,et al.Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation[J].Nat Genet,2015,47(11):1282-1293.
[23]Bai X,Lenhart KC,Bird KE,et al.The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension[J].Nat Commun,2013,4(11):2910-2918.
[24]Bai X,Mangum K,Kakoki,et al.GRAF3 serves as a blood volume-sensitive rheostat to control smooth muscle contractility and blood pressure[J].Small GTPases,2018,9(2):1-10.
[25]Bai X,Mangum KD,Dee RA,et al.Blood pressure-associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding[J].J Clin Invest,2017,127(2):670-680.
[26]Nagumo H,Sasaki Y,Ono Y,et al.Rho Kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells[J].Am J Physiol Cell Physio,2000,278(1):C57-C65.
[27]Takemoto M,Sun J,Hiroki J,et al.Rho-kinase mediates hypoxiainduced downregulation of endothelial nitric oxide synthase[J].Circulation,2002,106(1):57-62.
[28]Ocaranza MP,Rivera P,Novoa U,et al.Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9)axis in experimental hypertension[J].J Hypertens,2001,29(4):706-715.
[29]Garnock-Jones KP.Ripasudil:first global approval[J].Drugs,2014,74(18):2211-2215.
[30]Lu LJ,Tsai JC,Liu J.Novel pharmacological candidates for treatment of primary open-angle glaucoma[J].Yale J Biol Med,2017,90(1):111-118.
[31]Uehata M,Ishizaki T,Satoh H,et al.Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension[J].Nature,1997,389(6654):990-994.
[32]Lohn M,Plettenburg O,Ivashchenko Y,et al.Pharmacological characterization of SAR407899,a novel Rho-kinase inhibitor[J].Hypertension,2009,54(3):676-683.
[33]Grisk O,Schluter T,Reimer N,et al.The Rho kinase inhibitor SAR407899 potently inhibits endothelin-1-induced constriction of renal resistance arteries[J].J Hypertens,2012,30,(5):980-989.
[34]Loirand G,Pacaud P.Involvement of Rho GTPases and their regulators in the pathogenesis of hypertension[J].Small GTPases,2014,5(4):e28846.
[35]Surma M,Wei L,Shi J.Rho kinase as a therapeutic target in cardiovascular disease[J].Future Cardiol,2011,7(5):657-671.
[36]Jansen S,Gosens R,Wieland T,et al.Paving the Rho in cancer metastasis:Rho GTPases and beyond[J].Pharmacol Ther,2018,183(3):1-21.
[37]Olson MF.Rho GTPases,their post-translational modifications,disease-associated mutations and pharmacological inhibitors[J].Small GTPases,2018,9(3):203-215.
[38]Porter AP,Papaioannou A,Malliri A.Deregulation of Rho GTPases in cancer[J].Small GTPases,2016,7(3):123-138.
[39]Hong L,Kenney SR,Phillips GK,et al.Characterization of a Cdc42 protein inhibitor and its use as a molecular probe[J].JBiol Chem,2013,289(10):8531-8543.
[40]Oprea TI,Sklar LA,Agola JO,et al.Novel activities of select NSAID R-enantiomers against Rac1 and Cdc42 GTPases[J].PLoS One,2015,10(11):e0142182.
[41]Lemichez E.New aspects on bacterial effectors targeting Rho GTPases[J].Curr Top Micr Immunol,2017,399(10),155-174.
[42]Kanaki AI,Sarafidis PA,Georgianos PI,et al.Effects of lowdose atorvastatin on arterial stiffness and central aortic pressure augmentation in patients with hypertension and hypercholesterolemia[J].Am J Hypertens,2013,26(5):608-616.
[43]Cario-Toumaniantz C,Ferland-McCollough D,Chadeuf G,et al.RhoA guanine exchange factor expression profile in arteries:evidence for a Rho kinase-dependent negative feedback in angiotensinⅡ-dependent hypertension[J].Am J Physiol,2012,302(9):C1394-C1404.
[44]Beglov D,Hall DR,Wakefield A,et al.Exploring the structural origins of cryptic sites on proteins[J].Proc Nat Acad Sci USA,2018,115(15):E3416-E3425.
[45]Shang X,Marchioni F,Sipes N,et al.Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases[J].Chem Biol,2012,19(6):699-710.
[46]Cherfils J,Melancon P.On the action of brefeldin A on Sec7-stimulated membrane-recruitment and GDP/GTP exchange of Arf proteins[J].Biochem Soc Trans,2005,33(4):635-638.
[47]Gao J,Ma R,Wang W,et al.Automated NMR fragment based screening identified a novel interface blocker to the LARG/RhoA complex[J].PLoS One,2014,9(2):e88098.
[48]Smithers CC,Overduin M.Structural mechanisms and drug discovery prospects of Rho GTPases[J].Cell,2016,5(2):26.
[49]Shang X,Marchioni F,Evelyn CR,et al.Small molecule inhibitors targeting G-protein-coupled Rho guanine nucleotide exchange factors[J].Proc Nat Acad Sci USA,2013,110(8):3155-3160.
[50]Evelyn CR,Ferng T,Rojas RJ,et al.Highthroughput screening for small-molecule inhibitors of LARG-stimulated RhoA nucleotide binding via a novel fluorescence polarization assay[J].JBiomol Screen,2009,14(2):161-172.
[51]Guilluy C,Bregeon J,Toumaniantz G,et al.The Rho exchange factor Arhgef1 mediates the effects of angiotensinⅡon vascular tone and blood pressure[J].Nat Med,2010,16(2):183-190.
[52]Ying Z,Giachini FR,Tostes RC,et al.PYK2/PDZ-RhoGEFlinks Ca2+signaling to RhoA[J].Arterioscler Thromb Vasc Biol,2009,29(10):1657-1663.
[53]Shi GX,Yang WS,Jin L,et al.RSK2 drives cell motility by serine phosphorylation of LARG and activation of Rho GTPases[J].Proc Nati Acad Sci USA,2018,115(2):E190-E199.
[54]Bos JL,Rehmann H,Wittinghofer A.GEFs and GAPs:critical elements in the control of small G proteins[J].Cell,2007,129(5):865-877.
[55]Tcherkezian J,Lamarche-Vane N.Current knowledge of the large RhoGAP family of proteins[J].Biol Cell,2007,99(2):67-86.
[56]Kakoki M,Pochynyuk OM,Hathaway CM,et al.Primary aldosteronism and impaired natriuresis in mice underexpressing TGFbeta1[J].Proc Nat Acad Sci USA,2013,110(14):5600-5605.
[57]Eberth A,Lundmark R,Gremer L,et al.A BAR domain-mediated autoinhibitory mechanism for RhoGAPs of the GRAF family[J].Biochem J,2009,417(1):371-377.
[58]Luo W,Janostiak R,Tolde O,et al.ARHGAP42 is activated by Src-mediated tyrosine phosphorylation to promote cell motility[J].J Cell Sci,2017,130(14):2382-2393.
[2]Hinderliter AL,Voora RA,Viera AJ.Implementing ABPM into clinical practice[J].Curr Hypertens Rep,2018,20(1):5.
[3]Yoon S,Fryar C,Carroll M.Hypertension prevalence and control among adults:United States,2011-2014[J].NCHS Data Brief,2015,220(220):1-8.
[4]Achelrod D,Wenzel U,Frey S.Systematic review and metaanalysis of the prevalence of resistant hypertension in treated hypertensive populations[J].Am J Hypertens,2015,28(3):355-361.
[5]Ehret GB,Ferreira T,Chasman DI,et al.The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals[J].Nat Genet,2016,48(10):1171-1184.
[6]Guilluy C,Bregeon J,Toumaniantz G,et al.The Rho exchange factor Arhgef1 mediates the effects of angiotensinⅡon vascular tone and blood pressure[J].Nat Med,2010,16(2):183-190.
[7]Loirand G.Rho Kinases in health and disease:from basic science to translational research[J].Pharmacol Rev,2015,67(4):1074-1095.
[8]Narumiya S,Thumkeo D.Rho Signaling research:history,current status and future directions[J].FEBS Lett,2018,592(11):1763-1776.
[9]Cowley AW.The genetic dissection of essential hypertension[J].Nat Rev Genet,2006,7(11):829-840.
[10]Budzyn K,Marley PD,Sobey CG.Targeting Rho and Rho-kinase in the treatment of cardiovascular disease[J].Trends Pharmacol Sci,2006,27(2):97-104.
[11]Loirand G,Pacaud P.The role of Rho protein signaling in hypertension[J].Nat Rev Cardiol,2010,7(11):637-647.
[12]Carlstrom M,Wilcox CS,Arendshorst WJ.Renal autoregulation in health and disease[J].Physiol Rev,2015,95(2):405-511.
[13]Homma K,Hayashi K,Wakino S,et al.Rho-kinase contributes to pressure-induced constriction of renal microvessels[J].Keio JMed,2014,63(1):1-12.
[14]Feng Y,LoGrasso PV,Defert O,et al.Rho kinase(ROCK)inhibitors and their therapeutic potential[J].J Med Chem,2016,59(6):2269-2300.
[15]Ibeawuchi SR,Agbor LN,Quelle FW,et al.Hypertension-causing mutations in Cullin3 protein impair RhoA protein ubiquitination and augment the association with substrate adaptors[J].JBiol Chem,2015,290(31):19208-19217.
[16]Levy D,Ehret GB,Rice K,et al.Genome-wide association study of blood pressure and hypertension[J].Nat Genet,2009,41(6):677-687.
[17]Lin Y,Lai X,Chen B,et al.Genetic variations in CYP17A1,CACNB2 and PLEKHA7 are associated with blood pressure and/or hypertension in She ethnic minority of China[J].Atherosclerosis,2011,219(2):709-714.
[18]Citi S,Pulimeno P,Paschoud S.Cingulin,paracingulin,and PLEKHA7:signaling and cytoskeletal adaptors at the apical junctional complex[J].Ann N Y Acad Sci,2012,1257(1):125-132.
[19]Endres BT,Priestley JR,Palygin O,et al.Mutation of Plekha7attenuates salt-sensitive hypertension in the rat[J].Proc Nat Acad Sci USA,2014,111(35):12817-12822.
[20]Liao YC,Liu PY,Lin HF,et al.Two functional polymorphisms of ROCK2 enhance arterial stiffening through inhibiting its activity and expression[J].J Mol Cell Cardiol,2015,79(2):180-186.
[21]Li C,He J,Chen J,et al.Genome-wide gene-sodium interaction analyses on blood pressure:the genetic epidemiology network of saltsensitivity study[J].Hypertension,2016,68(2):348-355.
[22]Kato N,Loh M,Takeuchi F,et al.Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation[J].Nat Genet,2015,47(11):1282-1293.
[23]Bai X,Lenhart KC,Bird KE,et al.The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension[J].Nat Commun,2013,4(11):2910-2918.
[24]Bai X,Mangum K,Kakoki,et al.GRAF3 serves as a blood volume-sensitive rheostat to control smooth muscle contractility and blood pressure[J].Small GTPases,2018,9(2):1-10.
[25]Bai X,Mangum KD,Dee RA,et al.Blood pressure-associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding[J].J Clin Invest,2017,127(2):670-680.
[26]Nagumo H,Sasaki Y,Ono Y,et al.Rho Kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells[J].Am J Physiol Cell Physio,2000,278(1):C57-C65.
[27]Takemoto M,Sun J,Hiroki J,et al.Rho-kinase mediates hypoxiainduced downregulation of endothelial nitric oxide synthase[J].Circulation,2002,106(1):57-62.
[28]Ocaranza MP,Rivera P,Novoa U,et al.Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9)axis in experimental hypertension[J].J Hypertens,2001,29(4):706-715.
[29]Garnock-Jones KP.Ripasudil:first global approval[J].Drugs,2014,74(18):2211-2215.
[30]Lu LJ,Tsai JC,Liu J.Novel pharmacological candidates for treatment of primary open-angle glaucoma[J].Yale J Biol Med,2017,90(1):111-118.
[31]Uehata M,Ishizaki T,Satoh H,et al.Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension[J].Nature,1997,389(6654):990-994.
[32]Lohn M,Plettenburg O,Ivashchenko Y,et al.Pharmacological characterization of SAR407899,a novel Rho-kinase inhibitor[J].Hypertension,2009,54(3):676-683.
[33]Grisk O,Schluter T,Reimer N,et al.The Rho kinase inhibitor SAR407899 potently inhibits endothelin-1-induced constriction of renal resistance arteries[J].J Hypertens,2012,30,(5):980-989.
[34]Loirand G,Pacaud P.Involvement of Rho GTPases and their regulators in the pathogenesis of hypertension[J].Small GTPases,2014,5(4):e28846.
[35]Surma M,Wei L,Shi J.Rho kinase as a therapeutic target in cardiovascular disease[J].Future Cardiol,2011,7(5):657-671.
[36]Jansen S,Gosens R,Wieland T,et al.Paving the Rho in cancer metastasis:Rho GTPases and beyond[J].Pharmacol Ther,2018,183(3):1-21.
[37]Olson MF.Rho GTPases,their post-translational modifications,disease-associated mutations and pharmacological inhibitors[J].Small GTPases,2018,9(3):203-215.
[38]Porter AP,Papaioannou A,Malliri A.Deregulation of Rho GTPases in cancer[J].Small GTPases,2016,7(3):123-138.
[39]Hong L,Kenney SR,Phillips GK,et al.Characterization of a Cdc42 protein inhibitor and its use as a molecular probe[J].JBiol Chem,2013,289(10):8531-8543.
[40]Oprea TI,Sklar LA,Agola JO,et al.Novel activities of select NSAID R-enantiomers against Rac1 and Cdc42 GTPases[J].PLoS One,2015,10(11):e0142182.
[41]Lemichez E.New aspects on bacterial effectors targeting Rho GTPases[J].Curr Top Micr Immunol,2017,399(10),155-174.
[42]Kanaki AI,Sarafidis PA,Georgianos PI,et al.Effects of lowdose atorvastatin on arterial stiffness and central aortic pressure augmentation in patients with hypertension and hypercholesterolemia[J].Am J Hypertens,2013,26(5):608-616.
[43]Cario-Toumaniantz C,Ferland-McCollough D,Chadeuf G,et al.RhoA guanine exchange factor expression profile in arteries:evidence for a Rho kinase-dependent negative feedback in angiotensinⅡ-dependent hypertension[J].Am J Physiol,2012,302(9):C1394-C1404.
[44]Beglov D,Hall DR,Wakefield A,et al.Exploring the structural origins of cryptic sites on proteins[J].Proc Nat Acad Sci USA,2018,115(15):E3416-E3425.
[45]Shang X,Marchioni F,Sipes N,et al.Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases[J].Chem Biol,2012,19(6):699-710.
[46]Cherfils J,Melancon P.On the action of brefeldin A on Sec7-stimulated membrane-recruitment and GDP/GTP exchange of Arf proteins[J].Biochem Soc Trans,2005,33(4):635-638.
[47]Gao J,Ma R,Wang W,et al.Automated NMR fragment based screening identified a novel interface blocker to the LARG/RhoA complex[J].PLoS One,2014,9(2):e88098.
[48]Smithers CC,Overduin M.Structural mechanisms and drug discovery prospects of Rho GTPases[J].Cell,2016,5(2):26.
[49]Shang X,Marchioni F,Evelyn CR,et al.Small molecule inhibitors targeting G-protein-coupled Rho guanine nucleotide exchange factors[J].Proc Nat Acad Sci USA,2013,110(8):3155-3160.
[50]Evelyn CR,Ferng T,Rojas RJ,et al.Highthroughput screening for small-molecule inhibitors of LARG-stimulated RhoA nucleotide binding via a novel fluorescence polarization assay[J].JBiomol Screen,2009,14(2):161-172.
[51]Guilluy C,Bregeon J,Toumaniantz G,et al.The Rho exchange factor Arhgef1 mediates the effects of angiotensinⅡon vascular tone and blood pressure[J].Nat Med,2010,16(2):183-190.
[52]Ying Z,Giachini FR,Tostes RC,et al.PYK2/PDZ-RhoGEFlinks Ca2+signaling to RhoA[J].Arterioscler Thromb Vasc Biol,2009,29(10):1657-1663.
[53]Shi GX,Yang WS,Jin L,et al.RSK2 drives cell motility by serine phosphorylation of LARG and activation of Rho GTPases[J].Proc Nati Acad Sci USA,2018,115(2):E190-E199.
[54]Bos JL,Rehmann H,Wittinghofer A.GEFs and GAPs:critical elements in the control of small G proteins[J].Cell,2007,129(5):865-877.
[55]Tcherkezian J,Lamarche-Vane N.Current knowledge of the large RhoGAP family of proteins[J].Biol Cell,2007,99(2):67-86.
[56]Kakoki M,Pochynyuk OM,Hathaway CM,et al.Primary aldosteronism and impaired natriuresis in mice underexpressing TGFbeta1[J].Proc Nat Acad Sci USA,2013,110(14):5600-5605.
[57]Eberth A,Lundmark R,Gremer L,et al.A BAR domain-mediated autoinhibitory mechanism for RhoGAPs of the GRAF family[J].Biochem J,2009,417(1):371-377.
[58]Luo W,Janostiak R,Tolde O,et al.ARHGAP42 is activated by Src-mediated tyrosine phosphorylation to promote cell motility[J].J Cell Sci,2017,130(14):2382-2393.