Identification and characterization of the unique guanine nucleotide exchange factor, SmgGDS, in vascular smooth muscle cells

Thill, R; Campbell, William B.; Williams, Carol L.

doi:10.1002/jcb.21740

Cited by 7 publications

(7 citation statements)

References 45 publications

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“…12). This conclusion is supported by reports that many cellular processes regulated by small GTPases, including NF-κB activity, actin/myosin interactions, contractile responses, and cell migration and proliferation, are inhibited by diminishing SmgGDS expression in cancer cells (12, 13) or other cell types (14). …”

Section: Introductionmentioning

confidence: 52%

Splice Variants of SmgGDS Control Small GTPase Prenylation and Membrane Localization

Berg

Gastonguay

Lorimer

et al. 2010

Journal of Biological Chemistry

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183

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Ras and Rho small GTPases possessing a C-terminal polybasic region (PBR) are vital signaling proteins whose misregulation can lead to cancer. Signaling by these proteins depends on their ability to bind guanine nucleotides and their prenylation with a geranylgeranyl or farnesyl isoprenoid moiety and subsequent trafficking to cellular membranes. There is little previous evidence that cellular signals can restrain nonprenylated GTPases from entering the prenylation pathway, leading to the general belief that PBR-possessing GTPases are prenylated as soon as they are synthesized. Here, we present evidence that challenges this belief. We demonstrate that insertion of the dominant negative mutation to inhibit GDP/GTP exchange diminishes prenylation of Rap1A and RhoA, enhances prenylation of Rac1, and does not detectably alter prenylation of K-Ras. Our results indicate that the entrance and passage of these small GTPases through the prenylation pathway is regulated by two splice variants of SmgGDS, a protein that has been reported to promote GDP/GTP exchange by PBR-possessing GTPases and to be up-regulated in several forms of cancer. We show that the previously characterized 558-residue SmgGDS splice variant (SmgGDS-558) selectively associates with prenylated small GTPases and facilitates trafficking of Rap1A to the plasma membrane, whereas the less well characterized 607-residue SmgGDS splice variant (SmgGDS-607) associates with nonprenylated GTPases and regulates the entry of Rap1A, RhoA, and Rac1 into the prenylation pathway. These results indicate that guanine nucleotide exchange and interactions with SmgGDS splice variants can regulate the entrance and passage of PBR-possessing small GTPases through the prenylation pathway.

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Section: Introductionmentioning

confidence: 52%

Splice Variants of SmgGDS Control Small GTPase Prenylation and Membrane Localization

Berg

Gastonguay

Lorimer

et al. 2010

Journal of Biological Chemistry

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183

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“…Multiple siRNA duplexes were transfected and tested for maximal and specific suppression of their target protein as previously described. 18 A functional nontargeting siRNA that was bioinformatically designed by Qiagen was used as a control. Human umbilical venous endothelial cells (HUVECs) were transfected with HiPerFect Transfection Reagent (Qiagen) with either 10 nmol/L mock siRNA or 10 nmol/L siRNA specific for SmgGDS.…”

Section: Methodsmentioning

confidence: 99%

Statins Exert the Pleiotropic Effects Through Small GTP-Binding Protein Dissociation Stimulator Upregulation With a Resultant Rac1 Degradation

Tanaka

Fukumoto²,

Nochioka³

et al. 2013

ATVB

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Objective The pleiotropic effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) independent of cholesterol-lowering effects are thought to be mediated through inhibition of the Rho/Rho-kinase pathway. However, we have previously demonstrated that the pleiotropic effects of regular-dose statins are mediated mainly through inhibition of the Rac1 signaling pathway rather than the Rho/Rho-kinase pathway, although the molecular mechanisms of the selective inhibition of the Rac1 signaling pathway by regular-dose statins remain to be elucidated. In this study, we tested our hypothesis that small GTP-binding protein GDP dissociation stimulator (SmgGDS) plays a crucial role in the molecular mechanisms of the Rac1 signaling pathway inhibition by statins in endothelial cells. Approach and Results In cultured human umbilical venous endothelial cells, statins concentration-dependently increased SmgGDS expression and decreased nuclear Rac1. Statins also enhanced SmgGDS expression in mouse aorta. In control mice, the protective effects of statins against angiotensin II–induced medial thickening of coronary arteries and fibrosis were noted, whereas in SmgGDS-deficient mice, the protective effects of statins were absent. When SmgGDS was knocked down by its small interfering RNA in human umbilical venous endothelial cells, statins were no longer able to induce Rac1 degradation or inhibit angiotensin II–induced production of reactive oxygen species. Finally, in normal healthy volunteers, statins significantly increased SmgGDS expression with a significant negative correlation between SmgGDS expression and oxidative stress markers, whereas no correlation was noted with total or low-density lipoprotein-cholesterol. Conclusions These results indicate that statins exert their pleiotropic effects through SmgGDS upregulation with a resultant Rac1 degradation and reduced oxidative stress in animals and humans.

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“…Signaling to p21-activated kinase ( PAK ) can engender SMC proliferation by PAK-mediated phosphorylation of MEK and RAF1 (leading to ERK activation), phosphorylation of the p47 phox subunit of NADPH oxidase (increasing NADPH oxidase activation), and activation of NFκB-inducing kinase (activating NFκB), among other mechanisms. 15 Potential effects of Kalirin on Rho kinase, NADPH oxidase and inducible NO synthase (iNOS) are illustrated. Green, stimulation; red, inhibition; dotted lines, not yet demonstrated downstream of Kalirin in SMCs.…”

Section: Supplementary Materialsmentioning

confidence: 99%

Kalirin Promotes Neointimal Hyperplasia by Activating Rac in Smooth Muscle Cells

Wang

Sharma

et al. 2013

ATVB

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Objective Kalirin is a multifunctional protein that contains two guanine nucleotide exchange factor (GEF) domains for the GTPases Rac1 and RhoA. Variants of KALRN have been associated with atherosclerosis in humans, but Kalirin’s activity has been characterized almost exclusively in the CNS. We therefore tested the hypothesis that Kalirin functions as a RhoGEF in arterial smooth muscle cells (SMCs). Methods and Results Kalirin-9 protein is expressed abundantly in aorta and bone marrow, as well as in cultured SMCs, endothelial cells, and macrophages. Moreover, arterial Kalirin was up-regulated during early atherogenesis in apolipoprotein E-deficient mice. In cultured SMCs, signaling was affected similarly in three models of Kalirin loss-of-function: heterozygous Kalrn deletion, Kalirin RNAi, and treatment with the Kalirin RhoGEF-1 inhibitor 1-(3-nitrophenyl)-1H-pyrrole-2,5-dione. With reduced Kalirin function, SMCs showed normal RhoA activation but diminished Rac1 activation, assessed as reduced Rac-GTP levels, p21-activated kinase autophosphorylation, and SMC migration. Kalrn−/+ SMCs proliferated 30% less rapidly than WT SMCs. Neointimal hyperplasia engendered by carotid endothelial denudation was ~60% less in Kalrn−/+ and SMC-specific Kalrn−/+ mice than in control mice. Conclusions Kalirin functions as a GEF for Rac1 in SMCs, and promotes SMC migration and proliferation both in vitro and in vivo.

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Identification and characterization of the unique guanine nucleotide exchange factor, SmgGDS, in vascular smooth muscle cells

Cited by 7 publications

References 45 publications

Splice Variants of SmgGDS Control Small GTPase Prenylation and Membrane Localization

Splice Variants of SmgGDS Control Small GTPase Prenylation and Membrane Localization

Statins Exert the Pleiotropic Effects Through Small GTP-Binding Protein Dissociation Stimulator Upregulation With a Resultant Rac1 Degradation

Kalirin Promotes Neointimal Hyperplasia by Activating Rac in Smooth Muscle Cells

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