Rac Attack: Modulation of the Small GTPase Rac in Inflammatory Bowel Disease and Thiopurine Therapy

Overview

Journal Mol Diagn Ther

Specialties Molecular Biology
Pathology
Pharmacology

Date 2016 Sep 9

PMID 27604084

Citations 15

Authors

Margien L Seinen

Geerten P van Nieuw Amerongen

Nanne K H de Boer

Adriaan A van Bodegraven

Affiliations

Soon will be listed here.

Abstract

The incidence and prevalence of inflammatory bowel disease (IBD) are increasing. Although the etiology of IBD is unknown, it is thought that genetically susceptible individuals display an inappropriate inflammatory response to commensal microbes, resulting in intestinal tissue damage. Key proteins involved in regulating the immune response, and thus in inflammation, are the small triphosphate-binding protein Rac and its regulatory network. Recent data suggest these proteins to be involved in (dys)regulation of the characteristic inflammatory processes in IBD. Moreover, Rac-gene variants have been identified as susceptibility risk factors for IBD, and Rac1 GTPase signaling has been shown to be strongly suppressed in non-inflamed mucosa compared with inflamed colonic mucosa in IBD. In addition, first-line immunosuppressive treatment for IBD includes thiopurine therapy, and its immunosuppressive effect is primarily ascribed to Rac1 suppression. In this review, we focus on Rac modification and its potential role in the development of IBD, Rac as the molecular therapeutic target in current thiopurine therapy, and the modulation of the Rac signal transduction pathway as a promising novel therapeutic strategy.

Citing Articles

Ding H, Ding Z, Liu S, Mao X, Lu X World J Gastroenterol. 2025; 31(8):101585.

PMID: 40062325 PMC: 11886508. DOI: 10.3748/wjg.v31.i8.101585.

A report on the potential of Rac1/pSTAT3 protein levels in T lymphocytes to assess the pharmacodynamic effect of thiopurine therapy in Inflammatory Bowel Disease patients.

Deben D, Creemers R, van Adrichem A, Drent R, Merry A, Leers M Sci Rep. 2022; 12(1):15806.

PMID: 36138194 PMC: 9500076. DOI: 10.1038/s41598-022-20197-5.

Identification of shared and disease-specific host gene-microbiome associations across human diseases using multi-omic integration.

Priya S, Burns M, Ward T, Mars R, Adamowicz B, Lock E Nat Microbiol. 2022; 7(6):780-795.

PMID: 35577971 PMC: 9159953. DOI: 10.1038/s41564-022-01121-z.

TPMT and NUDT15 polymorphisms in thiopurine induced leucopenia in inflammatory bowel disease: a prospective study from India.

Grover N, Bhatia P, Kumar A, Singh M, Lad D, Mandavdhare H BMC Gastroenterol. 2021; 21(1):327.

PMID: 34425754 PMC: 8383411. DOI: 10.1186/s12876-021-01900-8.

How DNA damage and non-canonical nucleotides alter the telomerase catalytic cycle.

Sanford S, Welfer G, Freudenthal B, Opresko P DNA Repair (Amst). 2021; 107:103198.

PMID: 34371388 PMC: 8526386. DOI: 10.1016/j.dnarep.2021.103198.

References

Panaccione R, Ghosh S, Middleton S, Marquez J, Scott B, Flint L . Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014; 146(2):392-400.e3. DOI: 10.1053/j.gastro.2013.10.052. View

Khor B, Gardet A, Xavier R . Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011; 474(7351):307-17. PMC: 3204665. DOI: 10.1038/nature10209. View

Kreijne J, Seinen M, Wilhelm A, Bouma G, Mulder C, van Bodegraven A . Routinely Established Skewed Thiopurine Metabolism Leads to a Strikingly High Rate of Early Therapeutic Failure in Patients With Inflammatory Bowel Disease. Ther Drug Monit. 2015; 37(6):797-804. DOI: 10.1097/FTD.0000000000000213. View

Dignass A, Van Assche G, Lindsay J, Lemann M, Soderholm J, Colombel J . The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management. J Crohns Colitis. 2010; 4(1):28-62. DOI: 10.1016/j.crohns.2009.12.002. View

Bosco E, Kumar S, Marchioni F, Biesiada J, Kordos M, Szczur K . Rational design of small molecule inhibitors targeting the Rac GTPase-p67(phox) signaling axis in inflammation. Chem Biol. 2012; 19(2):228-42. PMC: 3292765. DOI: 10.1016/j.chembiol.2011.12.017. View

Huang Y, Xiao S, Jiang Q . Role of Rho kinase signal pathway in inflammatory bowel disease. Int J Clin Exp Med. 2015; 8(3):3089-97. PMC: 4443031. View

Etienne-Manneville S, Hall A . Rho GTPases in cell biology. Nature. 2002; 420(6916):629-35. DOI: 10.1038/nature01148. View

Gisbert J, Nino P, Cara C, Rodrigo L . Comparative effectiveness of azathioprine in Crohn's disease and ulcerative colitis: prospective, long-term, follow-up study of 394 patients. Aliment Pharmacol Ther. 2008; 28(2):228-38. DOI: 10.1111/j.1365-2036.2008.03732.x. View

Yang C, Kazanietz M . Chimaerins: GAPs that bridge diacylglycerol signalling and the small G-protein Rac. Biochem J. 2007; 403(1):1-12. DOI: 10.1042/BJ20061750. View

10.

Gilissen L, Wong D, Engels L, Bierau J, Bakker J, Paulussen A . Therapeutic drug monitoring of thiopurine metabolites in adult thiopurine tolerant IBD patients on maintenance therapy. J Crohns Colitis. 2012; 6(6):698-707. DOI: 10.1016/j.crohns.2011.12.003. View

11.

Rossman K, Der C, Sondek J . GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol. 2005; 6(2):167-80. DOI: 10.1038/nrm1587. View

12.

Vetter I, Wittinghofer A . The guanine nucleotide-binding switch in three dimensions. Science. 2001; 294(5545):1299-304. DOI: 10.1126/science.1062023. View

13.

Lev-Tzion R, Renbaum P, Beeri R, Ledder O, Mevorach R, Karban A . Rac1 Polymorphisms and Thiopurine Efficacy in Children With Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr. 2015; 61(4):404-7. DOI: 10.1097/MPG.0000000000000820. View

14.

DerMardirossian C, Bokoch G . GDIs: central regulatory molecules in Rho GTPase activation. Trends Cell Biol. 2005; 15(7):356-63. DOI: 10.1016/j.tcb.2005.05.001. View

15.

Seinen M, van Nieuw Amerongen G, de Boer N, Mulder C, van Bezu J, van Bodegraven A . Rac1 as a Potential Pharmacodynamic Biomarker for Thiopurine Therapy in Inflammatory Bowel Disease. Ther Drug Monit. 2016; 38(5):621-7. DOI: 10.1097/FTD.0000000000000326. View

16.

Neurath M, Kiesslich R, Teichgraber U, Fischer C, Hofmann U, Eichelbaum M . 6-thioguanosine diphosphate and triphosphate levels in red blood cells and response to azathioprine therapy in Crohn's disease. Clin Gastroenterol Hepatol. 2005; 3(10):1007-14. DOI: 10.1016/s1542-3565(05)00697-x. View

17.

Rose D . The role of the alpha4 integrin-paxillin interaction in regulating leukocyte trafficking. Exp Mol Med. 2006; 38(3):191-5. DOI: 10.1038/emm.2006.23. View

18.

Colombel J, Sandborn W, Reinisch W, Mantzaris G, Kornbluth A, Rachmilewitz D . Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010; 362(15):1383-95. DOI: 10.1056/NEJMoa0904492. View

19.

Muise A, Xu W, Guo C, Walters T, Wolters V, Fattouh R . NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2. Gut. 2011; 61(7):1028-35. PMC: 3806486. DOI: 10.1136/gutjnl-2011-300078. View

20.

Marinkovic G, Hamers A, de Vries C, de Waard V . 6-Mercaptopurine reduces macrophage activation and gut epithelium proliferation through inhibition of GTPase Rac1. Inflamm Bowel Dis. 2014; 20(9):1487-95. DOI: 10.1097/MIB.0000000000000122. View