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Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST-CNRS OPEN ACCESS JOURNAL Gene Section Short Communication GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor)) Erik S Blomain, Scott A Waldman Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA (ESB, SAW) Published in Atlas Database: February 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/GUCY2CID43303ch12p13.html DOI: 10.4267/2042/54131 This article is an update of : Schulz S, Waldman SA. GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor)). Atlas Genet Cytogenet Oncol Haematol 2012;16(1):18-19. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology Local order ATF7IP - PLBD1 - GUCY2C - H2AFJ HIST4H4. Abstract Abstract Short communication on GUCY2C, with data on DNA/RNA, on the protein encoded and where the gene is implicated. Keywords GUCY2C, guanylin, uroguanylin, guanylyl cyclase C, cyclic GMP DNA/RNA Description The GUCY2C gene is approximately 84 kb in length and has 27 exons. Identity Transcription Other names: DIAR6, GC-C, GUC2C, hSTAR, MECIL, MUCIL, STAR HGNC (Hugo): GUCY2C Location: 12p12.3 Pseudogene An approximately 3.8 mRNA is transcribed from the gene. None known. Image adapted from NCBI. Image adapted from Ensembl. Atlas Genet Cytogenet Oncol Haematol. 2014; 18(10) 715 GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor)) Blomain ES, Waldman SA SP: signal peptide; ECD: extracellular ligand binding domain; TM: transmembrane domain; KHD: regulatory kinase-homology domain; CAT: guanylyl cyclase catalytic domain; TAIL: C-terminal tail, interacts with scaffolding proteins. GUCY2C-mediated fluid secretion. The role of this mutation in cancer susceptibility remains unclear (Romi et al., 2012). Protein Note GUCY2C encodes a guanylyl cyclase. Implicated in Description Colorectal cancer 1073 amino acid protein with guanylyl cyclase catalytic activity (4.6.1.2). Note The endogenous GUCY2C ligands, guanylin and uroguanylin, are lost early in the neoplastic process, resulting in inactivation of downstream tumor suppressive GUCY2C signaling. Targeted deletion of GUCY2C in mice results in a phenotype of intestinal cancer susceptibility in the context of predisposing genetic mutations (apcmin) or exposure to carcinogen (azoxymethane). GUCY2C has a wide range of homeostatic functions in preventing tumorigenesis, including regulation of crypt proliferation, DNA damage repair and oncogenic signaling such as PI3K/Akt (Li et al., 2007a; Li et al., 2007b; Lin et al., 2010). Expression Primarily intestinal epithelial cells. Also expressed in hypothalamus and midbrain neurons. Localisation Apical membrane. Function In response to binding endogenous hormones guanylin and uroguanylin, or the exogenous ligand E. coli heat-stable enterotoxin, GUCY2C synthesizes cyclic GMP. Cyclic GMP activates downstream signaling pathways via cGMPdependent protein kinases, phosphodiesterases and cGMP-gated ion channels. Obesity Note GUCY2C is expressed in the hypothalamus, and targeted deletion in mice results in an obese phenotype which has been attributed to increased food consumption and dysregulated satiety. Importantly, the GUCY2C hormone ligand uroguanylin has been shown to mediate this effect. The uroguanylin peptide is released into the circulation postprandially and travels to the brain where it induces satiety in the hypothalamus, thus comprising a gut-brain neuroendocrine axis which regulates feeding (Valentino et al., 2011). Homology Adenylyl cyclase. Mutations Note - c.2519G→T This dominant missense mutation was identified in 32 members of a Norwegian family, and was characterized as an activating mutation. Affected patients had mild chronic diarrhea and an increased risk for several GI disorders. The role of this mutation in cancer susceptibility remains unclear (Fiskerstrand et al., 2012). - c.1160A>G This recessive missense mutation was identified in a Bedouin family, and was characterized as an inactivating mutation. Affected patients had perinatal meconium ileus secondary to impaired GUCY2C-mediated fluid secretion. The role of this mutation in cancer susceptibility remains unclear (Romi et al., 2012). - c.2270dupA This recessive nonsense mutation was identified in a Bedouin family, and resulted in a premature stop codon two amino acids following the insertion which resulted in a truncated GUCY2C protein lacking its catalytic domain. Affected patients had perinatal meconium ileus secondary to impaired Atlas Genet Cytogenet Oncol Haematol. 2014; 18(10) Irritable bowel syndrome with constipation (IBS-C), and associated abdominal pain Note GUCY2C is a known mediator of intestinal fluid secretion. Work in mice and humans has demonstrated that the bacterial heat stable enterotoxin (ST) causes GI fluid secretion, motility and diarrhea via GUCY2C activation in the intestine. Recently, an oral GUCY2C ligand linaclotide (Linzess Ironwood Pharmaceuticals) was approved by the FDA for treatment of constipation-predominant irritable bowel syndrome (IBS). Further work has revealed a role for linaclotide in preventing GI pain associated with IBS. The mechanism for this effect is believed to be 716 GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor)) formation by inhibiting AKT signaling. Gastroenterology. 2010 Jan;138(1):241-54 release of cGMP by enterocytes from their basolateral membrane following ligand activation. This cGMP then inhibits nociception in adjacent visceral neurons, relieving pain (Chey et al., 2012; Castro et al., 2013). Gong R, Ding C, Hu J, Lu Y, Liu F, Mann E, Xu F, Cohen MB, Luo M. Role for the membrane receptor guanylyl cyclase-C in attention deficiency and hyperactive behavior. Science. 2011 Sep 16;333(6049):1642-6 Inflammatory bowel disease (IBD) / colitis Valentino MA, Lin JE, Snook AE, Li P, Kim GW, Marszalowicz G, Magee MS, Hyslop T, Schulz S, Waldman SA. A uroguanylin-GUCY2C endocrine axis regulates feeding in mice. J Clin Invest. 2011 Sep;121(9):3578-88 Note Work in mice has identified a possible role for GUCY2C in preventing colitis. Targeted deletion of GUCY2C results in more severe disease in a chemical model of colitis. Additionally, oral administration of GUCY2C ligand improved colitis in wild-type mice in the same model. These findings suggest a role for GUCY2C in regulating intestinal inflammation and associated disorders (Lin et al., 2012). Chey WD, Lembo AJ, Lavins BJ, Shiff SJ, Kurtz CB, Currie MG, MacDougall JE, Jia XD, Shao JZ, Fitch DA, Baird MJ, Schneier HA, Johnston JM. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol. 2012 Nov;107(11):170212 Fiskerstrand T, Arshad N, Haukanes BI, Tronstad RR, Pham KD, Johansson S, Håvik B, Tønder SL, Levy SE, Brackman D, Boman H, Biswas KH, Apold J, Hovdenak N, Visweswariah SS, Knappskog PM. Familial diarrhea syndrome caused by an activating GUCY2C mutation. N Engl J Med. 2012 Apr 26;366(17):1586-95 Attention deficit hyperactivity disorder (ADHD) Note Work in mice has demonstrated the presence of GUCY2C in midbrain neurons, and targeted deletion of GUCY2C resulted in a phenotype of hyperactivity, which was reversible by treating with either ADHD therapeutics or an activator of downstream GUCY2C signaling (PKG activator) (Gong et al., 2011). Lin JE, Snook AE, Li P, Stoecker BA, Kim GW, Magee MS, Garcia AV, Valentino MA, Hyslop T, Schulz S, Waldman SA. GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity. PLoS One. 2012;7(2):e31686 Romi H, Cohen I, Landau D, Alkrinawi S, Yerushalmi B, Hershkovitz R, Newman-Heiman N, Cutting GR, Ofir R, Sivan S, Birk OS. Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C. Am J Hum Genet. 2012 May 4;90(5):893-9 References Castro J, Harrington AM, Hughes PA, Martin CM, Ge P, Shea CM, Jin H, Jacobson S, Hannig G, Mann E, Cohen MB, MacDougall JE, Lavins BJ, Kurtz CB, Silos-Santiago I, Johnston JM, Currie MG, Blackshaw LA, Brierley SM. Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate. Gastroenterology. 2013 Dec;145(6):1334-46.e1-11 Li P, Lin JE, Chervoneva I, Schulz S, Waldman SA, Pitari GM. Homeostatic control of the crypt-villus axis by the bacterial enterotoxin receptor guanylyl cyclase C restricts the proliferating compartment in intestine. Am J Pathol. 2007a Dec;171(6):1847-58 Li P, Schulz S, Bombonati A, Palazzo JP, Hyslop TM, Xu Y, Baran AA, Siracusa LD, Pitari GM, Waldman SA. Guanylyl cyclase C suppresses intestinal tumorigenesis by restricting proliferation and maintaining genomic integrity. Gastroenterology. 2007b Aug;133(2):599-607 This article should be referenced as such: Blomain ES, Waldman SA. GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor)). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(10):715-717. Lin JE, Li P, Snook AE, Schulz S, Dasgupta A, Hyslop TM, Gibbons AV, Marszlowicz G, Pitari GM, Waldman SA. The hormone receptor GUCY2C suppresses intestinal tumor Atlas Genet Cytogenet Oncol Haematol. 2014; 18(10) Blomain ES, Waldman SA 717