Download Gene Section GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor))

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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
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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
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