GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor))

2014-02-01   Erik S Blomain , Scott A Waldman 

Identity

HGNC
LOCATION
12p12.3
IMAGE
Atlas Image
LEGEND
Image adapted from NCBI.
LOCUSID
ALIAS
DIAR6,GC-C,GUC2C,MECIL,MUCIL,STAR
FUSION GENES

DNA/RNA

Atlas Image
Image adapted from Ensembl.

Description

The GUCY2C gene is approximately 84 kb in length and has 27 exons.

Transcription

An approximately 3.8 mRNA is transcribed from the gene.

Pseudogene

None known.

Proteins

Note

GUCY2C encodes a guanylyl cyclase.
Atlas Image
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.

Description

1073 amino acid protein with guanylyl cyclase catalytic activity (4.6.1.2).

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 cGMP-dependent protein kinases, phosphodiesterases and cGMP-gated ion channels.

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 GUCY2C-mediated fluid secretion. The role of this mutation in cancer susceptibility remains unclear (Romi et al., 2012).

Implicated in

Entity name
Colorectal cancer
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).
Entity name
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).
Entity name
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 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).
Entity name
Inflammatory bowel disease (IBD) / colitis
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).
Entity name
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).

Bibliography

Pubmed IDLast YearTitleAuthors
239585402013Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate.Castro J et al
229864372012Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety.Chey WD et al
224360482012Familial diarrhea syndrome caused by an activating GUCY2C mutation.Fiskerstrand T et al
218359792011Role for the membrane receptor guanylyl cyclase-C in attention deficiency and hyperactive behavior.Gong R et al
179746012007Homeostatic control of the crypt-villus axis by the bacterial enterotoxin receptor guanylyl cyclase C restricts the proliferating compartment in intestine.Li P et al
176811792007Guanylyl cyclase C suppresses intestinal tumorigenesis by restricting proliferation and maintaining genomic integrity.Li P et al
197375662010The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling.Lin JE et al
223840562012GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity.Lin JE et al
225214172012Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C.Romi H et al
218656422011A uroguanylin-GUCY2C endocrine axis regulates feeding in mice.Valentino MA et al

Other Information

Locus ID:

NCBI: 2984
MIM: 601330
HGNC: 4688
Ensembl: ENSG00000070019

Variants:

dbSNP: 2984
ClinVar: 2984
TCGA: ENSG00000070019
COSMIC: GUCY2C

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000070019ENST00000261170P25092

Expression (GTEx)

0
5
10
15
20
25
30

Pathways

PathwaySourceExternal ID
Purine metabolismKEGGko00230
Purine metabolismKEGGhsa00230
DiseaseREACTOMER-HSA-1643685
Infectious diseaseREACTOMER-HSA-5663205
Uptake and actions of bacterial toxinsREACTOMER-HSA-5339562
MetabolismREACTOMER-HSA-1430728
Miscellaneous digestion eventsREACTOMER-HSA-8935690
Intestinal infectious diseasesREACTOMER-HSA-8942233

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
224360482012Familial diarrhea syndrome caused by an activating GUCY2C mutation.61
168996002006A validated quantitative assay to detect occult micrometastases by reverse transcriptase-polymerase chain reaction of guanylyl cyclase C in patients with colorectal cancer.44
223840562012GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity.39
225214172012Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C.33
215770132011Progression-free survival in ovarian cancer is reflected in epigenetic DNA methylation profiles.25
166184132006Bile acids induce ectopic expression of intestinal guanylyl cyclase C Through nuclear factor-kappaB and Cdx2 in human esophageal cells.23
267730962016Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin-GUCY2C Paracrine Signaling Axis.21
259942182016Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C.20
119508462002A novel PDZ protein regulates the activity of guanylyl cyclase C, the heat-stable enterotoxin receptor.19
196481152009The linker region in receptor guanylyl cyclases is a key regulatory module: mutational analysis of guanylyl cyclase C.15

Citation

Erik S Blomain ; Scott A Waldman

GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor))

Atlas Genet Cytogenet Oncol Haematol. 2014-02-01

Online version: http://atlasgeneticsoncology.org/gene/43303/gucy2c

Historical Card

2011-07-01 GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor)) by  Stephanie Schulz,Scott A Waldman 

Department of Pharmacology, Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA