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

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

Written	2011-07	Stephanie Schulz, Scott A Waldman
		Department of Pharmacology, Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA
Updated	2014-02	Erik S Blomain, Scott A Waldman
		Department of Pharmacology, Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA

Keywords

GUCY2C, guanylin, uroguanylin, guanylyl cyclase C, cyclic GMP

(Note : for Links provided by Atlas : click)

Identity

Alias_names	GUC2C
	guanylate cyclase 2C (heat stable enterotoxin receptor)
Alias_symbol (synonym)	STAR
Other alias	DIAR6
	GC-C
	hSTAR
	MECIL
	MUCIL
HGNC (Hugo)	GUCY2C
LocusID (NCBI)	2984
Atlas_Id	43303
Location	12p12.3 [Link to chromosome band 12p12]
Location_base_pair	Starts at 14612634 and ends at 14696585 bp from pter ( according to hg19-Feb_2009) [Mapping GUCY2C.png]
Local_order	ATF7IP - PLBD1 - GUCY2C - H2AFJ - HIST4H4.


	Image adapted from NCBI.

Fusion genes
(updated 2017)

Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

TSPAN9 (12p13.33) / GUCY2C (12p12.3)

DNA/RNA



	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.

Protein

Note	GUCY2C encodes a guanylyl cyclase.



	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

Note

Entity	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 (apc^min) 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	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	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	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	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

Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate.

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.

Gastroenterology. 2013 Dec;145(6):1334-46.e1-11. doi: 10.1053/j.gastro.2013.08.017. Epub 2013 Aug 16.

PMID 23958540

Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety.

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.

Am J Gastroenterol. 2012 Nov;107(11):1702-12.

PMID 22986437

Familial diarrhea syndrome caused by an activating GUCY2C mutation.

Fiskerstrand T, Arshad N, Haukanes BI, Tronstad RR, Pham KD, Johansson S, Havik B, Tonder SL, Levy SE, Brackman D, Boman H, Biswas KH, Apold J, Hovdenak N, Visweswariah SS, Knappskog PM.

N Engl J Med. 2012 Apr 26;366(17):1586-95. doi: 10.1056/NEJMoa1110132. Epub 2012 Mar 21.

PMID 22436048

Role for the membrane receptor guanylyl cyclase-C in attention deficiency and hyperactive behavior.

Gong R, Ding C, Hu J, Lu Y, Liu F, Mann E, Xu F, Cohen MB, Luo M.

Science. 2011 Sep 16;333(6049):1642-6. doi: 10.1126/science.1207675. Epub 2011 Aug 11.

PMID 21835979

Homeostatic control of the crypt-villus axis by the bacterial enterotoxin receptor guanylyl cyclase C restricts the proliferating compartment in intestine.

Li P, Lin JE, Chervoneva I, Schulz S, Waldman SA, Pitari GM.

Am J Pathol. 2007a Dec;171(6):1847-58. Epub 2007 Nov 1.

PMID 17974601

Guanylyl cyclase C suppresses intestinal tumorigenesis by restricting proliferation and maintaining genomic integrity.

Li P, Schulz S, Bombonati A, Palazzo JP, Hyslop TM, Xu Y, Baran AA, Siracusa LD, Pitari GM, Waldman SA.

Gastroenterology. 2007b Aug;133(2):599-607. Epub 2007 Jun 2.

PMID 17681179

The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling.

Lin JE, Li P, Snook AE, Schulz S, Dasgupta A, Hyslop TM, Gibbons AV, Marszlowicz G, Pitari GM, Waldman SA.

Gastroenterology. 2010 Jan;138(1):241-54. doi: 10.1053/j.gastro.2009.08.064. Epub 2009 Sep 6.

PMID 19737566

GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity.

Lin JE, Snook AE, Li P, Stoecker BA, Kim GW, Magee MS, Garcia AV, Valentino MA, Hyslop T, Schulz S, Waldman SA.

PLoS One. 2012;7(2):e31686. doi: 10.1371/journal.pone.0031686. Epub 2012 Feb 22.

PMID 22384056

Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C.

Romi H, Cohen I, Landau D, Alkrinawi S, Yerushalmi B, Hershkovitz R, Newman-Heiman N, Cutting GR, Ofir R, Sivan S, Birk OS.

Am J Hum Genet. 2012 May 4;90(5):893-9. doi: 10.1016/j.ajhg.2012.03.022. Epub 2012 Apr 19.

PMID 22521417

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice.

Valentino MA, Lin JE, Snook AE, Li P, Kim GW, Marszalowicz G, Magee MS, Hyslop T, Schulz S, Waldman SA.

J Clin Invest. 2011 Sep;121(9):3578-88. doi: 10.1172/JCI57925. Epub 2011 Aug 25.

PMID 21865642

Citation

This paper should be referenced as such :

ES Blomain, SA Waldman

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

Atlas Genet Cytogenet Oncol Haematol. 2014;18(10):715-717.

Free journal version : [ pdf ] [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Genes/GUCY2CID43303ch12p13.html

History of this paper:

Schulz, S ; Waldman, SA. GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor)). Atlas Genet Cytogenet Oncol Haematol. 2012;16(1):18-19.

http://documents.irevues.inist.fr/bitstream/handle/2042/47261/07-2011-GUCY2CID43303ch12p13.pdf

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]

t(12;12)(p12;p13) TSPAN9/GUCY2C

External links

	Nomenclature
HGNC (Hugo)	GUCY2C 4688
	Cards
Atlas	GUCY2CID43303ch12p13
Entrez_Gene (NCBI)	GUCY2C 2984 guanylate cyclase 2C
Aliases	DIAR6; GC-C; GUC2C; MECIL;
	MUCIL; STAR
GeneCards (Weizmann)	GUCY2C
Ensembl hg19 (Hinxton)	ENSG00000070019 [Gene_View]
Ensembl hg38 (Hinxton)	ENSG00000070019 [Gene_View] ENSG00000070019 [Sequence] chr12:14612634-14696585 [Contig_View] GUCY2C [Vega]
ICGC DataPortal	ENSG00000070019
TCGA cBioPortal	GUCY2C
AceView (NCBI)	GUCY2C
Genatlas (Paris)	GUCY2C
WikiGenes	2984
SOURCE (Princeton)	GUCY2C
Genetics Home Reference (NIH)	GUCY2C
	Genomic and cartography
GoldenPath hg38 (UCSC)	GUCY2C - chr12:14612634-14696585 - 12p12.3 [Description] (hg38-Dec_2013)
GoldenPath hg19 (UCSC)	GUCY2C - 12p12.3 [Description] (hg19-Feb_2009)
Ensembl	GUCY2C - 12p12.3 [CytoView hg19] GUCY2C - 12p12.3 [CytoView hg38]
Mapping of homologs : NCBI	GUCY2C [Mapview hg19] GUCY2C [Mapview hg38]
OMIM	601330 614616 614665
	Gene and transcription
Genbank (Entrez)	AK310034 AW848739 BC136544 BC136545 M73489
RefSeq transcript (Entrez)	NM_004963
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)	GUCY2C
Cluster EST : Unigene	Hs.524278 [ NCBI ]
CGAP (NCI)	Hs.524278
Alternative Splicing Gallery	ENSG00000070019
Gene Expression	GUCY2C [ NCBI-GEO ] GUCY2C [ EBI - ARRAY_EXPRESS ] GUCY2C [ SEEK ] GUCY2C [ MEM ]
Gene Expression Viewer (FireBrowse)	GUCY2C [ Firebrowse - Broad ]
SOURCE (Princeton)	Expression in : [Datasets] [Normal Tissue Atlas] [carcinoma Classsification] [NCI60]
Genevestigator	Expression in : [tissues] [cell-lines] [cancer] [perturbations]
BioGPS (Tissue expression)	2984
GTEX Portal (Tissue expression)	GUCY2C
Human Protein Atlas	ENSG00000070019-GUCY2C [pathology] [cell] [tissue]
	Protein : pattern, domain, 3D structure
UniProt/SwissProt	P25092 [function] [subcellular_location] [family_and_domains] [pathology_and_biotech] [ptm_processing] [expression] [interaction]
NextProt	P25092 [Sequence] [Exons] [Medical] [Publications]
With graphics : InterPro	P25092
Splice isoforms : SwissVar	P25092
Catalytic activity : Enzyme	4.6.1.2 [ Enzyme-Expasy ] 4.6.1.2 4.6.1.2 [ IntEnz-EBI ] 4.6.1.2 [ BRENDA ] 4.6.1.2 [ KEGG ]
PhosPhoSitePlus	P25092
Domaine pattern : Prosite (Expaxy)	GUANYLATE_CYCLASE_1 (PS00452) GUANYLATE_CYCLASE_2 (PS50125) PROTEIN_KINASE_DOM (PS50011)
Domains : Interpro (EBI)	A/G_cyclase A/G_cyclase_CS Kinase-like_dom Nucleotide_cyclase Peripla_BP_I Prot_kinase_dom Ser-Thr/Tyr_kinase_cat_dom
Domain families : Pfam (Sanger)	Guanylate_cyc (PF00211) Pkinase_Tyr (PF07714)
Domain families : Pfam (NCBI)	pfam00211 pfam07714
Domain families : Smart (EMBL)	CYCc (SM00044)
Conserved Domain (NCBI)	GUCY2C
DMDM Disease mutations	2984
Blocks (Seattle)	GUCY2C
Superfamily	P25092
Human Protein Atlas [tissue]	ENSG00000070019-GUCY2C [tissue]
Peptide Atlas	P25092
HPRD	07529
IPI	IPI00012491
	Protein Interaction databases
DIP (DOE-UCLA)	P25092
IntAct (EBI)	P25092
FunCoup	ENSG00000070019
BioGRID	GUCY2C
STRING (EMBL)	GUCY2C
ZODIAC	GUCY2C
	Ontologies - Pathways
QuickGO	P25092
Ontology : AmiGO	adenylate cyclase activity guanylate cyclase activity protein kinase activity protein binding ATP binding GTP binding endoplasmic reticulum membrane plasma membrane plasma membrane cGMP biosynthetic process protein phosphorylation receptor guanylyl cyclase signaling pathway digestion guanylate cyclase complex, soluble response to toxic substance toxic substance binding integral component of membrane intracellular signal transduction regulation of cell proliferation
Ontology : EGO-EBI	adenylate cyclase activity guanylate cyclase activity protein kinase activity protein binding ATP binding GTP binding endoplasmic reticulum membrane plasma membrane plasma membrane cGMP biosynthetic process protein phosphorylation receptor guanylyl cyclase signaling pathway digestion guanylate cyclase complex, soluble response to toxic substance toxic substance binding integral component of membrane intracellular signal transduction regulation of cell proliferation
Pathways : KEGG	Gap junction Purine metabolism Long-term depression
REACTOME	P25092 [protein]
REACTOME Pathways	R-HSA-8942233 [pathway]
NDEx Network	GUCY2C
Atlas of Cancer Signalling Network	GUCY2C
Wikipedia pathways	GUCY2C
	Orthology - Evolution
OrthoDB	2984
GeneTree (enSembl)	ENSG00000070019
Phylogenetic Trees/Animal Genes : TreeFam	GUCY2C
HOVERGEN	P25092
HOGENOM	P25092
Homologs : HomoloGene	GUCY2C
Homology/Alignments : Family Browser (UCSC)	GUCY2C
	Gene fusions - Rearrangements
Fusion : Quiver	GUCY2C
	Polymorphisms : SNP and Copy number variants
NCBI Variation Viewer	GUCY2C [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)	GUCY2C
dbVar	GUCY2C
ClinVar	GUCY2C
1000_Genomes	GUCY2C
Exome Variant Server	GUCY2C
ExAC (Exome Aggregation Consortium)	ENSG00000070019
GNOMAD Browser	ENSG00000070019
Genetic variants : HAPMAP	2984
Genomic Variants (DGV)	GUCY2C [DGVbeta]
DECIPHER	GUCY2C [patients] [syndromes] [variants] [genes]
CONAN: Copy Number Analysis	GUCY2C
	Mutations
ICGC Data Portal	GUCY2C
TCGA Data Portal	GUCY2C
Broad Tumor Portal	GUCY2C
OASIS Portal	GUCY2C [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMIC	GUCY2C [overview] [genome browser] [tissue] [distribution]
Mutations and Diseases : HGMD	GUCY2C
LOVD (Leiden Open Variation Database)	Whole genome datasets
LOVD (Leiden Open Variation Database)	LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)	LOVD 3.0 shared installation
BioMuta	search GUCY2C
DgiDB (Drug Gene Interaction Database)	GUCY2C
DoCM (Curated mutations)	GUCY2C (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)	GUCY2C (select a term)
intoGen	GUCY2C
NCG5 (London)	GUCY2C
Cancer3D	GUCY2C(select the gene name)
Impact of mutations	[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
	Diseases
OMIM	601330 614616 614665
Orphanet	21476 21477
DisGeNET	GUCY2C
Medgen	GUCY2C
Genetic Testing Registry	GUCY2C
NextProt	P25092 [Medical]
TSGene	2984
GENETests	GUCY2C
Target Validation	GUCY2C
Huge Navigator	GUCY2C [HugePedia]
snp3D : Map Gene to Disease	2984
BioCentury BCIQ	GUCY2C
ClinGen	GUCY2C (curated)
	Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD	2984
Chemical/Pharm GKB Gene	PA29069
Clinical trial	GUCY2C
	Miscellaneous
canSAR (ICR)	GUCY2C (select the gene name)
	Probes
	Litterature
PubMed	48 Pubmed reference(s) in Entrez
GeneRIFs	Gene References Into Functions (Entrez)
CoreMine	GUCY2C
EVEX	GUCY2C
GoPubMed	GUCY2C
iHOP	GUCY2C

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

Search in all EBI NCBI

indexed on : Fri Jun 22 17:08:33 CEST 2018

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