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

Written2011-07Stephanie Schulz, Scott A Waldman
Department of Pharmacology, Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA
Updated2014-02Erik 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_namesGUC2C
guanylate cyclase 2C (heat stable enterotoxin receptor)
Alias_symbol (synonym)STAR
Other aliasDIAR6
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 (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 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

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


External links

Nomenclature
HGNC (Hugo)GUCY2C   4688
Cards
AtlasGUCY2CID43303ch12p13
Entrez_Gene (NCBI)GUCY2C  2984  guanylate cyclase 2
AliasesDIAR6; GC-C; GUC2C; MECIL; 
MUCIL; STAR
GeneCards (Weizmann)GUCY2C
Ensembl hg19 (Hinxton)ENSG00000070019 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000070019 [Gene_View]  chr12:14612634-14696585 [Contig_View]  GUCY2C [Vega]
ICGC DataPortalENSG00000070019
TCGA cBioPortalGUCY2C
AceView (NCBI)GUCY2C
Genatlas (Paris)GUCY2C
WikiGenes2984
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)
EnsemblGUCY2C - 12p12.3 [CytoView hg19]  GUCY2C - 12p12.3 [CytoView hg38]
Mapping of homologs : NCBIGUCY2C [Mapview hg19]  GUCY2C [Mapview hg38]
OMIM601330   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 : UnigeneHs.524278 [ NCBI ]
CGAP (NCI)Hs.524278
Alternative Splicing GalleryENSG00000070019
Gene ExpressionGUCY2C [ 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]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2984
GTEX Portal (Tissue expression)GUCY2C
Human Protein AtlasENSG00000070019-GUCY2C [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP25092   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP25092  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP25092
Splice isoforms : SwissVarP25092
Catalytic activity : Enzyme4.6.1.2 [ Enzyme-Expasy ]   4.6.1.24.6.1.2 [ IntEnz-EBI ]   4.6.1.2 [ BRENDA ]   4.6.1.2 [ KEGG ]   
PhosPhoSitePlusP25092
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 mutations2984
Blocks (Seattle)GUCY2C
SuperfamilyP25092
Human Protein Atlas [tissue]ENSG00000070019-GUCY2C [tissue]
Peptide AtlasP25092
HPRD07529
IPIIPI00012491   
Protein Interaction databases
DIP (DOE-UCLA)P25092
IntAct (EBI)P25092
FunCoupENSG00000070019
BioGRIDGUCY2C
STRING (EMBL)GUCY2C
ZODIACGUCY2C
Ontologies - Pathways
QuickGOP25092
Ontology : AmiGOadenylate 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-EBIadenylate 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 : KEGGPurine metabolism   
REACTOMEP25092 [protein]
REACTOME PathwaysR-HSA-8942233 [pathway]   
NDEx NetworkGUCY2C
Atlas of Cancer Signalling NetworkGUCY2C
Wikipedia pathwaysGUCY2C
Orthology - Evolution
OrthoDB2984
GeneTree (enSembl)ENSG00000070019
Phylogenetic Trees/Animal Genes : TreeFamGUCY2C
HOVERGENP25092
HOGENOMP25092
Homologs : HomoloGeneGUCY2C
Homology/Alignments : Family Browser (UCSC)GUCY2C
Gene fusions - Rearrangements
Tumor Fusion PortalGUCY2C
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerGUCY2C [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)GUCY2C
dbVarGUCY2C
ClinVarGUCY2C
1000_GenomesGUCY2C 
Exome Variant ServerGUCY2C
ExAC (Exome Aggregation Consortium)ENSG00000070019
GNOMAD BrowserENSG00000070019
Genetic variants : HAPMAP2984
Genomic Variants (DGV)GUCY2C [DGVbeta]
DECIPHERGUCY2C [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisGUCY2C 
Mutations
ICGC Data PortalGUCY2C 
TCGA Data PortalGUCY2C 
Broad Tumor PortalGUCY2C
OASIS PortalGUCY2C [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICGUCY2C  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDGUCY2C
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
BioMutasearch 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)
intoGenGUCY2C
NCG5 (London)GUCY2C
Cancer3DGUCY2C(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM601330    614616    614665   
Orphanet21476    21477   
DisGeNETGUCY2C
MedgenGUCY2C
Genetic Testing Registry GUCY2C
NextProtP25092 [Medical]
TSGene2984
GENETestsGUCY2C
Target ValidationGUCY2C
Huge Navigator GUCY2C [HugePedia]
snp3D : Map Gene to Disease2984
BioCentury BCIQGUCY2C
ClinGenGUCY2C (curated)
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD2984
Chemical/Pharm GKB GenePA29069
Clinical trialGUCY2C
Miscellaneous
canSAR (ICR)GUCY2C (select the gene name)
Probes
Litterature
PubMed42 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineGUCY2C
EVEXGUCY2C
GoPubMedGUCY2C
iHOPGUCY2C
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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