Intestinal infectious diseases (Homo sapiens)

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Bibliography

1. Arshad N, Ballal S, Visweswariah SS.; ''Site-specific N-linked glycosylation of receptor guanylyl cyclase C regulates ligand binding, ligand-mediated activation and interaction with vesicular integral membrane protein 36, VIP36.''; PubMed Europe PMC Scholia
2. Vijayachandra K, Guruprasad M, Bhandari R, Manjunath UH, Somesh BP, Srinivasan N, Suguna K, Visweswariah SS.; ''Biochemical characterization of the intracellular domain of the human guanylyl cyclase C receptor provides evidence for a catalytically active homotrimer.''; PubMed Europe PMC Scholia
3. Gonzales-Siles L, Sjöling Å.; ''The different ecological niches of enterotoxigenic Escherichia coli.''; PubMed Europe PMC Scholia
4. Scott RO, Thelin WR, Milgram SL.; ''A novel PDZ protein regulates the activity of guanylyl cyclase C, the heat-stable enterotoxin receptor.''; PubMed Europe PMC Scholia
5. Basu N, Arshad N, Visweswariah SS.; ''Receptor guanylyl cyclase C (GC-C): regulation and signal transduction.''; PubMed Europe PMC Scholia
6. Kopic S, Geibel JP.; ''Toxin mediated diarrhea in the 21 century: the pathophysiology of intestinal ion transport in the course of ETEC, V. cholerae and rotavirus infection.''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
GUCY2C	Protein	P25092 (Uniprot-TrEMBL)
GUCY2C trimer:sta1	Complex	R-HSA-8936363 (Reactome)
GUCY2C trimer	Complex	R-HSA-8936213 (Reactome)
PDZD3	Protein	Q86UT5 (Uniprot-TrEMBL)
sta1	Protein	P01559 (Uniprot-TrEMBL)
sta1	Protein	P01559 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	GUCY2C trimer:sta1	Arrow	R-HSA-8936356 (Reactome)
GUCY2C trimer			R-HSA-8936356 (Reactome)
PDZD3		TBar	R-HSA-8936356 (Reactome)
			R-HSA-8936356 (Reactome)	Heat-stable enterotoxin receptor (GUCY2C, STAR) is the receptor for the endogenous peptides guanylin (GUCA2A) and uroguanylin (GUCA2B) and E.coli heat-stable enterotoxin (sta1). GUCY2C is an integral membrane protein composed of an extracellular ligand-binding domain, an intracellular domain and a guanylyl cyclase catalytic domain and functions in trimeric form (Vijayachandra et al. 2000). Once activated by its ligands, GUCY2C mediates fluid-ion homeostasis, intestinal inflammation, and cell proliferation in a cGMP-dependent manner (Arshad et al. 2013). In the intestine, E.coli heat-stable enterotoxin (sta1) binding to GUCY2C causes abnormally high levels of intracellular cGMP to be produced resulting in aberrant fluid-ion efflux, leading to secretory diarrhea, the leading cause of infectious diarrhea in humans (Basu et al. 2010, Kopic & Geibel 2010). GUCY2C requires glycosylation for correct ligand binding and cell-surface localisation. When glycosylation is prevented in systematic mutagenesis studies, both ligand binding and localisation were abolished (Arshad et al. 2013). Na(+)/H(+) exchange regulatory cofactor NHE-RF4 (PDZD3, aka IKEPP, NHERF4) is a regulatory protein that associates with GUCY2C and negatively modulates its heat-stable enterotoxin-mediated activation. PDZD3 is expressed in the intestinal epithelium, where it preferentially accumulates at the apical surface, and there associates with the COOH terminus of GUCY2C (Scott et al. 2002).
sta1			R-HSA-8936356 (Reactome)