GUCY2C

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0001653 peptide receptor activity	IBA GO_REF:0000033	ACCEPT	Summary: GC-C is the receptor for guanylin, uroguanylin and the peptide toxin STa. Reason: The extracellular domain binds peptide ligands (STa with nM affinity) and transduces binding into cyclase activation; the IBA node placement is consistent with the receptor guanylyl cyclase clade. Supporting Evidence: PMID:1680854 Stable mammalian cell lines over-expressing the STa receptor specifically bind 125I-STa (Kd approximately 1.0 nM) Reactome:R-HSA-8936214 is the receptor for the endogenous peptides guanylin (GUCA2A) and uroguanylin (GUCA2B) and E.coli heat-stable enterotoxin
GO:0004383 guanylate cyclase activity	EXP PMID:23269669 Site-specific N-linked glycosylation of receptor guanylyl cy...	ACCEPT	Summary: GC-C catalyses GTP to cGMP conversion; this is its core catalytic activity. Reason: Ligand-stimulated cGMP production is shown for recombinant human GC-C and is altered by disease mutations; UniProt curates the GTP to 3',5'-cyclic GMP reaction with experimental evidence. Supporting Evidence: PMID:1680854 respond to STa by dramatically increasing (approximately 50-fold) cellular cGMP levels PMID:11950846 Activation of GCC catalyzes the formation of cGMP file:human/GUCY2C/GUCY2C-uniprot.txt Guanylyl cyclase that catalyzes synthesis of cyclic GMP
GO:0004383 guanylate cyclase activity	IBA GO_REF:0000033	ACCEPT	Summary: GC-C catalyses GTP to cGMP conversion; this is its core catalytic activity. Reason: Ligand-stimulated cGMP production is shown for recombinant human GC-C and is altered by disease mutations; UniProt curates the GTP to 3',5'-cyclic GMP reaction with experimental evidence. Supporting Evidence: PMID:1680854 respond to STa by dramatically increasing (approximately 50-fold) cellular cGMP levels PMID:11950846 Activation of GCC catalyzes the formation of cGMP file:human/GUCY2C/GUCY2C-uniprot.txt Guanylyl cyclase that catalyzes synthesis of cyclic GMP
GO:0004383 guanylate cyclase activity	IDA PMID:11950846 A novel PDZ protein regulates the activity of guanylyl cycla...	ACCEPT	Summary: GC-C catalyses GTP to cGMP conversion; this is its core catalytic activity. Reason: Ligand-stimulated cGMP production is shown for recombinant human GC-C and is altered by disease mutations; UniProt curates the GTP to 3',5'-cyclic GMP reaction with experimental evidence. Supporting Evidence: PMID:1680854 respond to STa by dramatically increasing (approximately 50-fold) cellular cGMP levels PMID:11950846 Activation of GCC catalyzes the formation of cGMP file:human/GUCY2C/GUCY2C-uniprot.txt Guanylyl cyclase that catalyzes synthesis of cyclic GMP
GO:0004383 guanylate cyclase activity	IEA GO_REF:0000120	ACCEPT	Summary: GC-C catalyses GTP to cGMP conversion; this is its core catalytic activity. Reason: Ligand-stimulated cGMP production is shown for recombinant human GC-C and is altered by disease mutations; UniProt curates the GTP to 3',5'-cyclic GMP reaction with experimental evidence. Supporting Evidence: PMID:1680854 respond to STa by dramatically increasing (approximately 50-fold) cellular cGMP levels PMID:11950846 Activation of GCC catalyzes the formation of cGMP file:human/GUCY2C/GUCY2C-uniprot.txt Guanylyl cyclase that catalyzes synthesis of cyclic GMP
GO:0004383 guanylate cyclase activity	TAS PMID:1680854 Primary structure and functional expression of the human rec...	ACCEPT	Summary: GC-C catalyses GTP to cGMP conversion; this is its core catalytic activity. Reason: Ligand-stimulated cGMP production is shown for recombinant human GC-C and is altered by disease mutations; UniProt curates the GTP to 3',5'-cyclic GMP reaction with experimental evidence. Supporting Evidence: PMID:1680854 respond to STa by dramatically increasing (approximately 50-fold) cellular cGMP levels PMID:11950846 Activation of GCC catalyzes the formation of cGMP file:human/GUCY2C/GUCY2C-uniprot.txt Guanylyl cyclase that catalyzes synthesis of cyclic GMP
GO:0004672 protein kinase activity	IEA GO_REF:0000002	REMOVE	Summary: Kinase-homology domain is a pseudokinase; no phosphotransferase activity. Reason: The InterPro protein-kinase-domain mapping does not hold for the receptor guanylyl cyclase KHD, which lacks catalytic residues and is not expected to have kinase activity. It instead binds ATP and regulates the cyclase domain. Supporting Evidence: PMID:16460035 The KHD lacks many of the amino acids required for phosphotransfer activity and, therefore, is not expected to possess kinase activity. file:human/GUCY2C/GUCY2C-uniprot.txt The protein kinase domain is predicted to be catalytically inactive.
GO:0005515 protein binding	IPI PMID:11950846 A novel PDZ protein regulates the activity of guanylyl cycla...	MODIFY	Summary: Interaction with the PDZ protein NHERF4 (IKEPP) via the GC-C C-terminus. Reason: Bare protein binding is uninformative. The cited study shows that the GC-C COOH-terminus associates with the PDZ protein IKEPP/NHERF4, which supports PDZ domain binding as the more informative term. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11950846 We identified a novel protein, IKEPP (intestinal and kidney-enriched PDZ protein) that associates with the COOH terminus of GCC in biochemical assays and by co-immunoprecipitation.
GO:0005515 protein binding	IPI PMID:11950846 A novel PDZ protein regulates the activity of guanylyl cycla...	MODIFY	Summary: Interaction with the PDZ protein NHERF4 (IKEPP) via the GC-C C-terminus. Reason: Bare protein binding is uninformative. The cited study shows that the GC-C COOH-terminus associates with the PDZ protein IKEPP/NHERF4, which supports PDZ domain binding as the more informative term. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11950846 We identified a novel protein, IKEPP (intestinal and kidney-enriched PDZ protein) that associates with the COOH terminus of GCC in biochemical assays and by co-immunoprecipitation.
GO:0005524 ATP binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: The pseudokinase domain binds ATP, which modulates cyclase activity. Reason: Although the InterPro kinase mapping overstates catalysis, direct ATP binding to the GC-C KHD (dependent on Lys516) is shown experimentally. ATP binding is regulatory rather than the core activity. Supporting Evidence: PMID:16460035 we demonstrate that the intracellular domain of GC-C and the KHD bind ATP. Mutation of Lys516 to Ala abolishes ATP binding.
GO:0005789 endoplasmic reticulum membrane	EXP PMID:23269669 Site-specific N-linked glycosylation of receptor guanylyl cy...	KEEP AS NON CORE	Summary: A 130 kDa high-mannose precursor of GC-C resides in the ER membrane. Reason: The ER-resident glycoform is a biosynthetic precursor of the cell-surface receptor and binds ST with equal affinity; it is a real location but not where GC-C signals. Supporting Evidence: PMID:23269669 differentially glycosylated forms that are resident in the endoplasmic reticulum (130 kDa) and the plasma membrane (145 kDa) bind the ST peptide with equal affinity
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: A 130 kDa high-mannose precursor of GC-C resides in the ER membrane. Reason: The ER-resident glycoform is a biosynthetic precursor of the cell-surface receptor and binds ST with equal affinity; it is a real location but not where GC-C signals. Supporting Evidence: PMID:23269669 differentially glycosylated forms that are resident in the endoplasmic reticulum (130 kDa) and the plasma membrane (145 kDa) bind the ST peptide with equal affinity
GO:0005886 plasma membrane	EXP PMID:23269669 Site-specific N-linked glycosylation of receptor guanylyl cy...	ACCEPT	Summary: GC-C is a cell-surface transmembrane receptor in the plasma membrane, extracellular ligand-binding domain exposed. Reason: Surface localization of the mature 145 kDa glycoform is shown and abolished when glycosylation is prevented, and STa binds intact cells, so this plasma membrane row is accepted at the resolution its surface-localization evidence supports. In enterocytes the receptor is concentrated at the apical surface; that apical sub-localization is recorded separately as a NEW apical plasma membrane row (GO:0016324) rather than by narrowing this row. Supporting Evidence: PMID:23269669 When glycosylation of human GC-C was prevented, either by pharmacological intervention or by mutation of all of the 10 predicted glycosylation sites, ST binding and surface localization was abolished.
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: GC-C is a cell-surface transmembrane receptor in the plasma membrane, extracellular ligand-binding domain exposed. Reason: Surface localization of the mature 145 kDa glycoform is shown and abolished when glycosylation is prevented, and STa binds intact cells, so this plasma membrane row is accepted at the resolution its surface-localization evidence supports. In enterocytes the receptor is concentrated at the apical surface; that apical sub-localization is recorded separately as a NEW apical plasma membrane row (GO:0016324) rather than by narrowing this row. Supporting Evidence: PMID:23269669 When glycosylation of human GC-C was prevented, either by pharmacological intervention or by mutation of all of the 10 predicted glycosylation sites, ST binding and surface localization was abolished.
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: GC-C is a cell-surface transmembrane receptor in the plasma membrane, extracellular ligand-binding domain exposed. Reason: Surface localization of the mature 145 kDa glycoform is shown and abolished when glycosylation is prevented, and STa binds intact cells, so this plasma membrane row is accepted at the resolution its surface-localization evidence supports. In enterocytes the receptor is concentrated at the apical surface; that apical sub-localization is recorded separately as a NEW apical plasma membrane row (GO:0016324) rather than by narrowing this row. Supporting Evidence: PMID:23269669 When glycosylation of human GC-C was prevented, either by pharmacological intervention or by mutation of all of the 10 predicted glycosylation sites, ST binding and surface localization was abolished.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8936214	ACCEPT	Summary: GC-C is a cell-surface transmembrane receptor in the plasma membrane, extracellular ligand-binding domain exposed. Reason: Surface localization of the mature 145 kDa glycoform is shown and abolished when glycosylation is prevented, and STa binds intact cells, so this plasma membrane row is accepted at the resolution its surface-localization evidence supports. In enterocytes the receptor is concentrated at the apical surface; that apical sub-localization is recorded separately as a NEW apical plasma membrane row (GO:0016324) rather than by narrowing this row. Supporting Evidence: PMID:23269669 When glycosylation of human GC-C was prevented, either by pharmacological intervention or by mutation of all of the 10 predicted glycosylation sites, ST binding and surface localization was abolished.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8936356	ACCEPT	Summary: GC-C is a cell-surface transmembrane receptor in the plasma membrane, extracellular ligand-binding domain exposed. Reason: Surface localization of the mature 145 kDa glycoform is shown and abolished when glycosylation is prevented, and STa binds intact cells, so this plasma membrane row is accepted at the resolution its surface-localization evidence supports. In enterocytes the receptor is concentrated at the apical surface; that apical sub-localization is recorded separately as a NEW apical plasma membrane row (GO:0016324) rather than by narrowing this row. Supporting Evidence: PMID:23269669 When glycosylation of human GC-C was prevented, either by pharmacological intervention or by mutation of all of the 10 predicted glycosylation sites, ST binding and surface localization was abolished.
GO:0006182 cGMP biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: GC-C synthesises cGMP. Reason: Direct consequence of its guanylate cyclase activity; the IBA is consistent with the family. Supporting Evidence: PMID:1680854 respond to STa by dramatically increasing (approximately 50-fold) cellular cGMP levels
GO:0007168 receptor guanylyl cyclase signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: GC-C is a receptor guanylyl cyclase that initiates its own signaling pathway. Reason: Ligand binding to the extracellular domain activates the intracellular cyclase domain, the defining receptor guanylyl cyclase signaling mechanism. Supporting Evidence: PMID:1680854 The receptor contains both an extracellular ligand binding site and a cytoplasmic guanylyl cyclase catalytic domain
GO:0007168 receptor guanylyl cyclase signaling pathway	TAS PMID:1680854 Primary structure and functional expression of the human rec...	ACCEPT	Summary: GC-C is a receptor guanylyl cyclase that initiates its own signaling pathway. Reason: Ligand binding to the extracellular domain activates the intracellular cyclase domain, the defining receptor guanylyl cyclase signaling mechanism. Supporting Evidence: PMID:1680854 The receptor contains both an extracellular ligand binding site and a cytoplasmic guanylyl cyclase catalytic domain
GO:0009190 cyclic nucleotide biosynthetic process	IEA GO_REF:0000002	MODIFY	Summary: Cyclic nucleotide biosynthesis; GC-C specifically makes cGMP. Reason: Correct but general; GC-C makes cGMP, and the more specific cGMP biosynthetic process is already carried by this gene. Proposed replacements: cGMP biosynthetic process Supporting Evidence: PMID:11950846 Activation of GCC catalyzes the formation of cGMP
GO:0015643 toxic substance binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GC-C binds the E. coli heat-stable enterotoxin STa. Reason: STa binding with nM affinity is well established and underlies enterotoxigenic diarrhea, but it reflects hijacking of the guanylin/uroguanylin receptor; the core function is peptide receptor activity. Supporting Evidence: PMID:1680854 Stable mammalian cell lines over-expressing the STa receptor specifically bind 125I-STa (Kd approximately 1.0 nM)
GO:0016849 phosphorus-oxygen lyase activity	IEA GO_REF:0000002	MODIFY	Summary: Phosphorus-oxygen lyase activity is the parent of guanylate cyclase activity. Reason: Correct but general; the specific activity guanylate cyclase activity is established and already annotated. Proposed replacements: guanylate cyclase activity Supporting Evidence: file:human/GUCY2C/GUCY2C-uniprot.txt Guanylyl cyclase that catalyzes synthesis of cyclic GMP
GO:0035556 intracellular signal transduction	IEA GO_REF:0000002	MODIFY	Summary: cGMP is an intracellular second messenger generated by GC-C. Reason: Correct but general; the receptor guanylyl cyclase signaling pathway describes GC-C signaling more precisely and is already annotated. Proposed replacements: receptor guanylyl cyclase signaling pathway Supporting Evidence: PMID:1680854 The receptor contains both an extracellular ligand binding site and a cytoplasmic guanylyl cyclase catalytic domain
GO:0016324 apical plasma membrane	IDA PMID:11950846 A novel PDZ protein regulates the activity of guanylyl cycla...	NEW	Summary: In intestinal epithelium GC-C is targeted to the apical cell surface. Reason: The cited study shows efficient apical targeting of GCC in polarized cells, and STa binds the brush-border membrane; apical plasma membrane is the specific location of the signaling receptor. Supporting Evidence: PMID:11950846 The GCC-IKEPP interaction is not required for the efficient targeting of GCC to the apical cell surface. PMID:1680854 by binding to the brush border membrane of the small intestine and activating guanylyl cyclase

Gene Description

Existing Annotations Review

Core Functions

Cell-surface receptor guanylyl cyclase. The extracellular domain binds guanylin, uroguanylin or E. coli STa, activating the cytoplasmic catalytic domain to make cGMP, which drives CFTR-dependent intestinal chloride and fluid secretion.

Peptide receptor activity for the guanylin family and heat-stable enterotoxin through the glycosylated extracellular domain.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

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