CA9 (carbonic anhydrase IX) is a hypoxia-induced, single-pass type I transmembrane member of the alpha carbonic anhydrase family. Its extracellular region carries an N-terminal proteoglycan-like (PG) domain and a zinc-dependent catalytic carbonic-anhydrase domain that faces the cell exterior, so CA9 is a cell-surface ectoenzyme. It reversibly hydrates CO2 to bicarbonate and a proton and is one of the most catalytically active CA isozymes. Driven by the HIF pathway, it is strongly upregulated in hypoxic solid tumors (and a limited set of normal tissues, notably gastric mucosa), where its extracellular catalysis supports pH homeostasis, helping acidify the tumor microenvironment while maintaining intracellular pH. It forms disulfide-linked oligomers and has been implicated in tumor cell adhesion and proliferation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001666 response to hypoxia | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Response to hypoxia. CA9 is a HIF-induced hypoxia-response gene. Reason: CA IX is strongly induced by hypoxia and helps cells cope with the acidic hypoxic microenvironment. This is a regulatory/contextual process around the core catalytic role. Supporting Evidence: PMID:29564477 a tumour-associated enzyme present in a limited number of normal tissues, but overexpressed in several malignant human tumours |
| GO:0004089 carbonate dehydratase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Carbonate dehydratase (carbonic anhydrase) activity. Core catalytic function. Reason: Recombinant human CA IX catalyzes CO2 hydration with kcat/Km comparable to the highly active CA II. The IBA agrees with the alpha-CA family. Supporting Evidence: PMID:11676494 In kinetic constants for the hydration of CO2, CA IX closely resembled CA II with maximal proton transfer-dependent 18O exchange near 1 micros(-1) PMID:18703501 Carbonic anhydrase IX (CA IX) is an exceptional member of the CA protein family |
| GO:0004089 carbonate dehydratase activity | IDA PMID:11676494 The catalytic properties of human carbonic anhydrase IX. | ACCEPT | Summary: Carbonate dehydratase (carbonic anhydrase) activity. Core catalytic function. Reason: Recombinant human CA IX catalyzes CO2 hydration with kcat/Km comparable to the highly active CA II. The IBA agrees with the alpha-CA family. Supporting Evidence: PMID:11676494 In kinetic constants for the hydration of CO2, CA IX closely resembled CA II with maximal proton transfer-dependent 18O exchange near 1 micros(-1) PMID:18703501 Carbonic anhydrase IX (CA IX) is an exceptional member of the CA protein family |
| GO:0004089 carbonate dehydratase activity | IDA PMID:17314045 Phosph(on)ate as a zinc-binding group in metalloenzyme inhib... | ACCEPT | Summary: Carbonate dehydratase (carbonic anhydrase) activity. Core catalytic function. Reason: Recombinant human CA IX catalyzes CO2 hydration with kcat/Km comparable to the highly active CA II. The IBA agrees with the alpha-CA family. Supporting Evidence: PMID:11676494 In kinetic constants for the hydration of CO2, CA IX closely resembled CA II with maximal proton transfer-dependent 18O exchange near 1 micros(-1) PMID:18703501 Carbonic anhydrase IX (CA IX) is an exceptional member of the CA protein family |
| GO:0004089 carbonate dehydratase activity | IDA PMID:17705204 Saccharin inhibits carbonic anhydrases: possible explanation... | ACCEPT | Summary: Carbonate dehydratase (carbonic anhydrase) activity. Core catalytic function. Reason: Recombinant human CA IX catalyzes CO2 hydration with kcat/Km comparable to the highly active CA II. The IBA agrees with the alpha-CA family. Supporting Evidence: PMID:11676494 In kinetic constants for the hydration of CO2, CA IX closely resembled CA II with maximal proton transfer-dependent 18O exchange near 1 micros(-1) PMID:18703501 Carbonic anhydrase IX (CA IX) is an exceptional member of the CA protein family |
| GO:0004089 carbonate dehydratase activity | IDA PMID:18703501 Biochemical characterization of CA IX, one of the most activ... | ACCEPT | Summary: Carbonate dehydratase (carbonic anhydrase) activity. Core catalytic function. Reason: Recombinant human CA IX catalyzes CO2 hydration with kcat/Km comparable to the highly active CA II. The IBA agrees with the alpha-CA family. Supporting Evidence: PMID:11676494 In kinetic constants for the hydration of CO2, CA IX closely resembled CA II with maximal proton transfer-dependent 18O exchange near 1 micros(-1) PMID:18703501 Carbonic anhydrase IX (CA IX) is an exceptional member of the CA protein family |
| GO:0004089 carbonate dehydratase activity | IDA PMID:19186056 A thiabendazole sulfonamide shows potent inhibitory activity... | ACCEPT | Summary: Carbonate dehydratase (carbonic anhydrase) activity. Core catalytic function. Reason: Recombinant human CA IX catalyzes CO2 hydration with kcat/Km comparable to the highly active CA II. The IBA agrees with the alpha-CA family. Supporting Evidence: PMID:11676494 In kinetic constants for the hydration of CO2, CA IX closely resembled CA II with maximal proton transfer-dependent 18O exchange near 1 micros(-1) PMID:18703501 Carbonic anhydrase IX (CA IX) is an exceptional member of the CA protein family |
| GO:0004089 carbonate dehydratase activity | IDA PMID:19206230 Non-zinc mediated inhibition of carbonic anhydrases: coumari... | ACCEPT | Summary: Carbonate dehydratase (carbonic anhydrase) activity. Core catalytic function. Reason: Recombinant human CA IX catalyzes CO2 hydration with kcat/Km comparable to the highly active CA II. The IBA agrees with the alpha-CA family. Supporting Evidence: PMID:11676494 In kinetic constants for the hydration of CO2, CA IX closely resembled CA II with maximal proton transfer-dependent 18O exchange near 1 micros(-1) PMID:18703501 Carbonic anhydrase IX (CA IX) is an exceptional member of the CA protein family |
| GO:0004089 carbonate dehydratase activity | IDA PMID:19805286 Crystal structure of the catalytic domain of the tumor-assoc... | ACCEPT | Summary: Carbonate dehydratase (carbonic anhydrase) activity. Core catalytic function. Reason: Recombinant human CA IX catalyzes CO2 hydration with kcat/Km comparable to the highly active CA II. The IBA agrees with the alpha-CA family. Supporting Evidence: PMID:11676494 In kinetic constants for the hydration of CO2, CA IX closely resembled CA II with maximal proton transfer-dependent 18O exchange near 1 micros(-1) PMID:18703501 Carbonic anhydrase IX (CA IX) is an exceptional member of the CA protein family |
| GO:0004089 carbonate dehydratase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Carbonate dehydratase (carbonic anhydrase) activity. Core catalytic function. Reason: Recombinant human CA IX catalyzes CO2 hydration with kcat/Km comparable to the highly active CA II. The IBA agrees with the alpha-CA family. Supporting Evidence: PMID:11676494 In kinetic constants for the hydration of CO2, CA IX closely resembled CA II with maximal proton transfer-dependent 18O exchange near 1 micros(-1) PMID:18703501 Carbonic anhydrase IX (CA IX) is an exceptional member of the CA protein family |
| GO:0004089 carbonate dehydratase activity | TAS PMID:8661007 Human MN/CA9 gene, a novel member of the carbonic anhydrase ... | ACCEPT | Summary: Carbonate dehydratase (carbonic anhydrase) activity. Core catalytic function. Reason: Recombinant human CA IX catalyzes CO2 hydration with kcat/Km comparable to the highly active CA II. The IBA agrees with the alpha-CA family. Supporting Evidence: PMID:11676494 In kinetic constants for the hydration of CO2, CA IX closely resembled CA II with maximal proton transfer-dependent 18O exchange near 1 micros(-1) PMID:18703501 Carbonic anhydrase IX (CA IX) is an exceptional member of the CA protein family |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | REMOVE | Summary: Generic protein binding (NCCRP1, isoform-interaction screen). Reason: The protein-binding policy treats bare GO:0005515 as uninformative. These interactions (NCCRP1 and a splice-isoform interactome screen) give no evidence for a more informative CA9 molecular function. Removing the rows does not dispute them. Supporting Evidence: PMID:22087255 the non-specific cytotoxic cell receptor protein 1 (Nccrp1) transcript is significantly upregulated in the gastric mucosa of carbonic anhydrase IX (CA IX)-deficient (Car9(-/-)) mice |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding (NCCRP1, isoform-interaction screen). Reason: The protein-binding policy treats bare GO:0005515 as uninformative. These interactions (NCCRP1 and a splice-isoform interactome screen) give no evidence for a more informative CA9 molecular function. Removing the rows does not dispute them. Supporting Evidence: PMID:22087255 the non-specific cytotoxic cell receptor protein 1 (Nccrp1) transcript is significantly upregulated in the gastric mucosa of carbonic anhydrase IX (CA IX)-deficient (Car9(-/-)) mice |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding (NCCRP1, isoform-interaction screen). Reason: The protein-binding policy treats bare GO:0005515 as uninformative. These interactions (NCCRP1 and a splice-isoform interactome screen) give no evidence for a more informative CA9 molecular function. Removing the rows does not dispute them. Supporting Evidence: PMID:22087255 the non-specific cytotoxic cell receptor protein 1 (Nccrp1) transcript is significantly upregulated in the gastric mucosa of carbonic anhydrase IX (CA IX)-deficient (Car9(-/-)) mice |
| GO:0005634 nucleus | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: Nucleus / nucleolus. Reported nuclear pool of CA IX (MN antigen). Reason: CA IX is a single-pass type I transmembrane ectoenzyme whose catalytic domain is extracellular (UniProt topological domain 38-414), so a nuclear or nucleolar pool is topologically implausible. The signal rests on early MN-antigen antibody staining and an electronic UniProt-keyword mapping, so it is an over-annotation rather than a genuine location. Supporting Evidence: file:human/CA9/CA9-uniprot.txt Nucleus, nucleolus |
| GO:0005730 nucleolus | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: Nucleus / nucleolus. Reported nuclear pool of CA IX (MN antigen). Reason: CA IX is a single-pass type I transmembrane ectoenzyme whose catalytic domain is extracellular (UniProt topological domain 38-414), so a nuclear or nucleolar pool is topologically implausible. The signal rests on early MN-antigen antibody staining and an electronic UniProt-keyword mapping, so it is an over-annotation rather than a genuine location. Supporting Evidence: file:human/CA9/CA9-uniprot.txt Nucleus, nucleolus |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane. CA9 is a single-pass type I membrane protein. Reason: CA IX is an integral membrane protein localized to the plasma membrane; this row is accepted at the resolution its membrane-integrality evidence supports, and the IBA and multiple EXP/IDA rows agree. The external-side (ectoenzyme) topology of its extracellular catalytic domain is recorded separately on the NEW external side of plasma membrane row (GO:0009897). Supporting Evidence: PMID:11676494 Human carbonic anhydrase IX (CA IX) is an integral membrane protein PMID:18703501 To characterize the biochemical properties of this membrane protein |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Plasma membrane. CA9 is a single-pass type I membrane protein. Reason: CA IX is an integral membrane protein localized to the plasma membrane; this row is accepted at the resolution its membrane-integrality evidence supports, and the IBA and multiple EXP/IDA rows agree. The external-side (ectoenzyme) topology of its extracellular catalytic domain is recorded separately on the NEW external side of plasma membrane row (GO:0009897). Supporting Evidence: PMID:11676494 Human carbonic anhydrase IX (CA IX) is an integral membrane protein PMID:18703501 To characterize the biochemical properties of this membrane protein |
| GO:0005886 plasma membrane | IDA PMID:22087255 Characterization of non-specific cytotoxic cell receptor pro... | ACCEPT | Summary: Plasma membrane. CA9 is a single-pass type I membrane protein. Reason: CA IX is an integral membrane protein localized to the plasma membrane; this row is accepted at the resolution its membrane-integrality evidence supports, and the IBA and multiple EXP/IDA rows agree. The external-side (ectoenzyme) topology of its extracellular catalytic domain is recorded separately on the NEW external side of plasma membrane row (GO:0009897). Supporting Evidence: PMID:11676494 Human carbonic anhydrase IX (CA IX) is an integral membrane protein PMID:18703501 To characterize the biochemical properties of this membrane protein |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane. CA9 is a single-pass type I membrane protein. Reason: CA IX is an integral membrane protein localized to the plasma membrane; this row is accepted at the resolution its membrane-integrality evidence supports, and the IBA and multiple EXP/IDA rows agree. The external-side (ectoenzyme) topology of its extracellular catalytic domain is recorded separately on the NEW external side of plasma membrane row (GO:0009897). Supporting Evidence: PMID:11676494 Human carbonic anhydrase IX (CA IX) is an integral membrane protein PMID:18703501 To characterize the biochemical properties of this membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1235035 | ACCEPT | Summary: Plasma membrane. CA9 is a single-pass type I membrane protein. Reason: CA IX is an integral membrane protein localized to the plasma membrane; this row is accepted at the resolution its membrane-integrality evidence supports, and the IBA and multiple EXP/IDA rows agree. The external-side (ectoenzyme) topology of its extracellular catalytic domain is recorded separately on the NEW external side of plasma membrane row (GO:0009897). Supporting Evidence: PMID:11676494 Human carbonic anhydrase IX (CA IX) is an integral membrane protein PMID:18703501 To characterize the biochemical properties of this membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1475017 | ACCEPT | Summary: Plasma membrane. CA9 is a single-pass type I membrane protein. Reason: CA IX is an integral membrane protein localized to the plasma membrane; this row is accepted at the resolution its membrane-integrality evidence supports, and the IBA and multiple EXP/IDA rows agree. The external-side (ectoenzyme) topology of its extracellular catalytic domain is recorded separately on the NEW external side of plasma membrane row (GO:0009897). Supporting Evidence: PMID:11676494 Human carbonic anhydrase IX (CA IX) is an integral membrane protein PMID:18703501 To characterize the biochemical properties of this membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1475025 | ACCEPT | Summary: Plasma membrane. CA9 is a single-pass type I membrane protein. Reason: CA IX is an integral membrane protein localized to the plasma membrane; this row is accepted at the resolution its membrane-integrality evidence supports, and the IBA and multiple EXP/IDA rows agree. The external-side (ectoenzyme) topology of its extracellular catalytic domain is recorded separately on the NEW external side of plasma membrane row (GO:0009897). Supporting Evidence: PMID:11676494 Human carbonic anhydrase IX (CA IX) is an integral membrane protein PMID:18703501 To characterize the biochemical properties of this membrane protein |
| GO:0008270 zinc ion binding | IDA PMID:18703501 Biochemical characterization of CA IX, one of the most activ... | ACCEPT | Summary: Zinc ion binding. Catalytic Zn2+ in the active site. Reason: Alpha carbonic anhydrases, including CA IX, use an active-site zinc for catalysis. Supporting Evidence: file:human/CA9/CA9-uniprot.txt Name=Zn(2+); Xref=ChEBI:CHEBI:29105; |
| GO:0008270 zinc ion binding | IDA PMID:19805286 Crystal structure of the catalytic domain of the tumor-assoc... | ACCEPT | Summary: Zinc ion binding. Catalytic Zn2+ in the active site. Reason: Alpha carbonic anhydrases, including CA IX, use an active-site zinc for catalysis. Supporting Evidence: file:human/CA9/CA9-uniprot.txt Name=Zn(2+); Xref=ChEBI:CHEBI:29105; |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: Zinc ion binding. Catalytic Zn2+ in the active site. Reason: Alpha carbonic anhydrases, including CA IX, use an active-site zinc for catalysis. Supporting Evidence: file:human/CA9/CA9-uniprot.txt Name=Zn(2+); Xref=ChEBI:CHEBI:29105; |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Response to xenobiotic stimulus and response to testosterone (IEA). Reason: Electronic transfer from the rat ortholog (IEA) with no human experimental support; for a tumor-associated carbonic anhydrase these transcriptional-response terms are an over-annotation rather than a peripheral real function. The earlier CO2-hydration quote did not address the transcriptional response and was removed. |
| GO:0016020 membrane | TAS PMID:8661007 Human MN/CA9 gene, a novel member of the carbonic anhydrase ... | MODIFY | Summary: Membrane (TAS). Too general. Reason: The specific supported location is the plasma membrane. Proposed replacements: plasma membrane Supporting Evidence: PMID:11676494 Human carbonic anhydrase IX (CA IX) is an integral membrane protein |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Basolateral plasma membrane, a polarized surface subdomain (IEA, from the rat ortholog). Reason: A cell-type-dependent surface subdomain inferred from the rat ortholog; peripheral to the core cell-surface location. UniProt documents the microvillus-membrane subdomain, not the basolateral one, so no microvillus quote is cited here (that quote supports the separate microvillus-membrane row). |
| GO:0031528 microvillus membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Basolateral plasma membrane and microvillus membrane. Polarized surface localization. Reason: CA IX localizes to specific plasma-membrane subdomains (basolateral and microvillar) in polarized epithelial and tumor cells, consistent with its curated cell-projection/microvillus-membrane localization in UniProt. Supporting Evidence: file:human/CA9/CA9-uniprot.txt Cell projection, microvillus membrane |
| GO:0009897 external side of plasma membrane | IDA PMID:19805286 Crystal structure of the catalytic domain of the tumor-assoc... | NEW | Summary: CA IX displays its catalytic carbonate dehydratase domain on the external face of the plasma membrane. Reason: CA IX is a single-pass type I membrane protein whose catalytic domain is extracellular (UniProt topological domain 38-414); it acts on extracellular CO2/bicarbonate and is displayed on the tumour cell surface, so the external side of the plasma membrane is where the core carbonate dehydratase activity acts. GO:0009897 is part_of plasma membrane and CA9 has no such GOA row yet. Supporting Evidence: PMID:19805286 its overexpression is seen on the cell surface of a large number of solid tumors file:human/CA9/CA9-uniprot.txt Extracellular |
| GO:0033574 response to testosterone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Response to xenobiotic stimulus and response to testosterone (IEA). Reason: Electronic transfer from the rat ortholog (IEA) with no human experimental support; for a tumor-associated carbonic anhydrase these transcriptional-response terms are an over-annotation rather than a peripheral real function. The earlier CO2-hydration quote did not address the transcriptional response and was removed. |
| GO:0140677 molecular function activator activity | IDA PMID:29564477 Biochemical, biophysical and molecular dynamics studies on t... | KEEP AS NON CORE | Summary: The CA9 proteoglycan-like (PG) domain activates the carbonic-anhydrase catalytic domain. Reason: The cached full text (not just the abstract) demonstrates the activity by stopped-flow assay in trans, a separate PG (38-136) fragment raising the CA domain's catalytic activity about 63%; in intact CA9 the PG and CA domains are one chain, so this is an accessory (effectively intramolecular) activator activity rather than a standalone core function. Supporting Evidence: PMID:29564477 was able to increase the CA catalytic activity of about 63% |
Loading supporting content…
Download this section (compressed HTML)Q: How much of CA9 catalytic output serves extracellular acidification versus intracellular pH maintenance in hypoxic tumor cells?
Q: Does the proteoglycan-like domain contribute catalytically (e.g. as a proton antenna) or mainly to adhesion?
Experiment: Surface-restricted CA-activity assays (membrane-impermeant inhibitors) on hypoxic tumor cells, plus PG-domain deletion, to separate extracellular catalysis and adhesion functions.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)