hif1an encodes factor inhibiting HIF, a 2-oxoglutarate/Fe(II)-dependent protein hydroxylase that hydroxylates HIF-alpha and ankyrin-repeat proteins in nucleus/cytoplasm. The core function is protein asparagine/histidine/aspartate dioxygenase activity; vascular and Notch/HIF pathway annotations are regulatory consequences of that catalytic role.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0030947 regulation of vascular endothelial growth factor receptor signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: regulation of vascular endothelial growth factor receptor signaling pathway: Fih1an modulates VEGF signaling indirectly, by hydroxylating HIF-alpha and thereby limiting transcription of vegfa. Reason: This is a downstream regulatory consequence of the hydroxylase activity, not work Fih1an performs within VEGFR signaling itself. In zebrafish, fih-1 knockdown raises vegf-aa165 and produces ectopic vessels, so the regulatory link is real but indirect (PMID:25347788). Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002647297 SUPPORTS TRANSFER FIH-family node; regulation of VEGFR signaling is an indirect consequence of HIF-alpha hydroxylation, conserved and correctly placed but downstream of the catalytic role. Supporting Evidence: PMID:25347788 the expression level of vegf-aa165 is substantially elevated in fih-1 MO-injected embryos PMID:25347788 our data suggest that FIH-1 negatively regulates VEGF-A signaling via HIF-1 |
| GO:0045746 negative regulation of Notch signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: negative regulation of Notch signaling pathway: mammalian FIH hydroxylates ankyrin repeats of the Notch intracellular domain; the ankyrin-repeat hydroxylase capacity is conserved in zebrafish Fih1an. Reason: Retained as a conserved biochemical capacity (Fih1an hydroxylates ankyrin-repeat proteins per UniProt), but flagged non-core: in zebrafish fih-1 morphants the canonical Notch targets grl and dll4 are unaltered, so a functional Notch-regulatory role in zebrafish is not established (PMID:25347788). Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN002647297 SUPPORTS SOURCE BUT NOT TARGET The IBD reflects mammalian FIH hydroxylation of the Notch ICD ankyrin repeats. The biochemical capacity (ankyrin-repeat hydroxylation) is conserved in zebrafish, but in fih-1 morphant embryos canonical Notch targets grl and dll4 are unaltered (PMID:25347788), so a zebrafish Notch-signaling role is not demonstrated. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Also hydroxylates specific Asn, Asp and His residues within ankyrin repeat domain-containing proteins PMID:25347788 expression of grl and dll4, known targets of Notch signaling, appears to be unaltered |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: nucleus: Fih1an localizes to the nucleus, consistent with hydroxylation of nuclear HIF-alpha and ankyrin-repeat substrates. Reason: UniProt subcellular-location records Nucleus for the ortholog; the nuclear pool is where HIF-alpha CAD hydroxylation controlling coactivator recruitment occurs. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: cytoplasm: Fih1an has a cytoplasmic pool where it hydroxylates ankyrin-repeat-domain proteins. Reason: UniProt records Cytoplasm as a subcellular location; FIH is described as predominantly cytoplasmic in vertebrate cells and the zebrafish protein co-localizes with the cytoplasmic E3 ligase Mib1. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Cytoplasm |
| GO:0036139 peptidyl-histidine dioxygenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: peptidyl-histidine dioxygenase activity: Fih1an also hydroxylates specific histidine residues of ankyrin-repeat-domain proteins (EC 1.14.11.n4), a second regiospecificity of the same active site. Reason: Directly supported by the UniProt catalytic-activity records for His hydroxylation of ankyrin-repeat proteins; conserved across the FIH family into which the zebrafish protein falls. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Also hydroxylates specific Asn, Asp and His residues within ankyrin repeat domain-containing proteins file:DANRE/hif1an/hif1an-uniprot.txt ligand="2-oxoglutarate" |
| GO:0036140 [protein]-asparagine 3-dioxygenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: [protein]-asparagine 3-dioxygenase activity: Fih1an hydroxylates the C-terminal transactivation-domain asparagine of HIF-alpha (and asparagines of ankyrin-repeat proteins), the defining reaction of factor-inhibiting HIF. Reason: This is the core molecular function. UniProt records the Asn-hydroxylation reaction (EC 1.14.11.30) and the zebrafish enzyme is 96% identical to human FIH across the JmjC catalytic domain; the IBD node sits on the ancestral FIH clade that the zebrafish ortholog is squarely within. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Hydroxylates a specific Asn residue in the C-terminal transactivation domain (CAD) of HIF-1 alpha. The hydroxylation prevents interaction of HIF-1 with transcriptional coactivators file:DANRE/hif1an/hif1an-uniprot.txt Also hydroxylates specific Asn, Asp and His residues within ankyrin repeat domain-containing proteins |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: nucleus: Fih1an localizes to the nucleus, consistent with hydroxylation of nuclear HIF-alpha and ankyrin-repeat substrates. Reason: UniProt subcellular-location records Nucleus for the ortholog; the nuclear pool is where HIF-alpha CAD hydroxylation controlling coactivator recruitment occurs. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: cytoplasm: Fih1an has a cytoplasmic pool where it hydroxylates ankyrin-repeat-domain proteins. Reason: UniProt records Cytoplasm as a subcellular location; FIH is described as predominantly cytoplasmic in vertebrate cells and the zebrafish protein co-localizes with the cytoplasmic E3 ligase Mib1. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Cytoplasm |
| GO:0009966 regulation of signal transduction | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: regulation of signal transduction: a broad InterPro2GO mapping capturing FIH's role as a hydroxylase that modulates HIF (and potentially other) signaling outputs. Reason: Correct but very general; the specific, evidence-backed regulatory outputs are captured by the VEGFR/HIF terms. Kept as non-core context rather than removed. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Hydroxylates a specific Asn residue in the C-terminal transactivation domain (CAD) of HIF-1 alpha. The hydroxylation prevents interaction of HIF-1 with transcriptional coactivators |
| GO:0036139 peptidyl-histidine dioxygenase activity | IEA GO_REF:0000116 | ACCEPT | Summary: peptidyl-histidine dioxygenase activity: Fih1an also hydroxylates specific histidine residues of ankyrin-repeat-domain proteins (EC 1.14.11.n4), a second regiospecificity of the same active site. Reason: Directly supported by the UniProt catalytic-activity records for His hydroxylation of ankyrin-repeat proteins; conserved across the FIH family into which the zebrafish protein falls. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Also hydroxylates specific Asn, Asp and His residues within ankyrin repeat domain-containing proteins file:DANRE/hif1an/hif1an-uniprot.txt ligand="2-oxoglutarate" |
| GO:0036140 [protein]-asparagine 3-dioxygenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: [protein]-asparagine 3-dioxygenase activity: Fih1an hydroxylates the C-terminal transactivation-domain asparagine of HIF-alpha (and asparagines of ankyrin-repeat proteins), the defining reaction of factor-inhibiting HIF. Reason: This is the core molecular function. UniProt records the Asn-hydroxylation reaction (EC 1.14.11.30) and the zebrafish enzyme is 96% identical to human FIH across the JmjC catalytic domain; the IBD node sits on the ancestral FIH clade that the zebrafish ortholog is squarely within. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Hydroxylates a specific Asn residue in the C-terminal transactivation domain (CAD) of HIF-1 alpha. The hydroxylation prevents interaction of HIF-1 with transcriptional coactivators file:DANRE/hif1an/hif1an-uniprot.txt Also hydroxylates specific Asn, Asp and His residues within ankyrin repeat domain-containing proteins |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: perinuclear region of cytoplasm: a perinuclear cytoplasmic pool of Fih1an is recorded, consistent with the reported perinuclear co-localization with Mib1. Reason: UniProt annotates a perinuclear cytoplasmic location; this refines the cytoplasmic pool rather than adding a distinct role. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Cytoplasm, perinuclear region |
| GO:0050793 regulation of developmental process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: regulation of developmental process: a broad InterPro2GO mapping; in zebrafish Fih1an constrains developmental angiogenesis via HIF/VEGF. Reason: Very general term; the concrete developmental role (vasculature) is captured more specifically by GO:1901343. Retained as non-core. Supporting Evidence: PMID:25347788 a significant fraction of fih-1 mRNA-injected embryos failed to develop intersegmental vessels (ISVs), whose formation is directly regulated by VEGF-A signaling |
| GO:0062101 peptidyl-aspartic acid 3-dioxygenase activity | ISS GO_REF:0000024 | ACCEPT | Summary: peptidyl-aspartic acid 3-dioxygenase activity: Fih1an hydroxylates specific aspartate residues within ankyrin-repeat-domain proteins (EC 1.14.11.n4). Reason: One of the three ankyrin-repeat-directed hydroxylation reactions in the UniProt record; part of the same conserved FIH catalytic repertoire. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Also hydroxylates specific Asn, Asp and His residues within ankyrin repeat domain-containing proteins file:DANRE/hif1an/hif1an-uniprot.txt ligand="2-oxoglutarate" |
| GO:0008198 ferrous iron binding | ISS GO_REF:0000024 | ACCEPT | Summary: ferrous iron binding: the FIH active site holds a catalytic Fe(II) via the 2-His-1-carboxylate facial triad; iron is the redox-active metal for the dioxygenase reaction. Reason: Fe(II) binding is an integral part of the core catalytic mechanism (2-OG/Fe(II) oxygenase), not a separable function. UniProt records Fe(2+) as the cofactor and annotates the Fe-coordinating residues. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Name=Fe(2+); Xref=ChEBI:CHEBI:29033 file:DANRE/hif1an/hif1an-uniprot.txt ligand="2-oxoglutarate" |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: cytoplasm: Fih1an has a cytoplasmic pool where it hydroxylates ankyrin-repeat-domain proteins. Reason: UniProt records Cytoplasm as a subcellular location; FIH is described as predominantly cytoplasmic in vertebrate cells and the zebrafish protein co-localizes with the cytoplasmic E3 ligase Mib1. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Cytoplasm |
| GO:0008270 zinc ion binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: zinc ion binding: the FIH catalytic metal site can be occupied by Zn(II) in vitro; crystal structures of the human ortholog used Zn(II) as an inactive surrogate for the catalytic Fe(II). Reason: The physiological catalytic metal is Fe(II); zinc binding reflects the same 2-His-1-carboxylate site occupied by Zn(II) in structural/inhibitor studies (PMID:12446723) rather than a separate zinc-dependent activity. Retained as non-core because it describes the catalytic metal centre, not a distinct function. Supporting Evidence: PMID:12446723 structures with the inhibitors Zn((II)) and N-oxaloylglycine file:DANRE/hif1an/hif1an-uniprot.txt Name=Fe(2+); Xref=ChEBI:CHEBI:29033 |
| GO:0031406 carboxylic acid binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: carboxylic acid binding: FIH binds the co-substrate 2-oxoglutarate (a dicarboxylic acid) in its active site, coordinated adjacent to the catalytic iron. Reason: This general term captures 2-oxoglutarate co-substrate binding, which is a mechanistic component of the dioxygenase activity rather than a distinct biological function; UniProt annotates the 2-oxoglutarate binding residues. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt ligand="2-oxoglutarate" file:DANRE/hif1an/hif1an-uniprot.txt Name=Fe(2+); Xref=ChEBI:CHEBI:29033 |
| GO:0042803 protein homodimerization activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: protein homodimerization activity: FIH is an obligate homodimer, and dimerization is required for its hydroxylase activity. Reason: UniProt states homodimerization is essential for catalytic activity; this is a structural prerequisite of the core enzyme rather than an independent core function. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Homodimer; homodimerization is essential for catalytic |
| GO:0048471 perinuclear region of cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: perinuclear region of cytoplasm: a perinuclear cytoplasmic pool of Fih1an is recorded, consistent with the reported perinuclear co-localization with Mib1. Reason: UniProt annotates a perinuclear cytoplasmic location; this refines the cytoplasmic pool rather than adding a distinct role. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Cytoplasm, perinuclear region |
| GO:0030947 regulation of vascular endothelial growth factor receptor signaling pathway | IGI PMID:25347788 FIH-1, a novel interactor of mindbomb, functions as an essen... | KEEP AS NON CORE | Summary: regulation of vascular endothelial growth factor receptor signaling pathway: in zebrafish, loss of fih-1 elevates vegf-aa165 and increases endothelial sprouting, while fih-1 overexpression suppresses it, in a HIF-1alpha-dependent manner. Reason: The genetic interactions with vegfaa and hif1a (PMID:25347788) place Fih1an upstream of VEGF signaling via HIF-1alpha; it regulates the pathway but does not itself carry out VEGFR signal transduction, so this is non-core. Supporting Evidence: PMID:25347788 the expression level of vegf-aa165 is substantially elevated in fih-1 MO-injected embryos PMID:25347788 our data suggest that FIH-1 negatively regulates VEGF-A signaling via HIF-1 |
| GO:1901343 negative regulation of vasculature development | IDA PMID:25347788 FIH-1, a novel interactor of mindbomb, functions as an essen... | KEEP AS NON CORE | Summary: negative regulation of vasculature development: in zebrafish, fih-1 overexpression reduces intersegmental-vessel formation and knockdown produces ectopic sprouts, identifying Fih1an as a brake on developmental angiogenesis (PMID:25347788). Reason: This is a downstream phenotype of the hydroxylase activity: Fih1an acts upstream of HIF-1alpha/VEGF-A rather than performing morphogenetic work in vessel development. The morphant and overexpression phenotypes are rescued by manipulating VEGF-A, confirming an upstream regulatory (not participatory) role, so KEEP_AS_NON_CORE rather than as a core function. Supporting Evidence: PMID:25347788 a significant fraction of fih-1 mRNA-injected embryos failed to develop intersegmental vessels (ISVs), whose formation is directly regulated by VEGF-A signaling PMID:25347788 functions as an anti-angiogenic factor by attenuating HIF-1 PMID:25347788 co-injection of fih-1 mRNA is able to rescue this phenotype |
| GO:1901343 negative regulation of vasculature development | IMP PMID:25347788 FIH-1, a novel interactor of mindbomb, functions as an essen... | KEEP AS NON CORE | Summary: negative regulation of vasculature development: in zebrafish, fih-1 overexpression reduces intersegmental-vessel formation and knockdown produces ectopic sprouts, identifying Fih1an as a brake on developmental angiogenesis (PMID:25347788). Reason: This is a downstream phenotype of the hydroxylase activity: Fih1an acts upstream of HIF-1alpha/VEGF-A rather than performing morphogenetic work in vessel development. The morphant and overexpression phenotypes are rescued by manipulating VEGF-A, confirming an upstream regulatory (not participatory) role, so KEEP_AS_NON_CORE rather than as a core function. Supporting Evidence: PMID:25347788 a significant fraction of fih-1 mRNA-injected embryos failed to develop intersegmental vessels (ISVs), whose formation is directly regulated by VEGF-A signaling PMID:25347788 functions as an anti-angiogenic factor by attenuating HIF-1 PMID:25347788 co-injection of fih-1 mRNA is able to rescue this phenotype |
| GO:0036140 [protein]-asparagine 3-dioxygenase activity | ISS GO_REF:0000024 | ACCEPT | Summary: [protein]-asparagine 3-dioxygenase activity: Fih1an hydroxylates the C-terminal transactivation-domain asparagine of HIF-alpha (and asparagines of ankyrin-repeat proteins), the defining reaction of factor-inhibiting HIF. Reason: This is the core molecular function. UniProt records the Asn-hydroxylation reaction (EC 1.14.11.30) and the zebrafish enzyme is 96% identical to human FIH across the JmjC catalytic domain; the IBD node sits on the ancestral FIH clade that the zebrafish ortholog is squarely within. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Hydroxylates a specific Asn residue in the C-terminal transactivation domain (CAD) of HIF-1 alpha. The hydroxylation prevents interaction of HIF-1 with transcriptional coactivators file:DANRE/hif1an/hif1an-uniprot.txt Also hydroxylates specific Asn, Asp and His residues within ankyrin repeat domain-containing proteins |
| GO:0036139 peptidyl-histidine dioxygenase activity | ISS GO_REF:0000024 | ACCEPT | Summary: peptidyl-histidine dioxygenase activity: Fih1an also hydroxylates specific histidine residues of ankyrin-repeat-domain proteins (EC 1.14.11.n4), a second regiospecificity of the same active site. Reason: Directly supported by the UniProt catalytic-activity records for His hydroxylation of ankyrin-repeat proteins; conserved across the FIH family into which the zebrafish protein falls. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Also hydroxylates specific Asn, Asp and His residues within ankyrin repeat domain-containing proteins file:DANRE/hif1an/hif1an-uniprot.txt ligand="2-oxoglutarate" |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: nucleus: Fih1an localizes to the nucleus, consistent with hydroxylation of nuclear HIF-alpha and ankyrin-repeat substrates. Reason: UniProt subcellular-location records Nucleus for the ortholog; the nuclear pool is where HIF-alpha CAD hydroxylation controlling coactivator recruitment occurs. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0030947 regulation of vascular endothelial growth factor receptor signaling pathway | IGI PMID:25347788 FIH-1, a novel interactor of mindbomb, functions as an essen... | KEEP AS NON CORE | Summary: regulation of vascular endothelial growth factor receptor signaling pathway: in zebrafish, loss of fih-1 elevates vegf-aa165 and increases endothelial sprouting, while fih-1 overexpression suppresses it, in a HIF-1alpha-dependent manner. Reason: The genetic interactions with vegfaa and hif1a (PMID:25347788) place Fih1an upstream of VEGF signaling via HIF-1alpha; it regulates the pathway but does not itself carry out VEGFR signal transduction, so this is non-core. Supporting Evidence: PMID:25347788 the expression level of vegf-aa165 is substantially elevated in fih-1 MO-injected embryos PMID:25347788 our data suggest that FIH-1 negatively regulates VEGF-A signaling via HIF-1 |
| GO:0062101 peptidyl-aspartic acid 3-dioxygenase activity | IEA GO_REF:0000116 | ACCEPT | Summary: peptidyl-aspartic acid 3-dioxygenase activity: Fih1an hydroxylates specific aspartate residues within ankyrin-repeat-domain proteins (EC 1.14.11.n4). Reason: One of the three ankyrin-repeat-directed hydroxylation reactions in the UniProt record; part of the same conserved FIH catalytic repertoire. Supporting Evidence: file:DANRE/hif1an/hif1an-uniprot.txt Also hydroxylates specific Asn, Asp and His residues within ankyrin repeat domain-containing proteins file:DANRE/hif1an/hif1an-uniprot.txt ligand="2-oxoglutarate" |
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