PTCH1 (Protein patched homolog 1) is the cell-surface receptor for the Hedgehog family of secreted morphogens - Sonic, Indian and Desert hedgehog - and the constitutive brake on the Hedgehog signalling pathway in vertebrates. It is a 1447-residue polytopic glycoprotein built from twelve transmembrane helices and two large extracellular domains, belonging to the RND-permease-like patched family whose founding member is the Drosophila segment-polarity gene ptc; human carries a paralogue, PTCH2. PTCH1 resides in the plasma membrane and, functionally most importantly, in the membrane of the non-motile primary cilium. Its molecular activity is not classical signal transduction but lipid movement: the transmembrane core contains a sterol-sensing domain and a conduit through which cholesterol is carried, and by depleting accessible cholesterol from the ciliary membrane the unliganded receptor starves the class-F GPCR Smoothened of the sterol it needs to adopt an active conformation. Hedgehog ligands inactivate PTCH1 by a two-lipid grasp: the ligand's N-terminal palmitate and C-terminal cholesteroyl group both insert into the receptor's extracellular domains, closing the sterol conduit; two receptors engage one ligand through distinct epitopes, and the complex is then ubiquitinated, internalised and degraded, clearing PTCH1 from the cilium so that Smoothened can enter and signal to the GLI transcription factors. Because PTCH1 sets the threshold of this pathway, it shapes embryonic patterning across many tissues - the dorsoventral neural tube, limb bud, somites, pharyngeal arches, skin and urogenital tract - and it acts as a tumour suppressor in adult tissue. Germline loss-of-function variants cause nevoid basal cell carcinoma (Gorlin) syndrome and holoprosencephaly, and somatic inactivation drives sporadic basal cell carcinoma and medulloblastoma. Reported secondary activities include sequestration of phosphorylated cyclin B1 away from the nucleus and a Smoothened-independent dampening of GLI1-driven transcription.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:16229683 Inhibition of GLI1 gene activation by Patched1. | KEEP AS NON CORE | Summary: Rahnama et al. showed in human cells that PTCH1 suppresses GLI1-driven reporter and endogenous target-gene activation, and that this suppression survives cyclopamine and does not require SUFU, i.e. it is not routed through the canonical SMO cascade. Deletion mapping put the activity in residues 180-786 and 1058-1210 rather than the C-terminal tail used for Hedgehog signalling. Reason: The experiment is real and human, so it is retained, but it is kept off the core set for two reasons. PTCH1 is a 12-pass membrane protein with no DNA-binding or chromatin activity; whatever it does to GLI1-dependent transcription it does at a distance, and the assay is a transfection/overexpression readout. The core molecular function established by structure and transport biochemistry is sterol movement, and the core process is negative regulation of the smoothened signalling pathway, which this non-canonical arm sits alongside rather than inside. Supporting Evidence: PMID:16229683 We show that gene activation by GLI1, the transcriptional effector of the pathway, can be down-regulated by PTCH1 without involvement of the canonical cascade of HH signalling events. |
| GO:0001841 neural tube formation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neural tube formation depends on graded Hedgehog signalling from the notochord and floor plate, and PTCH1 sets the gain of that gradient by repressing SMO in cells that have not received ligand. Loss of patched function in human NBCCS produces the developmental abnormalities of the syndrome, spina bifida among them. Reason: The process is genuinely PTCH1-dependent, so the term is kept, but neural tube formation is a downstream organismal outcome of pathway derepression rather than an activity PTCH1 itself executes. This row reaches human by Ensembl-Compara transfer from mouse Ptch1; the mouse gene also carries neural tube closure by IMP, so the transfer lands on a real mouse phenotype even though the specific source row is an IDA in a paper about the Sonic hedgehog ligand. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q61115 · Ptch1 SUPPORTS TRANSFER Mouse Ptch1 independently carries neural tube closure by IMP; the neural-tube requirement is not in doubt, only its status as a direct PTCH1 activity. Supporting Evidence: PMID:8681379 We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types. |
| GO:0005113 patched binding | IEA GO_REF:0000107 | MODIFY | Summary: As transferred, this asserts that PTCH1 binds a patched protein. PTCH1 is a patched protein, so the only non-vacuous reading is self-association - and that reading is directly established: one SHH-N molecule bridges two PTCH1 receptors through two chemically distinct epitopes, and higher-order cryo-EM shows four protomers arranged as a dimer of dimers. Reason: The essence survives but the term does not. Traced back, this row comes by Ensembl-Compara transfer from a mouse Ptch1 annotation whose source paper measures Sonic hedgehog binding to Patched - the activity described by the term belongs to the entity that binds patched, and on the receptor itself it is self-referential. Rather than discard it, it is re-pointed at identical protein binding, which is what the human structural work actually shows and which carries the oligomerisation information that matters for how ligand inactivates the receptor. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q61115 · Ptch1 SUPPORTS SOURCE BUT NOT TARGET The mouse source row is an IDA from a study of the Sonic hedgehog ligand; "patched binding" describes the ligand side of that interaction, not the receptor side. Proposed replacements: identical protein binding Supporting Evidence: PMID:30139912 one SHH-N molecule engages both epitopes to bind two PTCH1 receptors in an asymmetric manner PMID:30139912 One SHH-N forms a complex with two PTCH1* molecules (PTCH1-A and PTCH1-B) using two distinct interfaces PMID:31127104 The structure shows that four Ptch1 protomers are organized as a loose dimer of dimers. |
| GO:0005119 smoothened binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The PAINT node places smoothened binding on the Patched clade, seeded by human PTCH1 and PTCH2, both of which were shown biochemically to form a complex with SMO. The node placement is sound: complex formation was demonstrated for both vertebrate paralogues in the same experiment. Reason: Kept rather than removed - the co-immunoprecipitation evidence is experimental and stands on its own - but marked non-core because of a real mechanistic tension. PTCH1 inhibits SMO sub-stoichiometrically and catalytically, by depleting the sterol pool SMO needs, not by occupying it; the structures resolve PTCH1 with Hedgehog and with sterols, never with SMO. The module (modules/hedgehog_signaling.yaml) and all six human GO-CAM models listed in gocams/index.tsv encode the PTCH1-to-SMO relationship as causal inhibition downstream of GO:0140303 intramembrane lipid carrier activity, not as a binding event, and this review follows that. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000847539 SUPPORTS TRANSFER Patched-clade ancestral node; PTCH1 appears in its own WITH/FROM because its experimental complex-formation data is one of the descendant evidences behind the IBD, which is expected rather than circular. Supporting Evidence: PMID:9811851 Biochemical analysis of PTCH and PTCH2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with SMO. |
| GO:0005119 smoothened binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: An ARBA machine-learned rule assigning smoothened binding to the Patched family. It duplicates the phylogenetic and experimental rows at the same level of specificity. Reason: Kept rather than removed - the co-immunoprecipitation evidence is experimental and stands on its own - but marked non-core because of a real mechanistic tension. PTCH1 inhibits SMO sub-stoichiometrically and catalytically, by depleting the sterol pool SMO needs, not by occupying it; the structures resolve PTCH1 with Hedgehog and with sterols, never with SMO. The module (modules/hedgehog_signaling.yaml) and all six human GO-CAM models listed in gocams/index.tsv encode the PTCH1-to-SMO relationship as causal inhibition downstream of GO:0140303 intramembrane lipid carrier activity, not as a binding event, and this review follows that. Supporting Evidence: PMID:9811851 Biochemical analysis of PTCH and PTCH2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with SMO. |
| GO:0005119 smoothened binding | IPI PMID:11278759 The sonic hedgehog receptor patched associates with caveolin... | KEEP AS NON CORE | Summary: Karpen et al. found PTCH1 and SMO together in caveolin-1-enriched raft microdomains of the plasma membrane and co-isolated them from buoyant density fractions, supporting a Patched-Smoothened receptor complex in cholesterol-rich membrane. Reason: Kept rather than removed - the co-immunoprecipitation evidence is experimental and stands on its own - but marked non-core because of a real mechanistic tension. PTCH1 inhibits SMO sub-stoichiometrically and catalytically, by depleting the sterol pool SMO needs, not by occupying it; the structures resolve PTCH1 with Hedgehog and with sterols, never with SMO. The module (modules/hedgehog_signaling.yaml) and all six human GO-CAM models listed in gocams/index.tsv encode the PTCH1-to-SMO relationship as causal inhibition downstream of GO:0140303 intramembrane lipid carrier activity, not as a binding event, and this review follows that. Supporting Evidence: PMID:11278759 In this study, we demonstrate that both Smoothened and Patched are in caveolin-1-enriched/raft microdomains. PMID:11278759 Immunoprecipitation studies show that Patched specifically interacts with caveolin-1, whereas Smoothened does not. |
| GO:0005119 smoothened binding | IPI PMID:9811851 Characterization of two patched receptors for the vertebrate... | KEEP AS NON CORE | Summary: Carpenter et al. showed directly that PTCH1 and PTCH2 can form a complex with SMO, in the same set of binding experiments that established Hedgehog ligand binding. Reason: Kept rather than removed - the co-immunoprecipitation evidence is experimental and stands on its own - but marked non-core because of a real mechanistic tension. PTCH1 inhibits SMO sub-stoichiometrically and catalytically, by depleting the sterol pool SMO needs, not by occupying it; the structures resolve PTCH1 with Hedgehog and with sterols, never with SMO. The module (modules/hedgehog_signaling.yaml) and all six human GO-CAM models listed in gocams/index.tsv encode the PTCH1-to-SMO relationship as causal inhibition downstream of GO:0140303 intramembrane lipid carrier activity, not as a binding event, and this review follows that. Supporting Evidence: PMID:9811851 Biochemical analysis of PTCH and PTCH2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with SMO. |
| GO:0005515 protein binding | IPI PMID:19502428 Kinase activity-independent regulation of cyclin pathway by ... | MODIFY | Summary: PTCH1 associates with cyclin B1; the GRK2 study measured that association directly and showed it is competed by the GRK2 PTCH1-binding region, which relieves PTCH1-mediated block of cyclin B1 nuclear translocation. Reason: Bare protein binding records nothing about what PTCH1 does. The cited paper supports a specific and more informative molecular function against this partner - cyclin binding - which GOA already carries for PTCH1 from an independent study, so the row is re-pointed there rather than discarded. Proposed replacements: cyclin binding Supporting Evidence: PMID:19502428 Interaction of GRK2, K220R, and BP with PTCH1 reduces the association of PTCH1 with cyclin B1 and disrupts PTCH1-mediated inhibition of cyclin B1 nuclear translocation, whereas the PTCH1-binding deficient GRK2 mutant (Delta312-379) does not. |
| GO:0005515 protein binding | IPI PMID:19502428 Kinase activity-independent regulation of cyclin pathway by ... | MODIFY | Summary: PTCH1 binds GRK2. The interaction is the mechanistic centre of the paper: it is stimulated by Hedgehog, is mapped to GRK2 residues 262-379, and is independent of GRK2 kinase activity, since a kinase-dead mutant rescues the knockdown phenotype. This row records the bovine GRK2 ortholog used in the interaction assays. Reason: Bare protein binding is uninformative, and the policy for GO:0005515 requires MODIFY where the cited paper supports a better molecular function. It does here: GRK2 is a serine/threonine protein kinase, so the measured association is protein kinase binding, a term that preserves the information the generic row throws away. Note that the functional consequence runs the other way (GRK2 binding displaces cyclin B1 from PTCH1), so no kinase-regulatory term is proposed. Proposed replacements: protein kinase binding Supporting Evidence: PMID:19502428 A physical interaction between GRK2 and cyclin B1 regulator patched homolog 1 (PTCH1), stimulated by Hedgehog (Hh), rather than GRK2-mediated phosphorylation of downstream targets, appears as the underlying mechanism. PMID:19502428 Interaction of GRK2, K220R, and BP with PTCH1 reduces the association of PTCH1 with cyclin B1 and disrupts PTCH1-mediated inhibition of cyclin B1 nuclear translocation, whereas the PTCH1-binding deficient GRK2 mutant (Delta312-379) does not. |
| GO:0005515 protein binding | IPI PMID:19502428 Kinase activity-independent regulation of cyclin pathway by ... | MODIFY | Summary: PTCH1 binds GRK2. The interaction is the mechanistic centre of the paper: it is stimulated by Hedgehog, is mapped to GRK2 residues 262-379, and is independent of GRK2 kinase activity, since a kinase-dead mutant rescues the knockdown phenotype. This row records the human GRK2 partner. Reason: Bare protein binding is uninformative, and the policy for GO:0005515 requires MODIFY where the cited paper supports a better molecular function. It does here: GRK2 is a serine/threonine protein kinase, so the measured association is protein kinase binding, a term that preserves the information the generic row throws away. Note that the functional consequence runs the other way (GRK2 binding displaces cyclin B1 from PTCH1), so no kinase-regulatory term is proposed. Proposed replacements: protein kinase binding Supporting Evidence: PMID:19502428 A physical interaction between GRK2 and cyclin B1 regulator patched homolog 1 (PTCH1), stimulated by Hedgehog (Hh), rather than GRK2-mediated phosphorylation of downstream targets, appears as the underlying mechanism. PMID:19502428 Interaction of GRK2, K220R, and BP with PTCH1 reduces the association of PTCH1 with cyclin B1 and disrupts PTCH1-mediated inhibition of cyclin B1 nuclear translocation, whereas the PTCH1-binding deficient GRK2 mutant (Delta312-379) does not. |
| GO:0005515 protein binding | IPI PMID:19561609 The structure of SHH in complex with HHIP reveals a recognit... | MODIFY | Summary: The partner in this row is SHH, PTCH1's own ligand. The HHIP-SHH structure paper mapped the SHH pseudo-active-site groove and used PTCH1 ectodomain peptides to show that Patched recognises the same surface, proposing a 'patch for Patched' there. Reason: Recording the receptor-ligand interaction as generic protein binding discards exactly the information that matters. The cited work supports the specific term, which GOA already carries for PTCH1 from direct binding assays against all three Hedgehog ligands, so the row is re-pointed to hedgehog family protein binding. Proposed replacements: hedgehog family protein binding Supporting Evidence: PMID:19561609 sequence comparisons of this SHH binding loop with the Hh receptor Patched (Ptc1) ectodomains and HHIP- and PTC1-peptide binding studies suggest a 'patch for Patched' at the Shh pseudo active site PMID:9811851 Biochemical analysis of PTCH and PTCH2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with SMO. |
| GO:0005515 protein binding | IPI PMID:21802063 Mutations in CDON, encoding a hedgehog receptor, result in h... | REMOVE | Summary: PTCH1 associates with the Ig/FNIII co-receptor CDON (rat ortholog in this row). CDON missense variants found in human holoprosencephaly retain SHH binding but associate poorly with PTCH1 and GAS1, and lose signalling activity in proportion. Reason: Removed because the bare term carries no functional information, not because the interaction is doubtful - it is well measured, and its loss in the holoprosencephaly variants is the paper's point. No GO molecular function describes receptor-co-receptor association more informatively than GO:0005515 does: signaling receptor binding would mis-cast a co-receptor as a ligand, and protein-containing complex binding is no more specific. The functional content of this interaction is already captured on the other side, where CDON carries GO:0140597 protein carrier activity in GO-CAM 696022cd00000908 and in the module's co-receptor annoton. Supporting Evidence: PMID:21802063 In contrast, wild-type CDON associates with PTCH1 and GAS1, but the variants do so inefficiently, in a manner that parallels their activity in cell-based assays. |
| GO:0005515 protein binding | IPI PMID:21802063 Mutations in CDON, encoding a hedgehog receptor, result in h... | REMOVE | Summary: PTCH1 associates with human CDON. Wild-type CDON binds PTCH1 and GAS1; the holoprosencephaly variants do so inefficiently even though their SHH-binding domain is intact, which is the mechanism the paper proposes for the disease. Reason: Removed because the bare term carries no functional information, not because the interaction is doubtful - it is well measured, and its loss in the holoprosencephaly variants is the paper's point. No GO molecular function describes receptor-co-receptor association more informatively than GO:0005515 does: signaling receptor binding would mis-cast a co-receptor as a ligand, and protein-containing complex binding is no more specific. The functional content of this interaction is already captured on the other side, where CDON carries GO:0140597 protein carrier activity in GO-CAM 696022cd00000908 and in the module's co-receptor annoton. Supporting Evidence: PMID:21802063 In contrast, wild-type CDON associates with PTCH1 and GAS1, but the variants do so inefficiently, in a manner that parallels their activity in cell-based assays. |
| GO:0005515 protein binding | IPI PMID:25283809 Ligand binding to WW tandem domains of YAP2 transcriptional ... | REMOVE | Summary: An interaction between PTCH1 and the Hippo-pathway coactivator YAP1, recorded from a biophysical study of ligand binding to the YAP2 WW tandem domains. Reason: Bare protein binding conveys no functional information, and unlike the CCNB1, GRK2 and SHH rows there is no more informative molecular function the cited work supports for PTCH1: the paper is about cooperativity between two WW domains of YAP2, not about Hedgehog reception, and it connects to no established PTCH1 activity. Removal does not assert that the interaction is false. |
| GO:0005794 Golgi apparatus | IDA PMID:11278759 The sonic hedgehog receptor patched associates with caveolin... | KEEP AS NON CORE | Summary: In the caveolin-1 study, Patched immunostaining included a Golgi/perinuclear pool alongside the plasma-membrane and raft signal. Reason: A 12-pass glycoprotein necessarily transits the secretory pathway, so a Golgi pool is expected and the observation is not disputed. It is not a site of function: Hedgehog reception and sterol handling both happen at the cell surface and at the ciliary membrane, which is where the module and every GO-CAM model place the PTCH1 activity. Supporting Evidence: PMID:11278759 In this study, we demonstrate that both Smoothened and Patched are in caveolin-1-enriched/raft microdomains. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The PAINT node places plasma membrane on the Patched clade, spanning Drosophila ptc, the C. elegans members, rodent and human PTCH1/PTCH2 - a location conserved since the family's origin. Reason: This is where PTCH1 works. UniProt records Cell membrane, multi-pass, from direct human evidence, and the functionally decisive pool is the continuous ciliary membrane, annotated separately. Ligand binding, sterol transport and the SMO-restricting activity all occur here, and the module and all six human GO-CAM activities place the PTCH1 annoton at the plasma/ciliary membrane. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0005886 plasma membrane | IDA PMID:11278759 The sonic hedgehog receptor patched associates with caveolin... | ACCEPT | Summary: Karpen et al. localised Patched to the plasma membrane and to its caveolin-1-enriched raft subdomains by confocal microscopy and buoyant-density fractionation. Reason: This is where PTCH1 works. UniProt records Cell membrane, multi-pass, from direct human evidence, and the functionally decisive pool is the continuous ciliary membrane, annotated separately. Ligand binding, sterol transport and the SMO-restricting activity all occur here, and the module and all six human GO-CAM activities place the PTCH1 annoton at the plasma/ciliary membrane. Supporting Evidence: PMID:11278759 In this study, we demonstrate that both Smoothened and Patched are in caveolin-1-enriched/raft microdomains. |
| GO:0005886 plasma membrane | IDA PMID:12635140 Expression of the developmental Sonic hedgehog (Shh) signall... | ACCEPT | Summary: Stewart et al. detected Patched protein at the surface of infiltrating mononuclear cells, alveolar macrophages and resting peripheral blood T lymphocytes in human tissue and blood. Reason: This is where PTCH1 works. UniProt records Cell membrane, multi-pass, from direct human evidence, and the functionally decisive pool is the continuous ciliary membrane, annotated separately. Ligand binding, sterol transport and the SMO-restricting activity all occur here, and the module and all six human GO-CAM activities place the PTCH1 annoton at the plasma/ciliary membrane. Supporting Evidence: PMID:12635140 This study demonstrates that patched is present in human peripheral CD4 and CD8 lymphocytes at both protein and mRNA levels. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated pipelines place PTCH1 at the plasma membrane, drawing on the mouse ortholog and the UniProt subcellular-location vocabulary. Reason: This is where PTCH1 works. UniProt records Cell membrane, multi-pass, from direct human evidence, and the functionally decisive pool is the continuous ciliary membrane, annotated separately. Ligand binding, sterol transport and the SMO-restricting activity all occur here, and the module and all six human GO-CAM activities place the PTCH1 annoton at the plasma/ciliary membrane. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Curator-judged sequence-similarity transfer of the plasma-membrane location from mouse Ptch1, which carries it by IDA from several independent studies. Reason: This is where PTCH1 works. UniProt records Cell membrane, multi-pass, from direct human evidence, and the functionally decisive pool is the continuous ciliary membrane, annotated separately. Ligand binding, sterol transport and the SMO-restricting activity all occur here, and the module and all six human GO-CAM activities place the PTCH1 annoton at the plasma/ciliary membrane. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0005901 caveola | IDA PMID:11278759 The sonic hedgehog receptor patched associates with caveolin... | KEEP AS NON CORE | Summary: Patched co-fractionates and co-localises with caveolin-1 in buoyant, cholesterol-rich membrane microdomains, and co-immunoprecipitates with caveolin-1 through the caveolin scaffolding domain and a consensus site in Patched; Smoothened is in the same domains but does not itself bind caveolin-1. Reason: The observation is direct and it fits PTCH1's biology - a cholesterol transporter enriched in cholesterol-rich membrane is not a coincidence. It is kept off the core set because the caveolar subdomain is one compartment of the plasma-membrane pool observed in one cell system, whereas the compartment that carries the signalling function across systems is the ciliary membrane. Supporting Evidence: PMID:11278759 In this study, we demonstrate that both Smoothened and Patched are in caveolin-1-enriched/raft microdomains. PMID:11278759 Immunoprecipitation studies show that Patched specifically interacts with caveolin-1, whereas Smoothened does not. |
| GO:0005929 cilium | IEA GO_REF:0000107 | ACCEPT | Summary: PTCH1 localises to the primary cilium, where it holds ciliary cholesterol low and keeps SMO out; Hedgehog binding clears PTCH1 from the cilium and permits SMO entry. Reason: Correct and central, if less precise than the ciliary-membrane and non-motile-cilium-membrane terms annotated alongside it. A broader electronic term at a location that the specific rows also cover is not a problem, and the cilium is where the module and the GO-CAM models put the activity. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt Note=Localizes to primary cilium and prevents cilium localization of PMID:40128518 Several studies showed that PTCH1 functions as a cholesterol transporter to maintain the low concentration of cholesterol in cilia |
| GO:0007165 signal transduction | IEA GO_REF:0000107 | MODIFY | Summary: A root-level statement that PTCH1 participates in signal transduction, transferred from mouse. PTCH1's role in signalling is specific and well defined: it is the Hedgehog receptor and, unliganded, the pathway's brake on SMO. Reason: Not wrong, but maximally general on a gene whose specific process term is directly annotated nine times over by IBA, IDA, ISS and TAS. An electronic term that is broader than the literature is usually harmless; this one sits at the very top of the biological process branch and conveys nothing that the specific term does not, so it is re-pointed to the established process. Proposed replacements: negative regulation of smoothened signaling pathway Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt Negative regulator of the smoothened signaling pathway, which |
| GO:0007286 spermatid development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Transferred from rat Ptch1, where the term rests on expression of Ptch1 during spermatid development. Desert hedgehog signalling is genuinely required in the testis, but the vertebrate receptor for that ligand there is generally taken to be PTCH2, which is expressed at high levels in spermatocytes. Reason: PTCH1 is the canonical transcriptional readout of Hedgehog pathway activity: its mRNA rises wherever GLI activity rises, in essentially any tissue. An expression-correlation annotation therefore records that the pathway was engaged, not that PTCH1 performs a function in the process named. Here the case is further weakened by paralogue specificity: the testis Hedgehog receptor is reported to be PTCH2 rather than PTCH1. The term is not false, but it over-states what the evidence shows, and there is no human evidence behind the transfer. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK ROLE CONFLATION Sources checked: UniProtKB:Q6UY90 · Ptch1 SOURCE WEAK OR INFERRED Rat Ptch1 carries this term by IEP - a change in transcript or protein abundance - and the row reaches human by Ensembl-Compara transfer with no human evidence behind it. |
| GO:0007420 brain development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog transfer from mouse Ptch1, which carries brain development by IMP. PTCH1 modulates Hedgehog signalling throughout central nervous system patterning and growth. Reason: Genuine but downstream and pleiotropic. Hedgehog signalling patterns the ventral neural tube, cerebellum and much else, and PTCH1 sets the threshold for all of it, which is why PTCH1 loss causes medulloblastoma and holoprosencephaly. It is kept off the core set because brain development is an organismal outcome of altered pathway gain rather than something PTCH1 executes; the executing activity is sterol transport at the ciliary membrane. Supporting Evidence: PMID:8681379 We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types. |
| GO:0007420 brain development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator sequence-similarity transfer of the same mouse phenotype-based annotation. Reason: Genuine but downstream and pleiotropic. Hedgehog signalling patterns the ventral neural tube, cerebellum and much else, and PTCH1 sets the threshold for all of it, which is why PTCH1 loss causes medulloblastoma and holoprosencephaly. It is kept off the core set because brain development is an organismal outcome of altered pathway gain rather than something PTCH1 executes; the executing activity is sterol transport at the ciliary membrane. Supporting Evidence: PMID:8681379 We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types. |
| GO:0008158 hedgehog receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: The PAINT node assigns hedgehog receptor activity across the Patched clade - Drosophila ptc, mouse Ptch1 and Ptch2, human PTCH1 and a non-mammalian vertebrate member. Ligand binding by Patched is one of the oldest and most conserved features of the pathway. Reason: This is PTCH1's defining receptor-tier activity and it is kept as core. One caveat is worth recording rather than acting on: PTCH1 does not itself transmit a conformational signal across the membrane in the way the term's definition suggests - SMO does that, and PTCH1's contribution is to stop doing something (moving sterol) when ligand binds. GO nonetheless maintains this term for the Patched tier specifically, the IBA places it at the Patched clade node, and six independent human structures underpin it, so re-terming would fight a deliberate ontology decision rather than an annotation error. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000847539 SUPPORTS TRANSFER Patched-clade ancestral node. Human PTCH1 appears among the descendant evidences, which is the expected marker that the node is grounded on experimental data including the target itself. Supporting Evidence: PMID:9811851 Biochemical analysis of PTCH and PTCH2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with SMO. file:human/PTCH1/PTCH1-uniprot.txt Negative regulator of the smoothened signaling pathway, which |
| GO:0008158 hedgehog receptor activity | IDA PMID:29954986 Structural basis for the recognition of Sonic Hedgehog by hu... | ACCEPT | Summary: Cryo-EM of human PTCH1 alone and bound to ShhN at 3.9 and 3.6 A. PTCH1 is built from two interacting extracellular domains and twelve transmembrane helices, with TM2-6 forming the sterol-sensing domain; steroid-shaped densities sit both in the ECD cavity and in the membrane-facing SSD cavity, and ShhN binding is steroid-dependent. Reason: This is PTCH1's defining receptor-tier activity and it is kept as core. One caveat is worth recording rather than acting on: PTCH1 does not itself transmit a conformational signal across the membrane in the way the term's definition suggests - SMO does that, and PTCH1's contribution is to stop doing something (moving sterol) when ligand binds. GO nonetheless maintains this term for the Patched tier specifically, the IBA places it at the Patched clade node, and six independent human structures underpin it, so re-terming would fight a deliberate ontology decision rather than an annotation error. Supporting Evidence: PMID:29954986 Ptch1 comprises two interacting extracellular domains, ECD1 and ECD2, and 12 transmembrane segments (TMs), with TMs 2 to 6 constituting the sterol-sensing domain (SSD). |
| GO:0008158 hedgehog receptor activity | IDA PMID:29995851 Structures of human Patched and its complex with native palm... | ACCEPT | Summary: Cryo-EM of human PTCH1 alone and with natively lipidated SHH-N. The ligand's N-terminal palmitate inserts into a cavity between the two PTCH1 extracellular domains and dominates the interface, and the transmembrane core carries a sterol-sensing domain with internal two-fold pseudosymmetry. Reason: This is PTCH1's defining receptor-tier activity and it is kept as core. One caveat is worth recording rather than acting on: PTCH1 does not itself transmit a conformational signal across the membrane in the way the term's definition suggests - SMO does that, and PTCH1's contribution is to stop doing something (moving sterol) when ligand binds. GO nonetheless maintains this term for the Patched tier specifically, the IBA places it at the Patched clade node, and six independent human structures underpin it, so re-terming would fight a deliberate ontology decision rather than an annotation error. Supporting Evidence: PMID:29995851 The palmitoylated N terminus of SHH-N inserts into a cavity between the extracellular domains of PTCH1 and dominates the PTCH1-SHH-N interface |
| GO:0008158 hedgehog receptor activity | IDA PMID:30139912 Two Patched molecules engage distinct sites on Hedgehog yiel... | ACCEPT | Summary: Cryo-EM at physiological calcium showing that one SHH-N engages two PTCH1 molecules through two distinct epitopes - the palmitate-dominated interface and the calcium-mediated interface - reconciling the earlier 1:1 and co-receptor-site models. Reason: This is PTCH1's defining receptor-tier activity and it is kept as core. One caveat is worth recording rather than acting on: PTCH1 does not itself transmit a conformational signal across the membrane in the way the term's definition suggests - SMO does that, and PTCH1's contribution is to stop doing something (moving sterol) when ligand binds. GO nonetheless maintains this term for the Patched tier specifically, the IBA places it at the Patched clade node, and six independent human structures underpin it, so re-terming would fight a deliberate ontology decision rather than an annotation error. Supporting Evidence: PMID:30139912 one SHH-N molecule engages both epitopes to bind two PTCH1 receptors in an asymmetric manner |
| GO:0008158 hedgehog receptor activity | IDA PMID:31127104 Inhibition of tetrameric Patched1 by Sonic Hedgehog through ... | ACCEPT | Summary: Cryo-EM of tetrameric PTCH1 with palmitoylated ShhNp at 4:2 stoichiometry, organised as a loose dimer of dimers with each dimer inhibited asymmetrically through the two ligand interfaces. Reason: This is PTCH1's defining receptor-tier activity and it is kept as core. One caveat is worth recording rather than acting on: PTCH1 does not itself transmit a conformational signal across the membrane in the way the term's definition suggests - SMO does that, and PTCH1's contribution is to stop doing something (moving sterol) when ligand binds. GO nonetheless maintains this term for the Patched tier specifically, the IBA places it at the Patched clade node, and six independent human structures underpin it, so re-terming would fight a deliberate ontology decision rather than an annotation error. Supporting Evidence: PMID:31127104 The structure shows that four Ptch1 protomers are organized as a loose dimer of dimers. |
| GO:0008158 hedgehog receptor activity | IDA PMID:31548691 The morphogen Sonic hedgehog inhibits its receptor Patched b... | ACCEPT | Summary: Structural and biochemical dissection showing that the ligand's C-terminal cholesteroyl group, as well as its N-terminal palmitate, inserts into PTCH1 - a pincer grasp on the receptor's first extracellular domain that inactivates it. Reason: This is PTCH1's defining receptor-tier activity and it is kept as core. One caveat is worth recording rather than acting on: PTCH1 does not itself transmit a conformational signal across the membrane in the way the term's definition suggests - SMO does that, and PTCH1's contribution is to stop doing something (moving sterol) when ligand binds. GO nonetheless maintains this term for the Patched tier specifically, the IBA places it at the Patched clade node, and six independent human structures underpin it, so re-terming would fight a deliberate ontology decision rather than an annotation error. Supporting Evidence: PMID:31548691 Shh inactivates PTCH1 by grasping its extracellular domain with two lipidic pincers, the N-terminal palmitate and the C-terminal cholesterol, which are both inserted into the PTCH1 protein core. |
| GO:0008158 hedgehog receptor activity | IDA PMID:31555730 Structural basis of sterol recognition by human hedgehog rec... | ACCEPT | Summary: Cryo-EM of human PTCH1 bound to a palmitoylation-mimicking ShhN at 3.4 A, with ten sterol molecules resolved around the transmembrane region contacting both the sterol-sensing domain and its pseudosymmetric counterpart. Reason: This is PTCH1's defining receptor-tier activity and it is kept as core. One caveat is worth recording rather than acting on: PTCH1 does not itself transmit a conformational signal across the membrane in the way the term's definition suggests - SMO does that, and PTCH1's contribution is to stop doing something (moving sterol) when ligand binds. GO nonetheless maintains this term for the Patched tier specifically, the IBA places it at the Patched clade node, and six independent human structures underpin it, so re-terming would fight a deliberate ontology decision rather than an annotation error. Supporting Evidence: PMID:31555730 The membrane-embedded part of PTCH1 is surrounded by 10 sterol molecules at the inner and outer lipid bilayer portion of the protein. |
| GO:0008158 hedgehog receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated annotation assigning hedgehog receptor activity from the mouse ortholog and from the Patched InterPro signature. Reason: This is PTCH1's defining receptor-tier activity and it is kept as core. One caveat is worth recording rather than acting on: PTCH1 does not itself transmit a conformational signal across the membrane in the way the term's definition suggests - SMO does that, and PTCH1's contribution is to stop doing something (moving sterol) when ligand binds. GO nonetheless maintains this term for the Patched tier specifically, the IBA places it at the Patched clade node, and six independent human structures underpin it, so re-terming would fight a deliberate ontology decision rather than an annotation error. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt Negative regulator of the smoothened signaling pathway, which |
| GO:0008201 heparin binding | IEA GO_REF:0000107 | REMOVE | Summary: An asserted heparin-binding activity for PTCH1, reaching human only by ortholog transfer. Reason: This is an over-propagated electronic inference and it should not stand on the human protein. Heparin binding in the Hedgehog system is a property of the secreted ligand, which carries a basic Cardin-Weintraub heparin-binding motif and whose distribution through tissue depends on heparan sulfate; PTCH1 is a twelve-pass membrane protein whose extracellular domains are characterised in six independent structures, and no heparin-binding site or activity has been reported in any of them. The transfer traces to a mouse row whose source paper measured properties of the Sonic hedgehog protein, and no human evidence supports the activity. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION SOURCE MISCITATION Sources checked: UniProtKB:Q61115 · Ptch1 SUPPORTS SOURCE BUT NOT TARGET Mouse source row is an IDA from a study of the Sonic hedgehog ligand; heparin binding is a ligand property and no PTCH1 heparin-binding site is described in the receptor structures. |
| GO:0008589 regulation of smoothened signaling pathway | ISS GO_REF:0000024 | MODIFY | Summary: A direction-neutral statement that PTCH1 regulates the smoothened signalling pathway, transferred from mouse by curator sequence-similarity judgment. The direction is not in doubt: unliganded PTCH1 represses SMO, and Hedgehog binding relieves that repression. Reason: The parent term loses the one thing that is best established about PTCH1. Its child, negative regulation of the smoothened signalling pathway, is directly annotated here ten times over by IBA, seven IDAs, ISS and TAS, and is the process term used for the PTCH1 annoton in the module and in every human GO-CAM model. The row is re-pointed to it. Proposed replacements: negative regulation of smoothened signaling pathway Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt Negative regulator of the smoothened signaling pathway, which file:human/PTCH1/PTCH1-uniprot.txt smoothened protein (SMO) by preventing SMO access to cholesterol: |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Transferred from rat Ptch1, where Ptch1 transcript levels changed on exposure to a xenobiotic compound. Reason: PTCH1 is the canonical transcriptional readout of Hedgehog pathway activity: its mRNA rises wherever GLI activity rises, in essentially any tissue. An expression-correlation annotation therefore records that the pathway was engaged, not that PTCH1 performs a function in the process named. Response-to-chemical terms built from transcript changes in one rodent tissue say little about human PTCH1. The term is not false, but it over-states what the evidence shows, and there is no human evidence behind the transfer. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK ROLE CONFLATION Sources checked: UniProtKB:Q6UY90 · Ptch1 SOURCE WEAK OR INFERRED Rat Ptch1 carries this term by IEP - a change in transcript or protein abundance - and the row reaches human by Ensembl-Compara transfer with no human evidence behind it. |
| GO:0009612 response to mechanical stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Transferred from rat Ptch1, where Ptch1 expression changed following a mechanical stimulus. Reason: PTCH1 is the canonical transcriptional readout of Hedgehog pathway activity: its mRNA rises wherever GLI activity rises, in essentially any tissue. An expression-correlation annotation therefore records that the pathway was engaged, not that PTCH1 performs a function in the process named. Mechanical loading modulates Hedgehog signalling in several tissues, so a change in the pathway's own reporter gene is the expected readout rather than evidence of participation. The term is not false, but it over-states what the evidence shows, and there is no human evidence behind the transfer. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK ROLE CONFLATION Sources checked: UniProtKB:Q6UY90 · Ptch1 SOURCE WEAK OR INFERRED Rat Ptch1 carries this term by IEP - a change in transcript or protein abundance - and the row reaches human by Ensembl-Compara transfer with no human evidence behind it. |
| GO:0009887 animal organ morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A general statement that PTCH1 participates in animal organ morphogenesis, transferred from mouse. Hedgehog signalling shapes limb, neural tube, gut, skin, lung, bone and urogenital structures, and PTCH1 gates all of them. Reason: True but unspecific and organismal. It is kept because the breadth is itself accurate - PTCH1 is pleiotropic precisely because the pathway it brakes is - and not promoted to core because morphogenesis is the consequence of pathway gain rather than an activity of the protein. Supporting Evidence: PMID:8681379 The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. |
| GO:0009953 dorsal/ventral pattern formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Dorsal-ventral patterning of the neural tube is the textbook Hedgehog gradient readout, and PTCH1 both limits and shapes it: it represses SMO where ligand is absent and, as a ligand-sequestering transcriptional target, restricts how far the gradient spreads. Reason: A genuine and well-documented role, retained. It is non-core on the same principle as the other patterning terms: the tissue-level outcome is downstream of the sterol-transport activity that PTCH1 actually performs. Supporting Evidence: PMID:8681379 We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types. |
| GO:0010875 positive regulation of cholesterol efflux | IDA PMID:21931618 The hedgehog receptor patched is involved in cholesterol tra... | MODIFY | Summary: Bidet et al. showed that Patched expression raises, and Patched inhibition lowers, efflux of a fluorescent cholesterol analogue; that Shh binding to Patched increases intracellular cholesterol and decreases efflux; and that heterologous expression of human Patched in yeast boosts cholesterol efflux. Purified Patched binds cholesterol, and Shh blocks that binding. Reason: The data are good, but the term casts PTCH1 as a regulator of someone else's transport when the same experiments show PTCH1 doing the moving: expressed alone in yeast, it suffices to increase cholesterol efflux, and the purified protein binds the substrate. The regulation framing also fixes a direction and destination - out of the cell - that later work reframed as leaflet-level accessibility within the ciliary membrane, with the authors themselves hedging the cellular interpretation. Lipid translocation states what the structures, simulations and the UniProt cholesterol(in) = cholesterol(out) reaction support, and GOA already carries it here as the inter-ontology counterpart of GO:0140303. Proposed replacements: lipid translocation Supporting Evidence: PMID:21931618 We also show that over-expression of human Patched in the yeast S. cerevisiae results in a significant boost of BODIPY-cholesterol efflux. PMID:21931618 Our results suggest that Patched may contribute to cholesterol efflux from cells, and to modulation of the intracellular cholesterol concentration. PMID:37611095 PTCH1 inhibits the G protein-coupled receptor Smoothened (SMO) via a debated mechanism involving modulating ciliary cholesterol accessibility. file:human/PTCH1/PTCH1-uniprot.txt Reaction=cholesterol(in) = cholesterol(out) |
| GO:0015485 cholesterol binding | IDA PMID:21931618 The hedgehog receptor patched is involved in cholesterol tra... | ACCEPT | Summary: Purified Patched binds cholesterol directly, and the interaction of Shh with Patched inhibits that binding - the biochemical basis for ligand switching the transporter off. The structures corroborate it: sterol densities occupy the extracellular-domain cavity and the sterol-sensing domain, and ten sterols line the transmembrane region. Reason: Direct, human, and mechanistically central. Cholesterol is both the substrate PTCH1 moves and the ligand whose accessibility to SMO PTCH1 controls, so substrate binding belongs to the core molecular description alongside the transport activity itself. Supporting Evidence: PMID:21931618 we demonstrate that purified Patched binds to cholesterol, and that the interaction of Shh with Patched inhibits the binding of Patched to cholesterol. PMID:31555730 The membrane-embedded part of PTCH1 is surrounded by 10 sterol molecules at the inner and outer lipid bilayer portion of the protein. PMID:29954986 Ptch1 comprises two interacting extracellular domains, ECD1 and ECD2, and 12 transmembrane segments (TMs), with TMs 2 to 6 constituting the sterol-sensing domain (SSD). |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro's Patched signature maps to membrane, consistent with the twelve transmembrane helices in the UniProt feature table and in every solved structure. Reason: Correct, if far broader than the plasma-membrane and ciliary-membrane terms annotated alongside. A domain-based electronic term at the top of the compartment branch is acceptable as-is; it is not a mis-mapping, just an uninformative one. Supporting Evidence: PMID:29954986 Ptch1 comprises two interacting extracellular domains, ECD1 and ECD2, and 12 transmembrane segments (TMs), with TMs 2 to 6 constituting the sterol-sensing domain (SSD). |
| GO:0016485 protein processing | ISS GO_REF:0000024 | REMOVE | Summary: A transferred assertion that PTCH1 is involved in protein processing. The mouse source is a cilia/Hedgehog-responsiveness study in which perturbing Ptch1 changes GLI processing, annotated there with an upstream-of qualifier. Reason: PTCH1 cleaves nothing. Protein processing sits under proteolysis and names the entity that performs the cleavage; for GLI3 that is the proteasome acting on a PKA/CK1/GSK3-primed substrate, several steps downstream of the receptor. PTCH1's contribution is to keep the pathway off so that processing continues, which is a regulatory relationship already stated by the ten GO:0045879 rows. Transferred as an involved_in claim, the term asserts participation the protein does not have. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION GRANULARITY MISMATCH Sources checked: UniProtKB:Q61115 · Ptch1 SUPPORTS SOURCE BUT NOT TARGET Mouse row is an IMP qualified acts_upstream_of_or_within - a statement about what changes when Ptch1 is perturbed. Transferred to human as involved_in, it becomes a participation claim the source never made. |
| GO:0021532 neural tube patterning | IMP PMID:8681379 Mutations of the human homolog of Drosophila patched in the ... | KEEP AS NON CORE | Summary: Germline PTCH1 mutations in nevoid basal cell carcinoma syndrome produce developmental abnormalities including neural tube defects, identifying PTCH1 as required for normal neural tube patterning in humans. Reason: A human loss-of-function genetics annotation, and the developmental features of the syndrome are real. It is kept as non-core because the causal chain runs through pathway derepression: losing PTCH1 removes the brake on SMO, GLI activity rises, and patterning goes wrong. The protein's own activity is sterol transport at the ciliary membrane; the morphological outcome is the phenotype of that activity failing. Supporting Evidence: PMID:8681379 We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types. PMID:8681379 The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. |
| GO:0021997 neural plate axis specification | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog transfer from mouse Ptch1, where neural plate axis specification rests on an IMP from a Smoothened-mutant study dissecting redundant Shh and Ihh input to axis formation. Reason: Retained: specification of neural axes depends on the Hedgehog gradient, and PTCH1 sets how much SMO activity a given ligand concentration produces. Non-core for the same reason as the other patterning terms - it names a tissue-level outcome rather than the receptor activity that produces it. Supporting Evidence: PMID:8681379 We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types. |
| GO:0021997 neural plate axis specification | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator sequence-similarity transfer of the same mouse annotation. Reason: Retained: specification of neural axes depends on the Hedgehog gradient, and PTCH1 sets how much SMO activity a given ligand concentration produces. Non-core for the same reason as the other patterning terms - it names a tissue-level outcome rather than the receptor activity that produces it. Supporting Evidence: PMID:8681379 We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types. |
| GO:0030326 embryonic limb morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Ptch1, which carries embryonic limb morphogenesis by IMP and IGI. Hedgehog signalling from the zone of polarising activity patterns the limb bud, and PTCH1 shapes that gradient both as its receptor and as a ligand-sequestering target gene. Reason: Well supported across species and consistent with the polydactyly seen in NBCCS, so it is kept. It duplicates the human limb-morphogenesis IMP at a more specific developmental stage, and like it names a downstream developmental outcome rather than a PTCH1 activity. Supporting Evidence: PMID:8681379 The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. |
| GO:0030332 cyclin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog transfer of the cyclin B1 interaction from mouse Ptch1, which carries it by IPI from the same study. Reason: A genuine experimental interaction, retained but non-core. Barnes et al. identified it in a two-hybrid screen designed around phosphorylated cyclin B1, showed that PTCH1 alters cyclin B1's subcellular distribution, that Shh disrupts the interaction and releases cyclin B1 to the nucleus, and that endogenous proteins interact - so this is not merely an overexpression artefact. It is kept off the core set because it is a non-canonical arm separate from the receptor/transporter function, because every structure of PTCH1 addresses ligand and sterol rather than cyclin, and because the independent human support for it is limited. Supporting Evidence: PMID:11331587 The findings reported here demonstrate that ptc1 participates in determining the subcellular localization of cyclin B1 and suggest a link between the tumor suppressor activity of ptc1 and the regulation of cell division. |
| GO:0030332 cyclin binding | IPI PMID:11331587 Patched1 interacts with cyclin B1 to regulate cell cycle pro... | KEEP AS NON CORE | Summary: The two-hybrid arm of the study, using a Xenopus cyclin B1 bait engineered to mimic the constitutively phosphorylated protein; PTCH1 interacted specifically with the phosphorylation-mimicking derivatives. Reason: A genuine experimental interaction, retained but non-core. Barnes et al. identified it in a two-hybrid screen designed around phosphorylated cyclin B1, showed that PTCH1 alters cyclin B1's subcellular distribution, that Shh disrupts the interaction and releases cyclin B1 to the nucleus, and that endogenous proteins interact - so this is not merely an overexpression artefact. It is kept off the core set because it is a non-canonical arm separate from the receptor/transporter function, because every structure of PTCH1 addresses ligand and sterol rather than cyclin, and because the independent human support for it is limited. Supporting Evidence: PMID:11331587 The findings reported here demonstrate that ptc1 participates in determining the subcellular localization of cyclin B1 and suggest a link between the tumor suppressor activity of ptc1 and the regulation of cell division. PMID:11331587 Expression of ptc1 in 293T cells was inhibitory to cell proliferation; this inhibition could be relieved by coexpression of a cyclin B1 derivative that constitutively localizes to the nucleus and that could not interact with ptc1 due to phosphorylation-site mutations to ALA |
| GO:0030332 cyclin binding | IPI PMID:11331587 Patched1 interacts with cyclin B1 to regulate cell cycle pro... | KEEP AS NON CORE | Summary: The mammalian arm of the same study: endogenous PTCH1 and endogenous cyclin B1 interact, PTCH1 expression inhibits proliferation of 293T cells, and that inhibition is relieved by a nuclear-localising, PTCH1-non-binding cyclin B1 mutant. Reason: A genuine experimental interaction, retained but non-core. Barnes et al. identified it in a two-hybrid screen designed around phosphorylated cyclin B1, showed that PTCH1 alters cyclin B1's subcellular distribution, that Shh disrupts the interaction and releases cyclin B1 to the nucleus, and that endogenous proteins interact - so this is not merely an overexpression artefact. It is kept off the core set because it is a non-canonical arm separate from the receptor/transporter function, because every structure of PTCH1 addresses ligand and sterol rather than cyclin, and because the independent human support for it is limited. Supporting Evidence: PMID:11331587 The findings reported here demonstrate that ptc1 participates in determining the subcellular localization of cyclin B1 and suggest a link between the tumor suppressor activity of ptc1 and the regulation of cell division. PMID:11331587 Expression of ptc1 in 293T cells was inhibitory to cell proliferation; this inhibition could be relieved by coexpression of a cyclin B1 derivative that constitutively localizes to the nucleus and that could not interact with ptc1 due to phosphorylation-site mutations to ALA |
| GO:0030496 midbody | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Transferred from a mouse row whose source is a proteomic dissection of the mammalian midbody - a large-scale inventory of proteins recovered from isolated midbodies. Reason: Not impossible, and there is a thread of PTCH1 literature touching the cell cycle through cyclin B1, but the evidence here is a single organelle-proteomics inventory in another species with no functional follow-up on PTCH1, transferred electronically. Abundant plasma-membrane proteins are recovered routinely in such preparations. The location is retained as a flag rather than a claim. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: UniProtKB:Q61115 · Ptch1 SOURCE WEAK OR INFERRED Mouse IDA from a midbody proteome survey; no functional evidence places PTCH1 activity at the midbody in any species. |
| GO:0030666 endocytic vesicle membrane | TAS Reactome:R-HSA-5632677 | KEEP AS NON CORE | Summary: Reactome's 'PTCH is internalized' step. Hedgehog binding triggers SMURF1/SMURF2-dependent ubiquitination of PTCH1, endocytosis and lysosomal degradation, and this clearance is what removes PTCH1 from the primary cilium and permits pathway activation; unliganded PTCH1 is instead ubiquitinated by ITCH. Reason: Correct and mechanistically important, but it is a transit compartment on the route to degradation rather than a site where PTCH1 performs its function. The GO-CAM models make the same distinction, placing the PTCH1 activity at the non-motile cilium membrane while modelling SMURF1/2 ubiquitination as the separate step that ends it. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt SMURF1 and/or SMURF2 in response to SHH, promoting endocytosis and |
| GO:0030850 prostate gland development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Transferred from rat Ptch1, where the term rests on Ptch1 expression during prostate development. Hedgehog signalling does pattern the prostate, and PTCH1 is expressed in the responding mesenchyme. Reason: PTCH1 is the canonical transcriptional readout of Hedgehog pathway activity: its mRNA rises wherever GLI activity rises, in essentially any tissue. An expression-correlation annotation therefore records that the pathway was engaged, not that PTCH1 performs a function in the process named. The underlying biology is plausible, but the evidence is expression in rat, transferred electronically, with no perturbation of PTCH1 in either species behind it. The term is not false, but it over-states what the evidence shows, and there is no human evidence behind the transfer. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK ROLE CONFLATION Sources checked: UniProtKB:Q6UY90 · Ptch1 SOURCE WEAK OR INFERRED Rat Ptch1 carries this term by IEP - a change in transcript or protein abundance - and the row reaches human by Ensembl-Compara transfer with no human evidence behind it. |
| GO:0032355 response to estradiol | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Transferred from rat Ptch1, where Ptch1 transcript levels changed after estradiol exposure. Reason: PTCH1 is the canonical transcriptional readout of Hedgehog pathway activity: its mRNA rises wherever GLI activity rises, in essentially any tissue. An expression-correlation annotation therefore records that the pathway was engaged, not that PTCH1 performs a function in the process named. Estradiol modulates Hedgehog signalling in reproductive tissue, so the observation is most simply read as pathway activity registering on its own reporter. The term is not false, but it over-states what the evidence shows, and there is no human evidence behind the transfer. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK ROLE CONFLATION Sources checked: UniProtKB:Q6UY90 · Ptch1 SOURCE WEAK OR INFERRED Rat Ptch1 carries this term by IEP - a change in transcript or protein abundance - and the row reaches human by Ensembl-Compara transfer with no human evidence behind it. |
| GO:0032526 response to retinoic acid | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Transferred from rat Ptch1, where Ptch1 transcript levels changed after retinoic acid exposure. Reason: PTCH1 is the canonical transcriptional readout of Hedgehog pathway activity: its mRNA rises wherever GLI activity rises, in essentially any tissue. An expression-correlation annotation therefore records that the pathway was engaged, not that PTCH1 performs a function in the process named. Retinoid and Hedgehog signalling intersect during patterning, so again the transcript change reports pathway state rather than a PTCH1 function in retinoid response. The term is not false, but it over-states what the evidence shows, and there is no human evidence behind the transfer. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK ROLE CONFLATION Sources checked: UniProtKB:Q6UY90 · Ptch1 SOURCE WEAK OR INFERRED Rat Ptch1 carries this term by IEP - a change in transcript or protein abundance - and the row reaches human by Ensembl-Compara transfer with no human evidence behind it. |
| GO:0032880 regulation of protein localization | IEA GO_REF:0000107 | MODIFY | Summary: PTCH1 controls where SMO goes: unliganded PTCH1 in the ciliary membrane keeps ciliary cholesterol low and prevents SMO from accumulating there, and ligand-triggered clearance of PTCH1 lets SMO enter the cilium and signal. Reason: The general term states only that some protein's localisation is modulated, which on a gene this well characterised is a waste of a row. The established statement is specific in both target and direction, and UniProt records it directly from five independent human structural/cell studies, so the row is re-pointed to negative regulation of protein localization to cilium. Proposed replacements: negative regulation of protein localization to cilium Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt Note=Localizes to primary cilium and prevents cilium localization of PMID:40128518 Several studies showed that PTCH1 functions as a cholesterol transporter to maintain the low concentration of cholesterol in cilia |
| GO:0034204 lipid translocation | IEA GO_REF:0000108 | ACCEPT | Summary: The biological-process counterpart of PTCH1's molecular function, derived by logical inference from GO:0140303 intramembrane lipid carrier activity. UniProt records the reaction as cholesterol(in) = cholesterol(out), and simulation work puts a barrier of roughly 15-20 kJ/mol on cholesterol export with one to three Na+ or two to three K+ coupled to it. Reason: Correct and core. This is the process PTCH1 carries out and the mechanism by which it keeps SMO off; the inter-ontology inference from the molecular function is exactly right here, and it is the term the cholesterol-efflux row is also re-pointed to. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt Reaction=cholesterol(in) = cholesterol(out) PMID:37611095 we find an energetic barrier of ~15 to 20 kilojoule per mole for cholesterol export PMID:31555730 The structure reveals a possible route for sterol translocation across the lipid bilayer by PTCH1 and homologous transporters. |
| GO:0035108 limb morphogenesis | IMP PMID:8681379 Mutations of the human homolog of Drosophila patched in the ... | KEEP AS NON CORE | Summary: NBCCS includes skeletal and limb anomalies, notably polydactyly, placing PTCH1 in human limb morphogenesis - the same role Hedgehog gradients play in the vertebrate limb bud. Reason: A human loss-of-function genetics annotation, and the developmental features of the syndrome are real. It is kept as non-core because the causal chain runs through pathway derepression: losing PTCH1 removes the brake on SMO, GLI activity rises, and patterning goes wrong. The protein's own activity is sterol transport at the ciliary membrane; the morphological outcome is the phenotype of that activity failing. Supporting Evidence: PMID:8681379 We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types. PMID:8681379 The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. |
| GO:0040015 negative regulation of multicellular organism growth | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse, where Ptch1 heterozygotes show overgrowth alongside their tumour predisposition. Losing one brake on Hedgehog signalling raises proliferative drive, and the same is seen in human NBCCS, where macrocephaly and tall stature accompany the tumour phenotype. Reason: Consistent with the tumour-suppressor role that UniProt records and with the NBCCS phenotype, so it is retained. It is an organism-level consequence of removing pathway repression, several levels above the molecular function, so it does not belong in the core set. Supporting Evidence: PMID:8681379 We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types. |
| GO:0043279 response to alkaloid | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Transferred from rat Ptch1, where Ptch1 expression changed on exposure to an alkaloid. The Hedgehog pathway's best-known alkaloid is cyclopamine, which acts on SMO rather than on PTCH1. Reason: PTCH1 is the canonical transcriptional readout of Hedgehog pathway activity: its mRNA rises wherever GLI activity rises, in essentially any tissue. An expression-correlation annotation therefore records that the pathway was engaged, not that PTCH1 performs a function in the process named. If the alkaloid in question acts through the pathway, the transcript change is downstream of a target that is not PTCH1. The term is not false, but it over-states what the evidence shows, and there is no human evidence behind the transfer. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK ROLE CONFLATION Sources checked: UniProtKB:Q6UY90 · Ptch1 SOURCE WEAK OR INFERRED Rat Ptch1 carries this term by IEP - a change in transcript or protein abundance - and the row reaches human by Ensembl-Compara transfer with no human evidence behind it. |
| GO:0044294 dendritic growth cone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Transferred from rat Ptch1, localised by immunostaining to dendritic growth cones of hippocampal neurons. Reason: The underlying evidence is a direct immunolocalisation study of Patched and Smoothened in hippocampal neurons, not an expression correlation, and it is corroborated by the independent finding that PTCH1 is required in commissural axons for the Shh-dependent switch in Semaphorin responsiveness. A neuronal pool of PTCH1 is therefore credible and the row is kept. It is non-core because it is a cell-type-specific subcellular pool observed in one rodent study and transferred electronically, whereas the compartment that carries the conserved function is the ciliary membrane. |
| GO:0044295 axonal growth cone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Transferred from rat Ptch1, localised by immunostaining to axonal growth cones of hippocampal neurons - the compartment in which Shh-PTCH1 signalling reorients commissural axons at the midline. Reason: The underlying evidence is a direct immunolocalisation study of Patched and Smoothened in hippocampal neurons, not an expression correlation, and it is corroborated by the independent finding that PTCH1 is required in commissural axons for the Shh-dependent switch in Semaphorin responsiveness. A neuronal pool of PTCH1 is therefore credible and the row is kept. It is non-core because it is a cell-type-specific subcellular pool observed in one rodent study and transferred electronically, whereas the compartment that carries the conserved function is the ciliary membrane. |
| GO:0044877 protein-containing complex binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Protein-containing complex binding (IEA), transferred from mouse Ptch1, which interacts with cyclin B1 of the M-phase promoting factor (PMID:11331587). Reason: The row is transferred from mouse Ptch1, annotated by direct assay in the study showing that Patched1 interacts with phosphorylated cyclin B1 and thereby with the M-phase promoting factor complex (PMID:11331587), so it records a real interaction with a protein complex. The term names no partner and adds little beside the specific binding annotations of this review, but it is true as stated, and a true annotation is not removed for being uninformative. It is kept as non-core. Supporting Evidence: PMID:11331587 we identified a novel interaction between cyclin B1 and patched1 (ptc1) |
| GO:0045177 apical part of cell | IDA PMID:17850284 Immunohistochemical analysis of Sonic hedgehog signalling in... | KEEP AS NON CORE | Summary: Immunohistochemistry of normal developing human urinary tract localised PTCH to the apical surface of medullary collecting duct epithelium, a polarity the authors then exploited to track cyclin B1 redistribution when SHH expression fell. Reason: A direct observation in human tissue, and polarised apical residence is plausible for a receptor in a transporting epithelium - the primary cilium projects from the apical surface. It is kept off the core set because it is a tissue-specific refinement of the plasma-membrane location rather than an independent site of function, and because the same paper could not detect SMO in these cells. Supporting Evidence: PMID:17850284 Exploiting the polar distribution of PTCH at the apical surface of collecting duct cells PMID:17850284 In the developing kidney, SHH and PTCH were expressed in epithelia of the collecting system between 16-26 weeks--surprisingly, SMO was not detected. |
| GO:0045211 postsynaptic membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Transferred from rat Ptch1, localised by immunostaining to the postsynaptic membrane of hippocampal neurons. Reason: The underlying evidence is a direct immunolocalisation study of Patched and Smoothened in hippocampal neurons, not an expression correlation, and it is corroborated by the independent finding that PTCH1 is required in commissural axons for the Shh-dependent switch in Semaphorin responsiveness. A neuronal pool of PTCH1 is therefore credible and the row is kept. It is non-core because it is a cell-type-specific subcellular pool observed in one rodent study and transferred electronically, whereas the compartment that carries the conserved function is the ciliary membrane. |
| GO:0045668 negative regulation of osteoblast differentiation | IMP PMID:16229683 Inhibition of GLI1 gene activation by Patched1. | KEEP AS NON CORE | Summary: In the C3H10T1/2 osteogenic differentiation assay, GLI1 expression induced alkaline phosphatase-positive differentiation, and PTCH1 co-expression significantly inhibited it, as did SUFU; a PTCH1 deletion mutant lacking the relevant domains did not. The paper's figure legend states the result directly. Reason: The result is in the paper's full text and is a real cellular readout rather than a reporter artefact, so the annotation is supported. It is non-core because Hedgehog-driven osteogenesis is one of many differentiation programmes the pathway gates, because the assay is a transfection experiment in a mouse mesenchymal line, and because PTCH1's contribution is to set pathway tone rather than to act within osteoblast differentiation. Supporting Evidence: PMID:16229683 Inhibition of GLI1-induced osteogenic differentiation by PTCH1. PMID:16229683 We show that gene activation by GLI1, the transcriptional effector of the pathway, can be down-regulated by PTCH1 without involvement of the canonical cascade of HH signalling events. |
| GO:0045879 negative regulation of smoothened signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: The PAINT node places negative regulation of smoothened signalling on the Patched clade, spanning Drosophila ptc, mouse Ptch1 and Ptch2, zebrafish and human PTCH1. Patched as the pathway's brake is the oldest functional statement in Hedgehog biology and predates the protostome-deuterostome split. Reason: This is the core biological process of PTCH1 and the single best-supported statement in the whole annotation set. It is asserted by the Patched-clade PAINT node, by seven independent human experimental studies, by ortholog transfer and by review, and it is the process term attached to the PTCH1 annoton in modules/hedgehog_signaling.yaml and in all six human GO-CAM models in gocams/index.tsv. UniProt opens its function statement with it. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000847539 SUPPORTS TRANSFER Patched-clade node with experimental descendants in fly, fish, mouse and human. Human PTCH1 in the WITH/FROM reflects its own experimental grounding for the term. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt Negative regulator of the smoothened signaling pathway, which |
| GO:0045879 negative regulation of smoothened signaling pathway | IDA PMID:29954986 Structural basis for the recognition of Sonic Hedgehog by hu... | ACCEPT | Summary: The PTCH1-ShhN structures, with structure-guided mutagenesis showing that the interaction is steroid-dependent and that a steroid-binding-deficient PTCH1 mutant undergoes pronounced conformational rearrangement - the ligand-driven switch that ends SMO repression. Reason: This is the core biological process of PTCH1 and the single best-supported statement in the whole annotation set. It is asserted by the Patched-clade PAINT node, by seven independent human experimental studies, by ortholog transfer and by review, and it is the process term attached to the PTCH1 annoton in modules/hedgehog_signaling.yaml and in all six human GO-CAM models in gocams/index.tsv. UniProt opens its function statement with it. Supporting Evidence: PMID:29954986 Ptch1 comprises two interacting extracellular domains, ECD1 and ECD2, and 12 transmembrane segments (TMs), with TMs 2 to 6 constituting the sterol-sensing domain (SSD). |
| GO:0045879 negative regulation of smoothened signaling pathway | IDA PMID:29995851 Structures of human Patched and its complex with native palm... | ACCEPT | Summary: Structures of PTCH1 alone and with natively lipidated SHH-N, framed explicitly around palmitoylated Hedgehog releasing the repression of Patched on SMO. Reason: This is the core biological process of PTCH1 and the single best-supported statement in the whole annotation set. It is asserted by the Patched-clade PAINT node, by seven independent human experimental studies, by ortholog transfer and by review, and it is the process term attached to the PTCH1 annoton in modules/hedgehog_signaling.yaml and in all six human GO-CAM models in gocams/index.tsv. UniProt opens its function statement with it. Supporting Evidence: PMID:29995851 The palmitoylated N terminus of SHH-N inserts into a cavity between the extracellular domains of PTCH1 and dominates the PTCH1-SHH-N interface |
| GO:0045879 negative regulation of smoothened signaling pathway | IDA PMID:30139912 Two Patched molecules engage distinct sites on Hedgehog yiel... | ACCEPT | Summary: The 2:1 PTCH1-SHH-N structure, showing that one ligand must engage two receptors through two distinct interfaces to yield a signalling-competent complex - i.e. to inactivate PTCH1 and lift the brake on SMO. Reason: This is the core biological process of PTCH1 and the single best-supported statement in the whole annotation set. It is asserted by the Patched-clade PAINT node, by seven independent human experimental studies, by ortholog transfer and by review, and it is the process term attached to the PTCH1 annoton in modules/hedgehog_signaling.yaml and in all six human GO-CAM models in gocams/index.tsv. UniProt opens its function statement with it. Supporting Evidence: PMID:30139912 one SHH-N molecule engages both epitopes to bind two PTCH1 receptors in an asymmetric manner |
| GO:0045879 negative regulation of smoothened signaling pathway | IDA PMID:31548691 The morphogen Sonic hedgehog inhibits its receptor Patched b... | ACCEPT | Summary: The pincer-grasp study: the ligand's C-terminal cholesteroyl group binds PTCH1's first extracellular domain and promotes its inactivation, and simulations show the interaction closes the sterol conduit through the receptor - the physical act of switching the brake off. Reason: This is the core biological process of PTCH1 and the single best-supported statement in the whole annotation set. It is asserted by the Patched-clade PAINT node, by seven independent human experimental studies, by ortholog transfer and by review, and it is the process term attached to the PTCH1 annoton in modules/hedgehog_signaling.yaml and in all six human GO-CAM models in gocams/index.tsv. UniProt opens its function statement with it. Supporting Evidence: PMID:31548691 Shh inactivates PTCH1 by grasping its extracellular domain with two lipidic pincers, the N-terminal palmitate and the C-terminal cholesterol, which are both inserted into the PTCH1 protein core. PMID:31548691 Molecular dynamics simulations show that this interaction leads to the closure of a tunnel through PTCH1 that serves as the putative conduit for sterol transport. |
| GO:0045879 negative regulation of smoothened signaling pathway | IDA PMID:31555730 Structural basis of sterol recognition by human hedgehog rec... | ACCEPT | Summary: The sterol-recognition structure, with ten sterols resolved around the transmembrane region and a plausible translocation route across the bilayer, connecting ligand binding to loss of the sterol-handling activity that keeps SMO off. Reason: This is the core biological process of PTCH1 and the single best-supported statement in the whole annotation set. It is asserted by the Patched-clade PAINT node, by seven independent human experimental studies, by ortholog transfer and by review, and it is the process term attached to the PTCH1 annoton in modules/hedgehog_signaling.yaml and in all six human GO-CAM models in gocams/index.tsv. UniProt opens its function statement with it. Supporting Evidence: PMID:31555730 The membrane-embedded part of PTCH1 is surrounded by 10 sterol molecules at the inner and outer lipid bilayer portion of the protein. PMID:31555730 The structure reveals a possible route for sterol translocation across the lipid bilayer by PTCH1 and homologous transporters. |
| GO:0045879 negative regulation of smoothened signaling pathway | IDA PMID:37611095 The energetics and ion coupling of cholesterol transport thr... | ACCEPT | Summary: Free-energy calculations on cholesterol transport through PTCH1 coupled to in vivo assays of PTCH1 mutants, probing how cation sites and transmembrane motion connect to PTCH1 activity - the machinery by which PTCH1 modulates ciliary cholesterol accessibility and thereby restrains SMO. Reason: This is the core biological process of PTCH1 and the single best-supported statement in the whole annotation set. It is asserted by the Patched-clade PAINT node, by seven independent human experimental studies, by ortholog transfer and by review, and it is the process term attached to the PTCH1 annoton in modules/hedgehog_signaling.yaml and in all six human GO-CAM models in gocams/index.tsv. UniProt opens its function statement with it. Supporting Evidence: PMID:37611095 PTCH1 inhibits the G protein-coupled receptor Smoothened (SMO) via a debated mechanism involving modulating ciliary cholesterol accessibility. PMID:37611095 we find an energetic barrier of ~15 to 20 kilojoule per mole for cholesterol export |
| GO:0045879 negative regulation of smoothened signaling pathway | IDA PMID:40128518 Inhibiting hedgehog signal by a patched-1 antibody. | ACCEPT | Summary: An antibody study that makes the repression visible pharmacologically: Fab6H3 binds PTCH1 ECD1, competes with SHH, blocks PTCH1 endocytosis so the receptor is retained at the cell surface, and suppresses Hedgehog reporter activity in cells and Gli1 transcription in mouse kidney - without perturbing the sterol conduit. Reason: This is the core biological process of PTCH1 and the single best-supported statement in the whole annotation set. It is asserted by the Patched-clade PAINT node, by seven independent human experimental studies, by ortholog transfer and by review, and it is the process term attached to the PTCH1 annoton in modules/hedgehog_signaling.yaml and in all six human GO-CAM models in gocams/index.tsv. UniProt opens its function statement with it. Supporting Evidence: PMID:40128518 our data showed that Fab6H3 prevents the HH binding and retains the PTCH1 on the cell surface presumably to keep the low cholesterol concentration in the membrane, thus inhibiting the signaling PMID:40128518 Several studies showed that PTCH1 functions as a cholesterol transporter to maintain the low concentration of cholesterol in cilia |
| GO:0045879 negative regulation of smoothened signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer from mouse Ptch1, which carries the term by multiple independent IMPs and IGIs. Reason: This is the core biological process of PTCH1 and the single best-supported statement in the whole annotation set. It is asserted by the Patched-clade PAINT node, by seven independent human experimental studies, by ortholog transfer and by review, and it is the process term attached to the PTCH1 annoton in modules/hedgehog_signaling.yaml and in all six human GO-CAM models in gocams/index.tsv. UniProt opens its function statement with it. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt Negative regulator of the smoothened signaling pathway, which |
| GO:0045879 negative regulation of smoothened signaling pathway | TAS PMID:11001584 The sonic hedgehog-patched-gli pathway in human development ... | ACCEPT | Summary: A review of the sonic hedgehog-patched-gli pathway in human development and disease, cited by a curator as an authoritative statement of PTCH1's repressive role. Reason: This is the core biological process of PTCH1 and the single best-supported statement in the whole annotation set. It is asserted by the Patched-clade PAINT node, by seven independent human experimental studies, by ortholog transfer and by review, and it is the process term attached to the PTCH1 annoton in modules/hedgehog_signaling.yaml and in all six human GO-CAM models in gocams/index.tsv. UniProt opens its function statement with it. |
| GO:0045892 negative regulation of DNA-templated transcription | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: A transferred claim that PTCH1 negatively regulates DNA-templated transcription. The mouse source measures changes in hepatic Igf1/Igfbp1 transcription when Hedgehog signalling is perturbed. Reason: The effect is real but it is the pathway's output, not PTCH1's activity: PTCH1 is a twelve-pass membrane protein with no DNA-binding domain, and every transcriptional consequence of changing PTCH1 is mediated by GLI factors several steps downstream. That this row is paired with its exact opposite on the same gene, from the same source, is the clearest sign that both describe pathway output rather than a property of the protein. Flagged rather than removed because the direction of the effect is not in dispute, and because GOA separately carries a more specific, human, experimentally grounded transcription row (GO:0000122) for the non-canonical GLI1 arm. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION GRANULARITY MISMATCH Sources checked: UniProtKB:Q61115 · Ptch1 SUPPORTS SOURCE BUT NOT TARGET Mouse IMPs from a hepatic Hedgehog study measuring Igf1 and Igfbp1 serum and transcript levels after pathway perturbation - a downstream readout, not a PTCH1 activity at the promoter. |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The mirror-image transferred claim: PTCH1 positively regulates DNA-templated transcription, from the same mouse study and the same Igf1/Igfbp1 readouts. Reason: Flagged for the same reason as its negative counterpart, and with the same force. A membrane receptor that carries both positive and negative regulation of transcription from one source is not being described; its pathway is. Nothing PTCH1 does happens at a promoter. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION GRANULARITY MISMATCH Sources checked: UniProtKB:Q61115 · Ptch1 SUPPORTS SOURCE BUT NOT TARGET Mouse IMPs from a hepatic Hedgehog study measuring Igf1 and Igfbp1 serum and transcript levels after pathway perturbation - a downstream readout, not a PTCH1 activity at the promoter. |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:11278759 The sonic hedgehog receptor patched associates with caveolin... | KEEP AS NON CORE | Summary: Confocal imaging in the caveolin-1 study showed Patched in a perinuclear compartment in addition to the plasma-membrane and raft pools. Reason: Consistent with the Golgi/biosynthetic pool annotated from the same study, and with a large glycoprotein's route to the surface. Kept as an observation, not promoted: the sterol transport and ligand binding that define PTCH1 happen at the cell surface and in the cilium. Supporting Evidence: PMID:11278759 In this study, we demonstrate that both Smoothened and Patched are in caveolin-1-enriched/raft microdomains. |
| GO:0048745 smooth muscle tissue development | IEP PMID:17850284 Immunohistochemical analysis of Sonic hedgehog signalling in... | MARK AS OVER ANNOTATED | Summary: Immunohistochemistry of the developing human urinary tract found SHH in the urothelium of the nascent bladder and PTCH with SMO in the surrounding urogenital sinus, a pattern the authors read as long-range paracrine signalling accompanying detrusor smooth muscle differentiation. Reason: The evidence is a static expression pattern in fixed human tissue, with no perturbation of PTCH1 and no functional assay, and the authors themselves present it as hypothesis-generating. Hedgehog-driven smooth muscle differentiation is well established from mouse genetics, so the underlying biology is likely right; what is over-stated is the step from 'PTCH1 protein is present where this happens' to 'PTCH1 is involved in it'. Supporting Evidence: PMID:17850284 The expression patterns of the SHH-transducing proteins Patched (PTCH) and Smoothened (SMO) were consistent with long-range paracrine signalling associated with detrusor smooth muscle differentiation in the urogenital sinus. PMID:17850284 Collectively, these descriptive results generate new hypotheses regarding SHH signal transduction in human urinary tract development and help to explain the varied urinary tract malformation phenotypes noted in individuals with mutations in the SHH pathway. |
| GO:0051782 negative regulation of cell division | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog transfer from mouse Ptch1, where the term rests on the cyclin B1 study: PTCH1 sequesters phosphorylated cyclin B1 away from the nucleus, inhibiting proliferation, and Shh releases it - a proposed PTCH1 contribution to a G2/M checkpoint. Reason: Kept on the strength of the underlying experiments, which include endogenous co-interaction and a rescue by a nuclear-localising, non-binding cyclin B1 mutant. It is non-core for the same reasons as the cyclin binding rows: a non-canonical arm, separate from the receptor/transporter function, with limited independent human corroboration, and sitting alongside a tumour-suppressor phenotype that is more parsimoniously explained by loss of Hedgehog pathway repression. Supporting Evidence: PMID:11331587 The findings reported here demonstrate that ptc1 participates in determining the subcellular localization of cyclin B1 and suggest a link between the tumor suppressor activity of ptc1 and the regulation of cell division. PMID:11331587 Expression of ptc1 in 293T cells was inhibitory to cell proliferation; this inhibition could be relieved by coexpression of a cyclin B1 derivative that constitutively localizes to the nucleus and that could not interact with ptc1 due to phosphorylation-site mutations to ALA |
| GO:0060037 pharyngeal system development | IMP PMID:8681379 Mutations of the human homolog of Drosophila patched in the ... | KEEP AS NON CORE | Summary: NBCCS features of pharyngeal-arch origin, including cleft lip/palate and jaw keratocysts, implicate PTCH1 in human pharyngeal system development. Reason: A human loss-of-function genetics annotation, and the developmental features of the syndrome are real. It is kept as non-core because the causal chain runs through pathway derepression: losing PTCH1 removes the brake on SMO, GLI activity rises, and patterning goes wrong. The protein's own activity is sterol transport at the ciliary membrane; the morphological outcome is the phenotype of that activity failing. Supporting Evidence: PMID:8681379 We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types. PMID:8681379 The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. |
| GO:0060037 pharyngeal system development | IMP PMID:8981943 Most germ-line mutations in the nevoid basal cell carcinoma ... | KEEP AS NON CORE | Summary: A second NBCCS mutation series, screening 71 unrelated individuals and finding 28 mutations distributed through the gene, 86% causing protein truncation, with the developmental defects attributed to haploinsufficiency. Reason: A human loss-of-function genetics annotation, and the developmental features of the syndrome are real. It is kept as non-core because the causal chain runs through pathway derepression: losing PTCH1 removes the brake on SMO, GLI activity rises, and patterning goes wrong. The protein's own activity is sterol transport at the ciliary membrane; the morphological outcome is the phenotype of that activity failing. Supporting Evidence: PMID:8981943 The preponderance of truncation mutants in the germ line of NBCCS patients suggests that the developmental defects associated with the disorder are most likely due to haploinsufficiency. PMID:8981943 Two missense mutations have been identified, and their location within transmembrane domains supports the notion that PTCH may have a transport function. |
| GO:0060170 ciliary membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt's subcellular-location vocabulary maps PTCH1 to the ciliary membrane, from the curated Cell projection, cilium membrane assignment. Reason: The functionally decisive location. PTCH1 in the ciliary membrane holds local cholesterol low and keeps SMO out; ligand-triggered ubiquitination and clearance of PTCH1 from the cilium is what permits SMO entry and pathway activation. UniProt records cilium membrane as a subcellular location, and the six human GO-CAM models place the PTCH1 activity at the non-motile cilium membrane. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt projection, cilium membrane file:human/PTCH1/PTCH1-uniprot.txt Note=Localizes to primary cilium and prevents cilium localization of |
| GO:0060170 ciliary membrane | TAS Reactome:R-HSA-5612510 | ACCEPT | Summary: Reactome's step in which GLI3R represses PTCH1 expression in the absence of Hedgehog signalling, with PTCH1 placed at the ciliary membrane. Reason: The functionally decisive location. PTCH1 in the ciliary membrane holds local cholesterol low and keeps SMO out; ligand-triggered ubiquitination and clearance of PTCH1 from the cilium is what permits SMO entry and pathway activation. UniProt records cilium membrane as a subcellular location, and the six human GO-CAM models place the PTCH1 activity at the non-motile cilium membrane. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt projection, cilium membrane |
| GO:0060170 ciliary membrane | TAS Reactome:R-HSA-5632649 | ACCEPT | Summary: Reactome's step in which Hh-Npp binds GAS1 and PTCH at the ciliary membrane. Reason: The functionally decisive location. PTCH1 in the ciliary membrane holds local cholesterol low and keeps SMO out; ligand-triggered ubiquitination and clearance of PTCH1 from the cilium is what permits SMO entry and pathway activation. UniProt records cilium membrane as a subcellular location, and the six human GO-CAM models place the PTCH1 activity at the non-motile cilium membrane. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt projection, cilium membrane |
| GO:0060170 ciliary membrane | TAS Reactome:R-HSA-5632652 | ACCEPT | Summary: Reactome's step in which Hh-Npp binds CDON and PTCH at the ciliary membrane. Reason: The functionally decisive location. PTCH1 in the ciliary membrane holds local cholesterol low and keeps SMO out; ligand-triggered ubiquitination and clearance of PTCH1 from the cilium is what permits SMO entry and pathway activation. UniProt records cilium membrane as a subcellular location, and the six human GO-CAM models place the PTCH1 activity at the non-motile cilium membrane. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt projection, cilium membrane |
| GO:0060170 ciliary membrane | TAS Reactome:R-HSA-5632677 | ACCEPT | Summary: Reactome's PTCH internalisation step, with PTCH1 starting from the ciliary membrane. Reason: The functionally decisive location. PTCH1 in the ciliary membrane holds local cholesterol low and keeps SMO out; ligand-triggered ubiquitination and clearance of PTCH1 from the cilium is what permits SMO entry and pathway activation. UniProt records cilium membrane as a subcellular location, and the six human GO-CAM models place the PTCH1 activity at the non-motile cilium membrane. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt projection, cilium membrane file:human/PTCH1/PTCH1-uniprot.txt SMURF1 and/or SMURF2 in response to SHH, promoting endocytosis and |
| GO:0060170 ciliary membrane | TAS Reactome:R-HSA-5635865 | ACCEPT | Summary: Reactome's step in which SMURF1/2 dissociates from ubiquitinated PTCH1, with PTCH1 at the ciliary membrane. Reason: The functionally decisive location. PTCH1 in the ciliary membrane holds local cholesterol low and keeps SMO out; ligand-triggered ubiquitination and clearance of PTCH1 from the cilium is what permits SMO entry and pathway activation. UniProt records cilium membrane as a subcellular location, and the six human GO-CAM models place the PTCH1 activity at the non-motile cilium membrane. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt projection, cilium membrane file:human/PTCH1/PTCH1-uniprot.txt SMURF1 and/or SMURF2 in response to SHH, promoting endocytosis and |
| GO:0061053 somite development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog transfer from mouse Ptch1, which carries somite development by IMP. Hedgehog signalling from the notochord specifies the sclerotome and drives myotome formation, and PTCH1 gates the response. Reason: A human loss-of-function genetics annotation, and the developmental features of the syndrome are real. It is kept as non-core because the causal chain runs through pathway derepression: losing PTCH1 removes the brake on SMO, GLI activity rises, and patterning goes wrong. The protein's own activity is sterol transport at the ciliary membrane; the morphological outcome is the phenotype of that activity failing. Supporting Evidence: PMID:8681379 The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. |
| GO:0061053 somite development | IMP PMID:8681379 Mutations of the human homolog of Drosophila patched in the ... | KEEP AS NON CORE | Summary: Rib and vertebral anomalies are a consistent NBCCS feature, implicating PTCH1 in human somite-derived axial skeletal development. Reason: A human loss-of-function genetics annotation, and the developmental features of the syndrome are real. It is kept as non-core because the causal chain runs through pathway derepression: losing PTCH1 removes the brake on SMO, GLI activity rises, and patterning goes wrong. The protein's own activity is sterol transport at the ciliary membrane; the morphological outcome is the phenotype of that activity failing. Supporting Evidence: PMID:8681379 We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types. PMID:8681379 The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. |
| GO:0071397 cellular response to cholesterol | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog transfer from mouse Ptch1, where the term rests on an IEP from the cholesterol transport study - Patched levels and cholesterol handling change together. Reason: This is close to the heart of what PTCH1 does. Cholesterol is simultaneously its substrate, the ligand whose accessibility to SMO it controls, and a modifier of its own distribution and of Hedgehog ligand binding, so 'cellular response to cholesterol' is an accurate process-level statement rather than a peripheral one. Accepted. Supporting Evidence: PMID:21931618 We found that binding of Shh protein to its receptor Patched, which involves Patched internalization, increases the intracellular concentration of cholesterol and decreases the efflux of a fluorescent cholesterol derivative (BODIPY-cholesterol) from these cells. file:human/PTCH1/PTCH1-uniprot.txt smoothened protein (SMO) by preventing SMO access to cholesterol: |
| GO:0071397 cellular response to cholesterol | IMP PMID:11278759 The sonic hedgehog receptor patched associates with caveolin... | ACCEPT | Summary: Karpen et al. showed that depleting plasmalemmal cholesterol changes the distribution of the Patched-Smoothened receptor complex in caveolin-enriched raft microdomains - PTCH1's own membrane behaviour responds to cholesterol. Reason: This is close to the heart of what PTCH1 does. Cholesterol is simultaneously its substrate, the ligand whose accessibility to SMO it controls, and a modifier of its own distribution and of Hedgehog ligand binding, so 'cellular response to cholesterol' is an accurate process-level statement rather than a peripheral one. Accepted. Supporting Evidence: PMID:11278759 Depletion of plasmalemmal cholesterol influences the distribution of the Hh receptor complex in the caveolin-enriched/raft microdomains. |
| GO:0071397 cellular response to cholesterol | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer of the same response from mouse Ptch1. Reason: This is close to the heart of what PTCH1 does. Cholesterol is simultaneously its substrate, the ligand whose accessibility to SMO it controls, and a modifier of its own distribution and of Hedgehog ligand binding, so 'cellular response to cholesterol' is an accurate process-level statement rather than a peripheral one. Accepted. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt smoothened protein (SMO) by preventing SMO access to cholesterol: |
| GO:0071679 commissural neuron axon guidance | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Transferred from rat Ptch1, where the term rests on an IMP: Shh acting through Patched switches commissural axons from indifference to repulsion by Semaphorins during midline crossing, a non-transcriptional, growth-cone-local use of the receptor. Reason: The rat evidence is a perturbation experiment rather than an expression correlation, and it is coherent with the independent localisation of Patched to axonal growth cones, so the annotation is kept. It is non-core because axon guidance is one tissue-specific deployment of the receptor among many, and because no human evidence accompanies the transfer. |
| GO:0072205 metanephric collecting duct development | IEP PMID:17850284 Immunohistochemical analysis of Sonic hedgehog signalling in... | MARK AS OVER ANNOTATED | Summary: Immunohistochemistry found SHH and PTCH co-expressed in the epithelia of the human fetal kidney collecting system between 16 and 26 weeks, with SMO surprisingly undetectable there; the authors proposed a SMO-independent, cyclin B1-mediated influence on collecting duct growth. Reason: Expression-correlation evidence in fixed human tissue, explicitly presented by the authors as hypothesis-generating, and resting on an inference the same paper flags as surprising - that the pathway operates without its obligate transducer. Hedgehog signalling does shape the collecting system in mouse genetics, so the term is flagged rather than removed, but the human evidence here does not establish PTCH1 participation. Supporting Evidence: PMID:17850284 In the developing kidney, SHH and PTCH were expressed in epithelia of the collecting system between 16-26 weeks--surprisingly, SMO was not detected. PMID:17850284 Collectively, these descriptive results generate new hypotheses regarding SHH signal transduction in human urinary tract development and help to explain the varied urinary tract malformation phenotypes noted in individuals with mutations in the SHH pathway. |
| GO:0072659 protein localization to plasma membrane | IDA PMID:11278759 The sonic hedgehog receptor patched associates with caveolin... | MARK AS OVER ANNOTATED | Summary: The observation behind this row is that immunocytochemistry and fractionation suggested Patched is required for transport of Smoothened to the membrane - a positive, delivery-like role for PTCH1 in SMO's surface localisation. Reason: PTCH1 does govern where SMO ends up, so the term is not simply wrong, but the direction recorded here has not held up. The established statement is the opposite one: unliganded PTCH1 restricts SMO accumulation in the ciliary membrane, and it is PTCH1's clearance that lets SMO in - UniProt states this from five independent studies, and the same mechanism is what the antibody work exploits. The original authors hedged the claim themselves. Flagged rather than removed, since a role in controlling SMO's membrane localisation is real; the companion general term GO:0032880 is separately re-pointed to the specific negative statement. Supporting Evidence: PMID:11278759 Immunocytochemistry data and fractionation studies also show that Patched seems to be required for transport of Smoothened to the membrane. file:human/PTCH1/PTCH1-uniprot.txt Note=Localizes to primary cilium and prevents cilium localization of |
| GO:0097108 hedgehog family protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: The PAINT node assigns hedgehog family protein binding across the Patched clade, from Drosophila ptc to human PTCH1 and PTCH2 - ligand binding is the ancestral property of the family. Reason: Core. Binding the lipidated Hedgehog ligand is one of PTCH1's two defining molecular activities, it is established biochemically for all three mammalian ligands and structurally at near-atomic resolution, and it is conserved across the whole Patched clade. Unlike the smoothened binding rows there is no mechanistic tension here: the ligand-receptor complex is the thing the structures resolve. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000847539 SUPPORTS TRANSFER Patched-clade node; the human structures of PTCH1 with SHH-N are among the descendant evidences, so the target appearing in its own WITH/FROM marks direct experimental grounding. Supporting Evidence: PMID:9811851 Biochemical analysis of PTCH and PTCH2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with SMO. PMID:29995851 The palmitoylated N terminus of SHH-N inserts into a cavity between the extracellular domains of PTCH1 and dominates the PTCH1-SHH-N interface |
| GO:0097108 hedgehog family protein binding | IEA GO_REF:0000117 | ACCEPT | Summary: An ARBA machine-learned rule assigning hedgehog family protein binding to the Patched family, duplicating the phylogenetic and experimental rows. Reason: Core. Binding the lipidated Hedgehog ligand is one of PTCH1's two defining molecular activities, it is established biochemically for all three mammalian ligands and structurally at near-atomic resolution, and it is conserved across the whole Patched clade. Unlike the smoothened binding rows there is no mechanistic tension here: the ligand-receptor complex is the thing the structures resolve. Supporting Evidence: PMID:9811851 Biochemical analysis of PTCH and PTCH2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with SMO. |
| GO:0097108 hedgehog family protein binding | IPI PMID:9811851 Characterization of two patched receptors for the vertebrate... | ACCEPT | Summary: Direct binding of PTCH1 to Indian hedgehog. Carpenter et al. tested both human Patched proteins against all hedgehog family members and found comparable affinity for each. Reason: Core. Binding the lipidated Hedgehog ligand is one of PTCH1's two defining molecular activities, it is established biochemically for all three mammalian ligands and structurally at near-atomic resolution, and it is conserved across the whole Patched clade. Unlike the smoothened binding rows there is no mechanistic tension here: the ligand-receptor complex is the thing the structures resolve. Supporting Evidence: PMID:9811851 Biochemical analysis of PTCH and PTCH2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with SMO. |
| GO:0097108 hedgehog family protein binding | IPI PMID:9811851 Characterization of two patched receptors for the vertebrate... | ACCEPT | Summary: Direct binding of PTCH1 to Desert hedgehog, from the same comparative binding analysis. Reason: Core. Binding the lipidated Hedgehog ligand is one of PTCH1's two defining molecular activities, it is established biochemically for all three mammalian ligands and structurally at near-atomic resolution, and it is conserved across the whole Patched clade. Unlike the smoothened binding rows there is no mechanistic tension here: the ligand-receptor complex is the thing the structures resolve. Supporting Evidence: PMID:9811851 Biochemical analysis of PTCH and PTCH2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with SMO. |
| GO:0097108 hedgehog family protein binding | IPI PMID:9811851 Characterization of two patched receptors for the vertebrate... | ACCEPT | Summary: Direct binding of PTCH1 to Sonic hedgehog, from the same analysis and subsequently resolved structurally: the ligand's palmitate inserts into a cavity between PTCH1's extracellular domains and dominates the interface. Reason: Core. Binding the lipidated Hedgehog ligand is one of PTCH1's two defining molecular activities, it is established biochemically for all three mammalian ligands and structurally at near-atomic resolution, and it is conserved across the whole Patched clade. Unlike the smoothened binding rows there is no mechanistic tension here: the ligand-receptor complex is the thing the structures resolve. Supporting Evidence: PMID:9811851 Biochemical analysis of PTCH and PTCH2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with SMO. PMID:29995851 The palmitoylated N terminus of SHH-N inserts into a cavity between the extracellular domains of PTCH1 and dominates the PTCH1-SHH-N interface |
| GO:0097421 liver regeneration | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Transferred from rat Ptch1, where Ptch1 expression changed during liver regeneration. Hedgehog signalling is reactivated in regenerating and injured liver. Reason: PTCH1 is the canonical transcriptional readout of Hedgehog pathway activity: its mRNA rises wherever GLI activity rises, in essentially any tissue. An expression-correlation annotation therefore records that the pathway was engaged, not that PTCH1 performs a function in the process named. Pathway reactivation raises PTCH1 transcription by definition, so the expression change is the readout of the process rather than a contribution to it. The term is not false, but it over-states what the evidence shows, and there is no human evidence behind the transfer. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK ROLE CONFLATION Sources checked: UniProtKB:Q6UY90 · Ptch1 SOURCE WEAK OR INFERRED Rat Ptch1 carries this term by IEP - a change in transcript or protein abundance - and the row reaches human by Ensembl-Compara transfer with no human evidence behind it. |
| GO:0098804 non-motile cilium membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog transfer from mouse Ptch1, which carries this location by two independent IDAs. Reason: The most precise and most functionally apt location term in the set, and the one the curated GO-CAM models use for the PTCH1 annoton in all six human Hedgehog models. PTCH1 acts in the membrane of the non-motile primary cilium, where its sterol handling keeps SMO out until ligand arrives. Accepted as core. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt Note=Localizes to primary cilium and prevents cilium localization of PMID:40128518 Several studies showed that PTCH1 functions as a cholesterol transporter to maintain the low concentration of cholesterol in cilia |
| GO:0098804 non-motile cilium membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer of the same mouse annotation. Reason: The most precise and most functionally apt location term in the set, and the one the curated GO-CAM models use for the PTCH1 annoton in all six human Hedgehog models. PTCH1 acts in the membrane of the non-motile primary cilium, where its sterol handling keeps SMO out until ligand arrives. Accepted as core. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt Note=Localizes to primary cilium and prevents cilium localization of |
| GO:0140303 intramembrane lipid carrier activity | IDA PMID:31548691 The morphogen Sonic hedgehog inhibits its receptor Patched b... | ACCEPT | Summary: The pincer-grasp study: the Shh C-terminal cholesteroyl group binds PTCH1's first extracellular domain, and molecular dynamics show the interaction closes a tunnel through PTCH1 identified as the conduit for sterol transport - ligand binding shuts the carrier. Reason: This is PTCH1's core molecular function on the current understanding, and it is the term the module and all six human GO-CAM models assign to the PTCH1 annoton. Ligand binding does not trigger a conformational signal into the cell; it stops a transport activity, and the resulting rise in accessible cholesterol is what activates SMO. UniProt records the reaction directly as cholesterol(in) = cholesterol(out), and the same conclusion is restated independently in the 2025 antibody work. Supporting Evidence: PMID:31548691 Molecular dynamics simulations show that this interaction leads to the closure of a tunnel through PTCH1 that serves as the putative conduit for sterol transport. PMID:31548691 Shh inactivates PTCH1 by grasping its extracellular domain with two lipidic pincers, the N-terminal palmitate and the C-terminal cholesterol, which are both inserted into the PTCH1 protein core. |
| GO:0140303 intramembrane lipid carrier activity | IDA PMID:37611095 The energetics and ion coupling of cholesterol transport thr... | ACCEPT | Summary: Free-energy calculations across the PTCH1 transport cycle, with an energetic barrier of roughly 15-20 kJ/mol for cholesterol export, coupled to in vivo assays of PTCH1 mutants linking cation-binding sites and transmembrane motion to activity, and to comparison with Dispatched1's inward-open/occluded transition. Reason: This is PTCH1's core molecular function on the current understanding, and it is the term the module and all six human GO-CAM models assign to the PTCH1 annoton. Ligand binding does not trigger a conformational signal into the cell; it stops a transport activity, and the resulting rise in accessible cholesterol is what activates SMO. UniProt records the reaction directly as cholesterol(in) = cholesterol(out), and the same conclusion is restated independently in the 2025 antibody work. Supporting Evidence: PMID:37611095 we find an energetic barrier of ~15 to 20 kilojoule per mole for cholesterol export PMID:37611095 PTCH1 inhibits the G protein-coupled receptor Smoothened (SMO) via a debated mechanism involving modulating ciliary cholesterol accessibility. |
| GO:0140303 intramembrane lipid carrier activity | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog transfer from mouse Ptch1, which carries this molecular function by three independent IDAs including the structural cholesterol-transport work. Reason: This is PTCH1's core molecular function on the current understanding, and it is the term the module and all six human GO-CAM models assign to the PTCH1 annoton. Ligand binding does not trigger a conformational signal into the cell; it stops a transport activity, and the resulting rise in accessible cholesterol is what activates SMO. UniProt records the reaction directly as cholesterol(in) = cholesterol(out), and the same conclusion is restated independently in the 2025 antibody work. Supporting Evidence: file:human/PTCH1/PTCH1-uniprot.txt Reaction=cholesterol(in) = cholesterol(out) PMID:40128518 Several studies showed that PTCH1 functions as a cholesterol transporter to maintain the low concentration of cholesterol in cilia |
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Download this section (compressed HTML)Q: In which direction, and with what ion coupling, does PTCH1 move cholesterol in a native ciliary membrane? UniProt records the mechanism as unclear and offers outer-to-inner leaflet exchange against potassium or sodium export, while free-energy calculations model export coupled to one to three Na+ or two to three K+. No measurement has been made on a native cilium.
Q: Does the PTCH1-SMO complex detected by co-immunoprecipitation have any role, given that PTCH1 inhibits SMO sub-stoichiometrically and that no structure resolves the two proteins together? If the complex is real and functional, the module's purely causal PTCH1-to-SMO relation would need a binding component.
Q: Do the cyclin B1 sequestration and Smoothened-independent GLI1 repression arms operate at endogenous PTCH1 levels in human tissue, or are they properties of overexpression? Both currently rest on transfection experiments plus one endogenous co-immunoprecipitation.
Q: Do the four PTCH1 isoforms differ in ciliary targeting, sterol transport rate or ligand affinity? None of the GOA rows is isoform-scoped, so any isoform specialisation is invisible in the current annotation set.
Experiment: Reconstitute purified human PTCH1 into asymmetric proteoliposomes with defined leaflet-specific cholesterol and a Na+/K+ gradient, and measure directional sterol movement with leaflet-selective probes (accessible-cholesterol sensors such as ALOD4 applied from each side) under ligand-free, SHH-N-bound and conduit-mutant conditions. Pair this with ALOD4 labelling of accessible cholesterol in the cilia of PTCH1-null human cells rescued with wild-type, transport-dead and ligand-binding-dead PTCH1, reading out SMO ciliary accumulation and GLI transcription.
Hypothesis: PTCH1 exports cholesterol from the outer leaflet of the ciliary membrane, and the resulting depletion of accessible cholesterol - rather than any direct PTCH1-SMO contact - is what holds SMO inactive.
Type: reconstituted transport assay with cell-based accessible-sterol imaging
Experiment: Introduce separation-of-function PTCH1 alleles at the endogenous locus in human cells: one deleting the regions mapped as required for GLI1 repression (residues 180-786 and 1058-1210) without disturbing the sterol conduit, and one inactivating the conduit while leaving those regions intact. Measure Hedgehog reporter and endogenous GLI target transcription, ciliary SMO accumulation, cyclin B1 nuclear/cytoplasmic partitioning and proliferation, all at endogenous expression.
Hypothesis: The cyclin B1 and GLI1-repression arms of PTCH1 are separable from its transport activity, and are dispensable at endogenous expression levels.
Type: CRISPR knock-in separation-of-function alleles with signalling and cell-cycle readouts
Experiment: Test purified recombinant human PTCH1 ectodomains, and full-length PTCH1 in detergent or nanodisc, for binding to immobilised heparin and to defined heparan sulfate oligosaccharides by surface plasmon resonance, with SHH-N as the positive control and its Cardin-Weintraub-motif mutant as the negative. A clean negative result would close out the propagated annotation on direct evidence rather than on argument.
Hypothesis: Human PTCH1 has no heparin-binding activity; the heparin-binding annotation propagated to it reflects a property of the Hedgehog ligand.
Type: surface plasmon resonance binding assay
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