patched (ptc) is a 1286-residue, twelve-pass integral membrane protein of the RND permease superfamily and the cell-surface receptor for the Hedgehog (Hh) morphogen in Drosophila. It carries a sterol-sensing domain spanning transmembrane helices 2-6, two large glycosylated extracellular loops that form the ligand-binding face, and a long disordered cytoplasmic C-terminal tail. Patched has two linked activities. First, in the absence of ligand it is the pathway's brake: it holds the class-F receptor Smoothened inactive and destabilised, so that Cubitus interruptus is processed into its transcriptional repressor form. Hedgehog binding abolishes this restraint and triggers ubiquitin-dependent internalisation and degradation of Patched, allowing Smoothened to accumulate in a phosphorylated, active state at the plasma membrane. The restraint appears to be indirect and catalytic rather than a stoichiometric Patched-Smoothened association, and in Drosophila it is associated with Patched control of membrane lipid pools: Patched binds phosphatidylinositol 4-phosphate through its sterol-sensing domain and phosphatidic acid through its C-terminal tail, and mutating the phosphatidic acid sites abolishes Smoothened inhibition. Second, because patched is itself a Hedgehog target gene, ligand-induced Patched acts as a sink that binds and internalises Hedgehog and thereby shortens and steepens the morphogen gradient. High-affinity ligand binding and transduction additionally require the Ig/fibronectin co-receptors Interference hedgehog and Brother of ihog, which bind Patched directly and promote its surface presentation, although Patched alone is sufficient to sequester ligand. Patched functions at the plasma membrane, concentrated on the basal surface and on signalling filopodia where Hedgehog-sending and Hedgehog-receiving cells contact, and cycles through endocytic vesicles; in Drosophila olfactory sensory neurons, one of the few ciliated cell types in the animal, it also localises to the ciliary membrane. Independently of Hedgehog signalling, Patched internalises lipophorin particles and lowers intracellular lipid droplet content. Through its control of Hedgehog reception, patched is required for embryonic segment polarity and for anterior/posterior patterning and growth of the imaginal discs, and its loss causes ligand-independent pathway activation, overgrowth and mis-specification in many tissues.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001746 Bolwig's organ morphogenesis | IMP PMID:10704398 Transcriptional regulation of atonal required for Drosophila... | KEEP AS NON CORE | Summary: Bolwig's organ (the larval photoreceptor) requires Hedgehog input, and the cited study defines a Ci- and Fused-independent branch of the pathway acting in its formation. As the Hedgehog receptor, ptc participates by setting how much signal the primordium receives, not by any organ-specific activity of its own. Reason: Retained as a genuine but peripheral, tissue-level consequence of ptc's restraint of Smoothened signalling. The cached record is abstract-only and foregrounds hh, eya and so; the FlyBase curator read the full text and we do not overrule that, but the annotation is not evidence of a distinct molecular role for ptc in larval eye morphogenesis. Supporting Evidence: PMID:10704398 Neither Atonal expression nor Bolwig's organ formation occurred in the absence of hedgehog, eyes absent or sine oculis activity. PMID:10704398 the Hedgehog signaling pathway required for Bolwig's organ development is a new type and lacks Fused kinase and Cubitus interruptus as downstream components |
| GO:0005119 smoothened binding | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: A PAINT node assertion placing Smoothened binding on the ancestral Patched receptor, seeded by human PTCH1 and PTCH2. Drosophila ptc descends from that node, so the propagation is mechanically correct; the question is whether the term describes what fly Patched actually does. Reason: Not wrong at the level of complex membership - Patched and Smoothened do co-immunoprecipitate and co-fractionate in Drosophila (PMID:17284519) - but the fly evidence argues specifically against reading this as a direct receptor-transducer interaction. Inhibition of Smoothened persists when Smoothened is in 50-fold molar excess and substoichiometric Patched suffices, which is the signature of a catalytic, indirect mechanism (PMID:26863604), and the trafficking data were already interpreted that way (PMID:10966113). A bare binding term invites the reading that association is the mechanism, which is exactly the point the Drosophila literature contests. The node placement itself is defensible at family level and is not challenged here, so the row is marked as over-annotated rather than removed, and it is deliberately not carried into core_functions. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000847539 SUPPORTS SOURCE BUT NOT TARGET Ancestral Patched node. The IBD placement is defensible at family level and is not challenged; what does not carry to Drosophila is the enables-level binding claim, since the fly evidence indicates substoichiometric, catalytic restraint rather than association. UniProtKB:Q13635 Β· PTCH1 UNRESOLVED Human donor for the node; the directness of the PTCH1-SMO interaction was not adjudicated in this fly review. UniProtKB:Q9Y6C5 Β· PTCH2 UNRESOLVED Human donor for the node; not independently assessed here. Supporting Evidence: PMID:26863604 It is unlikely that Ptc inhibits Smo by direct association PMID:10966113 These findings raise the possibility that Patched acts indirectly to regulate Smoothened activity. PMID:17284519 We find that Cubitus interruptus, Sex-lethal, Patched and Smoothened co-immunoprecipitate and co-fractionate, suggesting a large complex of both membrane and cytoplasmic components of the Hedgehog pathway. |
| GO:0005515 protein binding | IPI PMID:12783860 Understanding human cancer using Drosophila: Tid47, a cytoso... | REMOVE | Summary: Interaction of the Patched cytoplasmic C-terminal region with Tid47, a cytosolic product of the DnaJ-like tumour suppressor l(2)tid (FB:FBgn0002174), proposed to regulate Patched homeostasis. Reason: The interaction is not in doubt and UniProt records it as a SUBUNIT feature, but the bare GO:0005515 term carries no functional information about what Patched does. The cited work characterises Tid47 as a cochaperone acting on Patched turnover, which is an activity of Tid47, not a molecular function of Patched, so no more informative replacement term can be assigned to ptc from this paper. Removal is a judgement about the uninformativeness of the term, not about the reported interaction. Supporting Evidence: PMID:12783860 We provide functional evidence for its direct in vivo interaction with the Hh-bound Ptc receptor during signal transmission. file:DROME/ptc/ptc-uniprot.txt Interacts (via C-terminal cytoplasmic region) with |
| GO:0005515 protein binding | IPI PMID:17284519 A large complex containing Patched and Smoothened initiates ... | REMOVE | Summary: Co-immunoprecipitation and co-fractionation of Patched with Sex-lethal (FB:FBgn0264270), Smoothened and Cubitus interruptus in a large membrane-plus-cytoplasmic Hedgehog pathway complex. Reason: The evidence is complex-level co-purification, which establishes co-membership rather than a defined activity, and the bare protein binding term adds nothing to what GO:0008158 and GO:0097108 already record about Patched. No more informative molecular function for Patched follows from an association with a sex-determination RNA-binding protein, so MODIFY is not available; removal does not imply the co-purification is false. Supporting Evidence: PMID:17284519 We find that Cubitus interruptus, Sex-lethal, Patched and Smoothened co-immunoprecipitate and co-fractionate, suggesting a large complex of both membrane and cytoplasmic components of the Hedgehog pathway. |
| GO:0005515 protein binding | IPI PMID:20048000 Genetic and biochemical definition of the Hedgehog receptor. | REMOVE | Summary: Direct interaction between the Fn2 fibronectin-III domain of the co-receptor Ihog (FB:FBgn0031872) and Patched, required for presentation of Patched at the cell surface and for high-affinity Hedgehog binding by the Patched-Ihog pair. Reason: This is the one protein-binding row with real functional content, but that content is already captured by the annotations this review accepts: GO:0008158 hedgehog receptor activity and GO:0097108 hedgehog family protein binding both describe the receptor whose assembly the Ihog interaction supports. GO has no term for the Patched side of a receptor/co-receptor pairing - GO:0015026 coreceptor activity describes Ihog, not Patched - so there is no evidence-backed MODIFY target, and the bare term is uninformative on its own. Removal does not question the interaction. Supporting Evidence: PMID:20048000 We demonstrate that Ihog interacts directly with Ptc, is required for presentation of Ptc on the cell surface, and that Ihog and Ptc are both required for high-affinity Hh binding. PMID:20048000 We demonstrate biochemically that the Fn2 domains of Ihog/Boi interact physically with Ptc, and that this domain is required for presentation of Ptc on the cell surface. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic propagation placing the Patched family at the plasma membrane, where ligand reception and restraint of Smoothened occur. Drosophila ptc appears in its own WITH/FROM list because it carries direct experimental evidence for this location, which is one of the descendant evidences the PAINT curator used. Reason: Correct and well grounded. The plasma membrane is where Patched receives Hedgehog and is removed from upon ligand binding (PMID:10966113), and UniProt curates Cell membrane as the primary location. The self-citation in WITH/FROM is expected for a gene with its own experimental annotation and is not circular. Supporting Evidence: file:DROME/ptc/ptc-uniprot.txt SUBCELLULAR LOCATION: Cell membrane PMID:10966113 Hedgehog binding causes removal of Patched from the cell surface. |
| GO:0005886 plasma membrane | IDA PMID:10966113 Hedgehog induces opposite changes in turnover and subcellula... | ACCEPT | Summary: Direct demonstration that Patched resides at the cell surface and is cleared from it upon Hedgehog binding, with the reciprocal stabilisation and surface accumulation of Smoothened. Reason: This is the experiment that anchors the plasma membrane location for fly Patched, and UniProt cites the same work for its Cell membrane annotation. Supporting Evidence: PMID:10966113 Hedgehog binding causes removal of Patched from the cell surface. PMID:10966113 In contrast, Hedgehog causes phosphorylation, stabilization, and accumulation of Smoothened at the cell surface. |
| GO:0005886 plasma membrane | IDA PMID:8898240 The role of segment polarity genes during early oogenesis in... | ACCEPT | Summary: Localisation of Patched in the somatic cells of the germarium and developing egg chambers during early oogenesis, where ptc expression is elevated near the Hedgehog source. Reason: Consistent with the independently established plasma membrane location and with the elevated ptc expression the same study reports in Hedgehog-responding somatic cells. The cached record is abstract-only so the staining itself cannot be inspected here, but the location is not in doubt and the curator's reading of the full text is not second-guessed. Supporting Evidence: PMID:8898240 patched (ptc) and cubitus interruptus (ci) are expressed in somatic cells throughout the germarium and in developing egg chambers, with ptc expression being elevated within 10 cell diameters of the source of the hh signal |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Automatic mapping from the UniProt Swiss-Prot subcellular location Cell membrane, itself curated from PMID:10966113. Reason: The mapping is correct and its source is an experimentally supported curated statement rather than a prediction. Supporting Evidence: file:DROME/ptc/ptc-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-DME-209178 | ACCEPT | Summary: Reactome's inferred Drosophila reaction for N-terminal Hedgehog binding to the Patched receptor complex places Patched at the plasma membrane. Reason: Agrees with the experimental and phylogenetic annotations for the same term; nothing in the fly record contradicts it. Supporting Evidence: file:DROME/ptc/ptc-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0005929 cilium | IDA PMID:24768000 Cilia-mediated hedgehog signaling in Drosophila. | ACCEPT | Summary: Drosophila olfactory sensory neurons are among the few ciliated cells in the animal, and the cited study identifies a cilium-based Hedgehog pathway in them in which the pathway components, including Patched, are found in the ciliary compartment. Reason: Accepted as a real but narrowly restricted location. UniProt independently curates cilium membrane for ptc from this same paper, so two curation groups reading the full text agree. The annotation should not be read as implying that fly Hedgehog signalling is generally ciliary: the paper itself stresses that Drosophila cells are non-ciliated during development, and the canonical wing-disc pathway runs on a cytoplasmic Costal-2 complex at the plasma membrane. Supporting Evidence: PMID:24768000 Drosophila cells are nonciliated during development, which has led to the assumption that cilia-mediated Hh signaling is restricted to vertebrates. Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. file:DROME/ptc/ptc-uniprot.txt Cell projection, cilium |
| GO:0007346 regulation of mitotic cell cycle | IMP PMID:11279500 Hedgehog acts as a somatic stem cell factor in the Drosophil... | MODIFY | Summary: Loss of ptc in ovarian somatic cells gives ligand-independent Hedgehog signalling and supernumerary somatic stem cells, while loss of Hedgehog signalling prevents these cells from proliferating as stem cells. The phenotype is a change in stem cell proliferation, which GO:0007346 describes only very loosely. Reason: The essence is sound - ptc restrains a proliferative response - but regulation of mitotic cell cycle is a generic cell-cycle term that does not capture what the experiment shows. The assayed phenotype is the size of the somatic stem cell pool, so GO:0072091 regulation of stem cell proliferation is the accurate term. Kept out of core_functions either way: this is a tissue-specific consequence of ptc restraining Smoothened, not a separate activity. Proposed replacements: regulation of stem cell proliferation Supporting Evidence: PMID:11279500 These cells cannot proliferate as stem cells in the absence of Hh signalling, whereas excessive Hh signalling produces supernumerary stem cells. PMID:11279500 Here we show that Hh acts specifically on stem cells in the Drosophila ovary. |
| GO:0007411 axon guidance | IMP PMID:15754211 Patched regulation of axon guidance is by specifying neural ... | MARK AS OVER ANNOTATED | Summary: In ptc mutants the medial longitudinal tract crosses the midline inappropriately. The cited study traces this to loss and mis-specification of the pioneer neuron vMP2 following loss of Ptc activity in the neuroectoderm, i.e. the guidance defect is a downstream, non-cell-autonomous consequence of altered neural identity. Reason: The paper's own title and conclusion state that Patched regulation of axon guidance works by specifying neural identity, and that mis-specification and loss of neurons contribute non-autonomously to the pathfinding defect. Annotating ptc as involved_in axon guidance therefore over-reads a real phenotype: Patched does none of the work of guiding a growth cone, and the mutant axons even ignore the Slit/Robo cues that do. The annotation is not removed, since the genetic requirement is real and the curator read the full text, but it should not be treated as a guidance function. Supporting Evidence: PMID:15754211 Our results show that guidance defects of this tract are due to loss and mis-specification of vMP2, which results in the projection from pCC to either stall or project outward near the location of vMP2. PMID:15754211 These results provide insight into how mis-specification and loss of neurons can non-autonomously contribute to defects in axon pathfinding. |
| GO:0007455 eye-antennal disc morphogenesis | IMP PMID:11934850 A positive role for patched-smoothened signaling in promotin... | KEEP AS NON CORE | Summary: Loss of ptc activity perturbs cell proliferation in the eye-antennal disc and produces adult head capsule defects. The authors interpret this as a non-canonical, positive Patched-Smoothened route acting through the Activin type I receptor Baboon rather than as simple derepression. Reason: A genuine tissue-level requirement for ptc, retained as non-core because it is a developmental outcome rather than a molecular activity. The proposed positive Ptc-Smo-Babo mechanism is a minority interpretation that has not been widely corroborated, so the annotation is kept on the strength of the loss-of-function phenotype rather than on that model. Supporting Evidence: PMID:11934850 We show that Ptc regulates Drosophila head development by promoting cell proliferation in the eye-antennal disc. PMID:11934850 Thus, loss of Ptc or Smoothened activity affects cell proliferation in the eye-antennal disc and results in adult head capsule defects. |
| GO:0007476 imaginal disc-derived wing morphogenesis | IMP PMID:16648592 Epidermal growth factor receptor and transforming growth fac... | KEEP AS NON CORE | Summary: A quantitative genetics study in which ptc was one of 43 loci whose heterozygous insertional mutations were scored by geometric morphometrics for effects on adult wing shape. Reason: The term is correct for ptc on independent grounds - Patched sets the width of the Hedgehog response domain that patterns the wing - but the cited evidence is weak for it, being a subtle shape effect of a heterozygous insertion in a screen of pathway loci rather than an analysis of ptc function. Kept as a non-core developmental outcome and flagged in the reference review. Supporting Evidence: PMID:16648592 In this study 50 insertional mutations, representing 43 loci in the RTK, Hedgehog, TGF-beta pathways, and their genetically interacting factors were used to study the role of these networks on wing shape. |
| GO:0008158 hedgehog receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assertion that Hedgehog receptor activity arose at the ancestral Patched node, with Drosophila ptc, mouse Ptch1 and Ptch2, human PTCH1 and a zebrafish member as descendant evidence. Reason: The node placement is exactly right: Patched is the ligand-binding, signal-gating component of Hedgehog reception in every lineage that has the pathway, and Drosophila ptc has its own experimental annotation to the same term. ptc appearing in its own WITH/FROM list marks that experimental grounding exists on the target itself and is expected rather than circular. This is the core molecular function carried forward. Supporting Evidence: PMID:8898207 Here, we present evidence that implicates another multiple-pass transmembrane protein, Patched (Ptc), in Hh reception file:DROME/ptc/ptc-uniprot.txt Segmentation polarity protein, which inhibits the smoothened |
| GO:0008158 hedgehog receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping from IPR004766 (Patched transmembrane receptor) to Hedgehog receptor activity. Reason: The signature is specific to the Patched receptor family rather than to the broader sterol-sensing or RND folds, so the mapping is appropriately narrow and agrees with the experimental and phylogenetic annotations of the same term. Supporting Evidence: file:DROME/ptc/ptc-uniprot.txt InterPro; IPR004766; TM_rcpt_patched |
| GO:0008158 hedgehog receptor activity | IMP PMID:8898207 Dual roles for patched in sequestering and transducing Hedge... | ACCEPT | Summary: Genetic dissection showing that Patched is required for Hedgehog reception and transduction, and separately that Hedgehog-induced Patched sequesters free ligand and limits its range - the two roles that define Patched as the receptor. Reason: This is the foundational fly evidence for the term and remains uncontested. Later work sharpened rather than overturned it: Ihog and Boi are required for high-affinity binding and transduction (PMID:20048000), but Patched alone still retains and sequesters ligand (PMID:25231763), so the receptor activity is properly annotated to ptc. Supporting Evidence: PMID:8898207 Here, we present evidence that implicates another multiple-pass transmembrane protein, Patched (Ptc), in Hh reception and suggests a novel signal transduction mechanism in which Hh binds to Ptc, or a Ptc-Smo complex, and thereby induces Smo activity. PMID:25231763 cells expressing Ptc can retain and sequester the Hh ligand without Ihog and Boi, but that Ihog and Boi cannot do so without Ptc |
| GO:0008406 gonad development | IMP PMID:21377458 A genetic screen for mutations affecting gonad formation in ... | KEEP AS NON CORE | Summary: ptc was recovered in a mutagenesis screen for embryonic gonad formation defects, in the compaction class (group com4): mutant gonads complete somatic gonadal precursor cluster fusion but fail to condense into the normal round shape. Reason: A real loss-of-function requirement, retained as a peripheral developmental role. The screen assigns ptc to a phenotypic class without defining a gonad-specific activity, and the straightforward reading is derepressed Hedgehog signalling in the somatic gonad, so this is not a core function. Supporting Evidence: PMID:21377458 These gonads had completed SGP cluster fusion, but failed to condense completely into the round shape characteristic of the mature embryonic gonad. PMID:21377458 we performed a mutagenesis screen in Drosophila and identified twenty-four genes required for gonadogenesis |
| GO:0009925 basal plasma membrane | IDA PMID:28825565 Cytoneme-mediated cell-cell contacts for Hedgehog reception. | ACCEPT | Summary: Extracellular staining places Patched, together with bound Hedgehog, on the basal surface of the wing disc epithelium and on cytonemes projecting from Hedgehog-receiving cells, where reception occurs at contact sites with cytonemes from Hedgehog-sending cells. Reason: A well-supported refinement of the plasma membrane annotation that identifies the specific membrane domain at which reception happens. Accepted and carried into core_functions alongside the general plasma membrane term. Supporting Evidence: PMID:28825565 Extracellular staining of Ptc and Hh confirms this basal localization of Hh-Ptc complex for signal reception PMID:28825565 The canonical Hh receptor Patched is localized in these cellular protrusions and Hh reception takes place in membrane contact sites between Hh-sending and Hh-receiving cytonemes. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping recording that the Patched receptor signature denotes an integral membrane protein. UniProt annotates twelve transmembrane helices for ptc. Reason: Correct though uninformatively general, being a parent of the plasma membrane, ciliary membrane and basal plasma membrane terms the same gene carries from direct evidence. Accepted rather than modified because the more specific terms already exist in the record, so a replacement would simply duplicate them. Supporting Evidence: file:DROME/ptc/ptc-uniprot.txt Multi-pass membrane protein |
| GO:0016192 vesicle-mediated transport | IEA GO_REF:0000108 | MODIFY | Summary: Inter-ontology inference from the lipoprotein particle receptor activity annotation, whose definition includes delivery of the particle into the cell by endocytosis. Reason: The inference is logically sound but lands on a term general enough to be uninformative. The underlying data are specifically receptor-mediated: Patched internalises lipophorin into early endocytic vesicles that label with the AP-2 clathrin adaptor, and it internalises Hedgehog by the same route, so GO:0006898 receptor-mediated endocytosis is the accurate level. Proposed replacements: receptor-mediated endocytosis Supporting Evidence: PMID:18198278 Ptc actively internalizes Lp into the endocytic compartment in a Hh-independent manner and physically interacts with Lp. PMID:18198278 We found a high percentage of colocalization of Hh, Ptc and ApoLs in early endocytic vesicles |
| GO:0030139 endocytic vesicle | IDA PMID:18198278 Patched, the receptor of Hedgehog, is a lipoprotein receptor... | ACCEPT | Summary: Patched colocalises with Hedgehog and with apolipophorins in early endocytic vesicles marked by the AP-2 adaptor, and subsequently with the late endosomal markers Hrs and Rab7. Reason: Directly observed, and consistent with the established Hedgehog-induced internalisation and lysosomal degradation of Patched reported independently (PMID:26446620, PMID:24302888). The endocytic compartment is a functionally meaningful location for ptc, since receptor removal is how ligand relieves the brake. Supporting Evidence: PMID:18198278 We found a high percentage of colocalization of Hh, Ptc and ApoLs in early endocytic vesicles PMID:18198278 We also observed a colocalization of Ptc and ApoLs with the late endosomes markers Hrs |
| GO:0030228 lipoprotein particle receptor activity | IDA PMID:18198278 Patched, the receptor of Hedgehog, is a lipoprotein receptor... | KEEP AS NON CORE | Summary: Patched actively internalises Drosophila lipophorin particles into the endocytic compartment and physically interacts with apolipophorin I, in a manner independent of Hedgehog and separable from its signalling role. Reason: The direct evidence is good - internalisation assays plus co-immunoprecipitation of ApoLI with Ptc - so the activity is real. It is marked non-core rather than accepted as a core function because the same study shows it is dissociable from Hedgehog signalling in both directions: the sterol-sensing-domain mutant that cannot repress Smoothened still internalises lipophorin, while Ptc14, which regulates Smoothened normally, does not. Much of the demonstration also relies on ectopic Patched. It is a second, Hedgehog-independent activity of the protein, not the evolved core. Supporting Evidence: PMID:18198278 Ptc actively internalizes Lp into the endocytic compartment in a Hh-independent manner and physically interacts with Lp. PMID:18198278 ApoLI protein was immunoprecipitated by Ptc in salivary glands overexpressing Ptc-GFP PMID:18198278 These data indicate that internalization of Lp is not absolutely required for normal Smo modulation |
| GO:0030707 follicle cell of egg chamber development | IMP PMID:29093440 Quantitative microscopy of the Drosophila ovary shows multip... | KEEP AS NON CORE | Summary: Follicle stem cell clones lacking ptc have hyperactive Hedgehog signalling and produce supernumerary, incompletely differentiated stalk cells that remain associated with the poles and continue to proliferate, showing that ptc sets the timing of the follicle-cell proliferation-to-differentiation transition. Reason: A well-supported tissue-level requirement demonstrated with ptc mutant clones, retained as a non-core developmental role. The mechanism is loss of the brake on Hedgehog signalling in the follicle lineage rather than any oogenesis-specific activity of Patched. Supporting Evidence: PMID:29093440 Hh signalling delayed differentiation of all follicle cell types PMID:29093440 Hh signalling independently controls the proliferation to differentiation transition. |
| GO:0035225 determination of genital disc primordium | IMP PMID:15893978 Allocation and specification of the genital disc precursor c... | KEEP AS NON CORE | Summary: ptc is one of the segment polarity genes required for proper allocation of the 22-cell genital disc precursor cluster along the anterior-posterior axis of the embryonic tail segments. Reason: A genuine embryonic patterning requirement, retained as non-core. It is the expected consequence of ptc's role in segment polarity - the same Hedgehog-reception function acting in another primordium - rather than a distinct activity. Supporting Evidence: PMID:15893978 Along the anterior-posterior axis, several segment polarity genes (wingless, engrailed, hedgehog, and patched) are required for the proper allocation of the GDPCs. |
| GO:0035332 positive regulation of hippo signaling | IMP PMID:28667262 The Hippo pathway acts downstream of the Hedgehog signaling ... | KEEP AS NON CORE | Summary: In ptc mutant follicle cell clones both the total and the nuclear level of Yorkie rise, and ptc yki double-mutant follicle stem cells are lost, placing Hedgehog signalling upstream of the Hippo pathway in follicle stem cell maintenance. Wild-type ptc therefore keeps Hippo signalling on by keeping Yorkie down. Reason: Directionally correct and experimentally supported, but entirely indirect: Patched acts on the Hippo pathway only by restraining Smoothened, and the authors place Hedgehog upstream of Hippo rather than assigning Patched any role in the Hippo kinase cassette. Kept as a non-core regulatory consequence. Supporting Evidence: PMID:28667262 Both the level and nuclear distribution of Yki were increased in ptc mutant clones. PMID:28667262 we demonstrate that the Hedgehog pathway acts upstream of the Hippo pathway in regulating FSC maintenance |
| GO:0042981 regulation of apoptotic process | IGI PMID:23018595 Non-cell autonomous control of apoptosis by ligand-independe... | MARK AS OVER ANNOTATED | Summary: Cells with ligand-independent Hedgehog signalling caused by loss of ptc do not protect themselves from apoptosis; instead they raise Diap-1 in neighbouring wild-type cells through Hedgehog-induced Notch signalling, conferring resistance to hid-induced death. Reason: The genetic interaction with hid is real, but the paper states explicitly that the survival effect is non-cell-autonomous and is a property of the deregulated neighbours rather than of the ptc mutant cells, and it is observed in a pathological gain-of-signalling condition rather than in normal development. Annotating ptc as involved_in regulation of apoptotic process reads a generic process term onto an indirect, two-steps-removed consequence. Not removed, since the experiment is sound and the curator read the full text. Supporting Evidence: PMID:23018595 Surprisingly, cells with deregulated Hh activity do not protect themselves from apoptosis; instead, they promote cell survival of neighboring wild-type cells. PMID:23018595 This non-cell autonomous effect is mediated by Hh-induced Notch signaling, which elevates the protein levels of Drosophila inhibitor of apoptosis protein-1 (Diap-1), conferring resistance to apoptosis. |
| GO:0045169 fusome | IDA PMID:8898240 The role of segment polarity genes during early oogenesis in... | UNDECIDED | Summary: A colocalizes_with annotation placing Patched staining at the fusome, the spectrin-rich germline organelle of the germarium, from the same early-oogenesis study that supports the plasma membrane annotation. Reason: Cannot be adjudicated from what is available. The cached record is abstract-only and says nothing about fusome staining; the abstract describes ptc as expressed in the somatic cells of the germarium, whereas the fusome is a germline structure, so the two statements sit awkwardly together. The annotation is nevertheless a weak colocalizes_with claim made by a FlyBase curator who saw the images, and the standing rule is not to overrule an experimental annotation on the strength of an abstract. Marked UNDECIDED and deliberately excluded from core_functions; full text would settle it. Supporting Evidence: PMID:8898240 patched (ptc) and cubitus interruptus (ci) are expressed in somatic cells throughout the germarium and in developing egg chambers |
| GO:0045879 negative regulation of smoothened signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assertion that restraint of Smoothened signalling in the unliganded state is the ancestral role of the Patched family, seeded by fly, mouse, human and zebrafish members. Reason: The node placement matches the biology in every lineage examined and is the single best-established fact about ptc. Drosophila ptc appears among the descendant evidences because it carries its own experimental annotations for the term, which is expected and not circular. This is the core biological process. Supporting Evidence: file:DROME/ptc/ptc-uniprot.txt Segmentation polarity protein, which inhibits the smoothened PMID:10966113 Here we present evidence that Patched destabilizes Smoothened in the absence of Hedgehog. |
| GO:0045879 negative regulation of smoothened signaling pathway | IDA PMID:10966113 Hedgehog induces opposite changes in turnover and subcellula... | ACCEPT | Summary: Direct demonstration that Patched destabilises Smoothened in the absence of Hedgehog, and that removing Patched by RNA interference reproduces the effects of Hedgehog on Smoothened phosphorylation, stability and surface accumulation. Reason: Among the strongest direct evidence for the term in any organism, and it is the experiment that established the reciprocal Patched-Smoothened trafficking logic. The same paper's conclusion that the restraint is indirect informs how the molecular function is framed in this review, but does not weaken the process annotation. Supporting Evidence: PMID:10966113 Here we present evidence that Patched destabilizes Smoothened in the absence of Hedgehog. PMID:10966113 Comparable effects can be produced by removing Patched from cells by RNA-mediated interference. |
| GO:0045879 negative regulation of smoothened signaling pathway | IDA PMID:14636583 Hedgehog signal transduction via Smoothened association with... | ACCEPT | Summary: Study of the Costal-2-scaffolded cytoplasmic Hedgehog signalling complex that Smoothened engages, which constitutively suppresses pathway activity until Hedgehog reverses its effect. The ptc annotation records Patched's position as the upstream repressor in this scheme. Reason: The cached record is abstract-only and foregrounds Smoothened and Costal-2, so the ptc-specific panel cannot be inspected here; the FlyBase curator read the full text and the asserted function is the one fact about ptc that is beyond dispute, so the annotation is accepted and the curator deferred to rather than second-guessed. Supporting Evidence: PMID:14636583 This complex constitutively suppresses pathway activity, but Hh signaling reverses its regulatory effect to promote Ci-mediated transcription. PMID:10966113 Here we present evidence that Patched destabilizes Smoothened in the absence of Hedgehog. |
| GO:0045879 negative regulation of smoothened signaling pathway | IDA PMID:30541874 Protein association changes in the Hedgehog signaling comple... | ACCEPT | Summary: Analysis of how graded Smoothened activation is converted into graded pathway output through changes in Fused and Costal-2 association within the Hedgehog signalling complex, with Patched as the upstream repressor whose relief sets the input level. Reason: Abstract-only in the cache, and the abstract is framed around Smo, Gprk2 and Fused; the annotation is nonetheless to the function of ptc that the whole experimental system depends on, so it is accepted and the curator's full-text reading deferred to rather than overruled. Supporting Evidence: PMID:30541874 In Drosophila, the Hh signal is transduced from the G protein-coupled receptor Smoothened (Smo) to the cytoplasmic Hh signaling complex (HSC). PMID:10966113 Here we present evidence that Patched destabilizes Smoothened in the absence of Hedgehog. |
| GO:0045879 negative regulation of smoothened signaling pathway | IGI PMID:1653906 Role of the Drosophila patched gene in positional signalling... | ACCEPT | Summary: The original genetic demonstration that ptc acts permissively to repress wingless transcription and that hedgehog (FB:FBgn0004644) antagonises that repression, from which the authors proposed that Patched is itself the Hedgehog receptor and that the ligand acts by inactivating it. Reason: This is the founding evidence for ptc as the pathway's brake and for ligand-dependent relief of that brake. Everything since has refined the mechanism without disturbing the genetic conclusion. Supporting Evidence: PMID:1653906 Here we show that the role of patched in positional signalling is permissive rather than instructive, its activity being required to suppress wingless transcription in cells predisposed to express the latter. PMID:1653906 We suggest that the patched protein may itself be the receptor for this signal, implying that this is an unusual mechanism of ligand-dependent receptor inactivation. |
| GO:0045879 negative regulation of smoothened signaling pathway | IGI PMID:24302888 Activation of Smurf E3 ligase promoted by smoothened regulat... | ACCEPT | Summary: Smurf (FB:FBgn0029006) ubiquitinates Patched at K1261 in a Smoothened-dependent manner, driving Patched turnover; the genetic interaction defines a feedback loop in which relief of Patched repression is amplified by Patched degradation. Reason: Directly on point for the term, and mechanistically informative: the existence of a dedicated degradation route whose loss raises Patched levels and lowers signalling confirms that Patched abundance is the variable that sets pathway output. UniProt records the K1261 isopeptide bond from this work. Supporting Evidence: PMID:24302888 Here we identified a novel role of Smurf E3 ligase in regulating Hedgehog signaling by controlling Patched ubiquitination and turnover. PMID:24302888 we found that Smo interacts with Smurf and promotes it to mediate Patched ubiquitination by targeting the K1261 site in Ptc |
| GO:0045879 negative regulation of smoothened signaling pathway | IGI PMID:25231763 Ihog and Boi elicit Hh signaling via Ptc but do not aid Ptc ... | ACCEPT | Summary: Epistasis with ihog (FB:FBgn0031872) and boi (FB:FBgn0040388) placing the co-receptors upstream of or at the level of Patched, and showing that they are required for pathway activation precisely because they let Hedgehog inhibit Patched and relieve its repression of Smoothened. Patched alone retains and sequesters ligand without them. Reason: A clean genetic demonstration that the repression being relieved is Patched's, which is exactly what the term asserts. It also settles that Patched, not the co-receptors, is the ligand sink. Supporting Evidence: PMID:25231763 they are essential for pathway activation because they allow Hh to inhibit Ptc and thereby relieve its repression of Smo PMID:25231763 cells expressing Ptc can retain and sequester the Hh ligand without Ihog and Boi, but that Ihog and Boi cannot do so without Ptc |
| GO:0045879 negative regulation of smoothened signaling pathway | IGI PMID:8898240 The role of segment polarity genes during early oogenesis in... | ACCEPT | Summary: In the germarium, ectopic hedgehog (FB:FBgn0004644) causes somatic cell overproliferation accompanied by elevated ptc, and ptc mutant somatic clones phenocopy it, leading the authors to conclude that Hedgehog acts by antagonising the negative effect of ptc on Ci activity. Reason: A clear genetic interaction supporting the term in an adult tissue, and an early demonstration of the feedback in which ptc is itself a Hedgehog target gene. Supporting Evidence: PMID:8898240 the somatic cell overproliferation caused by ectopic hh expression is accompanied by elevated levels of ptc and is phenocopied in ptc- somatic clones PMID:8898240 regulates the proliferation of nearby ovarian somatic cells by antagonizing the negative effects of ptc on ci activity in these cells |
| GO:0045879 negative regulation of smoothened signaling pathway | IGI PMID:9874371 Hedgehog stimulates maturation of Cubitus interruptus into a... | ACCEPT | Summary: Genetic interaction with Suppressor of fused (FB:FBgn0005355) in the pathway that converts Ci-155 into a labile nuclear activator, the transcriptional output that Patched repression keeps switched off. Reason: The cached record is abstract-only and centres on Fused and Su(fu); the ptc-specific data are in the full text the curator read. The asserted function is correct for ptc and the annotation is accepted rather than second-guessed. It adds the downstream endpoint - Ci activation - against which Patched repression is measured. Supporting Evidence: PMID:9874371 We propose that Fu kinase activity is required for Hh to stimulate the maturation of Ci-155 into a short-lived nuclear transcriptional activator and that Su(fu) opposes this maturation step through a stoichiometric interaction with Ci-155. |
| GO:0045879 negative regulation of smoothened signaling pathway | IMP PMID:14523402 Stability and association of Smoothened, Costal2 and Fused w... | ACCEPT | Summary: Hedgehog-dependent stabilisation of Smoothened at the plasma membrane, with consequent destabilisation of Costal-2 and Fused and release of Ci from the complex; ptc perturbation is the means by which the Hedgehog-off and Hedgehog-on states are compared. Reason: Abstract-only in the cache and written around Smo, Cos2, Fu and Ci, but the ptc annotation records the upstream repression whose removal produces every effect described. Accepted on the curator's full-text reading, consistent with the directly demonstrated Patched-dependent destabilisation of Smoothened (PMID:10966113). Supporting Evidence: PMID:14523402 Stabilization of the integral membrane protein Smoothened (Smo) at the plasma membrane is a crucial step in Hh signalling PMID:10966113 Here we present evidence that Patched destabilizes Smoothened in the absence of Hedgehog. |
| GO:0045879 negative regulation of smoothened signaling pathway | IMP PMID:15592457 Drosophila Smoothened phosphorylation sites essential for He... | ACCEPT | Summary: Identification of the PKA and PKA-primed CK1 phosphorylation cluster in the Smoothened cytoplasmic tail that is required for transduction and for normal control of Smoothened levels - the modification state that Patched keeps suppressed in the absence of ligand. Reason: Abstract-only in the cache; the ptc genotypes are in the full text. The annotation asserts the well-established repression of Smoothened by Patched and is accepted. It also supplies the molecular readout, Smoothened hyperphosphorylation, by which relief of that repression is scored. Supporting Evidence: PMID:15592457 All Hh responses require the seven transmembrane domain protein Smoothened, which itself becomes hyperphosphorylated during Hh signalling. PMID:10966113 In contrast, Hedgehog causes phosphorylation, stabilization, and accumulation of Smoothened at the cell surface. |
| GO:0045879 negative regulation of smoothened signaling pathway | IMP PMID:20435030 Dynamic phosphorylation of the kinesin Costal-2 in vivo reve... | ACCEPT | Summary: Use of a phospho-Costal-2 antibody as an in situ readout of Hedgehog transduction, which visualises the gradient of signalling activity; ptc manipulation defines the repressed baseline against which that gradient is read. Reason: Abstract-only in the cache and centred on Fused and Costal-2. The ptc annotation states the uncontested upstream repression and is accepted on the curator's full-text reading. The quantitative readout the paper introduces is what makes Patched-dependent graded repression visible in vivo. Supporting Evidence: PMID:20435030 For the first time, this tool allows the visualisation of a gradient of signalling activity and therefore the range of the activating Hh ligand in different tissues. PMID:8898207 Our results also show that Ptc limits the range of Hh action |
| GO:0045879 negative regulation of smoothened signaling pathway | IMP PMID:22306085 Distinct phosphorylations on kinesin costal-2 mediate differ... | ACCEPT | Summary: Low and high Smoothened activation states drive phosphorylation of Costal-2 on two distinct serines and relocate it to the plasma membrane, producing differential signalling strength within the gradient field that Patched shapes. Reason: Abstract-only in the cache; the ptc genotypes are in the full text. The annotation records the repression that sets the low end of the graded response and is accepted. The graded behaviour the paper describes only exists because Patched holds Smoothened off at low ligand. Supporting Evidence: PMID:22306085 The graded Hedgehog (Hh) signal is transduced by the transmembrane Smoothened (Smo) proteins in both vertebrates and invertebrates. PMID:8898207 Our results also show that Ptc limits the range of Hh action |
| GO:0045879 negative regulation of smoothened signaling pathway | IMP PMID:26446620 Control of the dynamics and homeostasis of the Drosophila He... | ACCEPT | Summary: Dissection of Patched trafficking and homeostasis by the C2-WW-HECT E3 ligases NEDD4 and SU(DX): mutating the Patched PY motif blocks internalisation without abolishing its autonomous and non-autonomous signalling activities, and the two ligases tune Patched accumulation. Reason: Directly about ptc and directly about the term: the study manipulates Patched levels and scores the consequences for pathway repression and gradient formation. It also shows that internalisation and repression are separable, which is a useful constraint on mechanism. Supporting Evidence: PMID:26446620 In Drosophila, the HH co-receptor Patched (PTC) controls both HH gradient formation and signalling. PMID:26446620 We demonstrate that mutation of the PTC PY motif, which mediates binding of C2-WW-HECT family members, inhibits its internalization but not its autonomous and non-autonomous signalling activities. |
| GO:0045879 negative regulation of smoothened signaling pathway | IMP PMID:35573695 Dissection of the microRNA Network Regulating Hedgehog Signa... | ACCEPT | Summary: In the wing imaginal disc, knockdown of ptc raises Smoothened protein in anterior cells next to the A-P boundary and expands the labile Ci activator domain and Collier expression - the standard in vivo signature of losing the Patched brake. Reason: Clear loss-of-function evidence for the term, generated as part of building miRNA sensors for the core pathway components. Both readouts, Smoothened accumulation and expansion of Ci-dependent target expression, are direct consequences of derepressed Smoothened signalling. Supporting Evidence: PMID:35573695 Knockdown of either ptc or ci resulted in a similar increase in Smo protein levels in the cells of the anterior compartment adjacent to the A-P boundary PMID:35573695 knockdown of ptc resulted in expansion of the labile CiA region as well as expansion and elevation of Col expression in dorsal compartment cells |
| GO:0045879 negative regulation of smoothened signaling pathway | IMP PMID:8898207 Dual roles for patched in sequestering and transducing Hedge... | ACCEPT | Summary: Genetic separation of Patched's two jobs: transducing the Hedgehog signal by permitting Smoothened activity when ligand is bound, and sequestering free ligand when Patched is induced to high levels. Reason: Together with PMID:1653906 this is the foundational evidence that ptc is the pathway's negative regulator, and it additionally establishes the feedback by which Hedgehog-induced Patched limits the range of the signal. Supporting Evidence: PMID:8898207 Here, we present evidence that implicates another multiple-pass transmembrane protein, Patched (Ptc), in Hh reception and suggests a novel signal transduction mechanism in which Hh binds to Ptc, or a Ptc-Smo complex, and thereby induces Smo activity. PMID:8898207 we provide evidence that high levels of Ptc induced by Hh serve to sequester any free Hh and therefore create a barrier to its further movement |
| GO:0048099 anterior/posterior lineage restriction, imaginal disc | TAS PMID:10625531 Subdividing cell populations in the developing limbs of Dros... | KEEP AS NON CORE | Summary: Traceable author statement attributing to ptc a role in maintaining the anterior/posterior lineage boundary of imaginal discs, cited to a review-style article on subdivision of the developing limb. Reason: The underlying biology is sound and independently supported: maintenance of the A-P affinity boundary in the wing depends on Hedgehog pathway activation in anterior cells adjacent to the boundary, which is the response Patched gates. It is kept as non-core because it is a tissue-level outcome rather than an activity of the protein, and because the citation itself cannot be checked - the cached record for PMID:10625531 contains no abstract text at all, which is recorded in the reference review. Supporting Evidence: PMID:25231763 In the Drosophila developing wing model we found that it is through Hh pathway activation that Ihog and Boi maintain the boundary between the anterior and posterior compartments. |
| GO:0048100 wing disc anterior/posterior pattern formation | TAS PMID:11253649 Sticking together and sorting things out: adhesion as a forc... | KEEP AS NON CORE | Summary: Traceable author statement assigning ptc a role in anterior/posterior patterning of the wing disc, cited to a general review about adhesion as a force in development. Reason: The term is right for ptc on independent grounds - Hedgehog-induced Patched sets how far the response to Hedgehog extends into the anterior compartment, which is what patterns the A-P axis of the wing disc - so the annotation is retained, as a developmental outcome rather than a core function. The citation is poor: the article is a review of differential adhesion and cell sorting, not a source for ptc function, and this is recorded in the reference review. Supporting Evidence: PMID:8898207 Our results also show that Ptc limits the range of Hh action PMID:11253649 recent work on the Drosophila wing and the vertebrate brain has shown that signalling between tissues is essential for the establishment of differential affinities |
| GO:0055088 lipid homeostasis | IMP PMID:18198278 Patched, the receptor of Hedgehog, is a lipoprotein receptor... | KEEP AS NON CORE | Summary: Patched lowers the intracellular lipid droplet content of wing disc cells: droplets are down-regulated at the compartment borders where Patched is high, ectopic Patched clones deplete them, and ptc mutant clones fail to show the down-regulation. The authors conclude this is separable from Hedgehog signal transduction. Reason: Supported by a genuine loss-of-function control rather than by overexpression alone, so the annotation stands. It is non-core because the effect is explicitly uncoupled from the Hedgehog pathway by the authors and follows from the lipoprotein internalisation activity rather than from the receptor function that defines the family. Supporting Evidence: PMID:18198278 in ptc 16 mutant clones, which do not produce Ptc protein at the A/P compartment border, we were unable to observe a down-regulation of lipid droplets PMID:18198278 Finally, we show that Ptc modulates intracellular lipid homeostasis independently of its role in the regulation of the Hh pathway. |
| GO:0060170 ciliary membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Automatic mapping from the UniProt subcellular location Cell projection, cilium membrane, curated from the experimental work on the ciliary Hedgehog pathway of Drosophila olfactory sensory neurons. Reason: More precise than the companion cilium annotation and derived from an experimentally supported curated statement rather than a prediction. As with GO:0005929, it applies to a small minority of Drosophila cell types. Supporting Evidence: file:DROME/ptc/ptc-uniprot.txt Cell projection, cilium PMID:24768000 Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. |
| GO:0070273 phosphatidylinositol-4-phosphate binding | IDA PMID:26863604 PI(4)P Promotes Phosphorylation and Conformational Change of... | ACCEPT | Summary: Patched binds PI(4)P through its sterol-sensing domain: wild-type Patched and the isolated SSD bind PI(4)P beads and liposomes while a Patched lacking the SSD does not, loss of Patched raises PI(4)P levels in the wing disc, and Hedgehog treatment reduces the Patched-PI(4)P interaction while increasing the Smoothened-PI(4)P interaction. Reason: Direct, well-controlled lipid-binding evidence with a domain-deletion negative control, and it is mechanistically load-bearing: the model that emerges is Patched sequestering a Smoothened-activating phosphoinositide in the absence of ligand. This is one of the two lipid-binding activities the fly record actually supports, and it is carried into core_functions. Supporting Evidence: PMID:26863604 PtcWT and HA-SSD strongly bound PI(4)P, whereas HA-PtcΞSSD did not bind PMID:26863604 Hh treatment increases the interaction between Smo and PI(4)P but decreases the interaction between Ptc and PI(4)P PMID:26863604 We found that mutation of ptc or knockdown of Ptc by RNAi increased PI(4)P levels in the wing disc |
| GO:0070300 phosphatidic acid binding | IDA PMID:37847757 Phosphatidic acid binding to Patched contributes to the inhi... | ACCEPT | Summary: The Patched C-terminal cytoplasmic tail binds phosphatidic acid directly in solid-phase and liposome assays through four arginine/lysine motifs; Hedgehog reduces the association, and deleting the tail or mutating the PA-binding motifs prevents Patched from inhibiting Smoothened in wing discs and in cultured cells. Reason: Strong direct binding evidence backed by a structure-function series in which the binding-site mutants lose the ability to repress Smoothened, which ties the lipid interaction to the protein's defining activity. Carried into core_functions as the second experimentally grounded lipid-binding activity of fly Patched. Supporting Evidence: PMID:37847757 The C-terminal tail of Ptc directly interacted with PA in vitro, an association that was reduced by Hh, and increased the amount of PA at the plasma membrane in cultured cells. PMID:37847757 Deleting the Ptc C-terminal tail or mutating the predicted PA-binding sites within it prevented Ptc from inhibiting Smo in wing discs and in cultured cells. PMID:37847757 Our findings suggest that Ptc may sequester PA in the absence of Hh and release it in the presence of Hh, thereby increasing the amount of PA that is locally available to promote Smo activation. |
| GO:0097108 hedgehog family protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assertion that ligand binding is an ancestral property of the Patched family, with Drosophila ptc and human PTCH1 and PTCH2 among the descendant evidences. Reason: Well placed. The fly-specific evidence is the genetic and cell-binding demonstration that Patched retains and sequesters Hedgehog, which it can do without the Ihog and Boi co-receptors, so ligand binding is properly an activity of Patched itself. ptc appearing in its own WITH/FROM list reflects its own experimental annotations and is expected. Supporting Evidence: PMID:25231763 cells expressing Ptc can retain and sequester the Hh ligand without Ihog and Boi, but that Ihog and Boi cannot do so without Ptc PMID:25231763 Together, these results reinforce the central role for Ptc in Hh binding in vivo |
| GO:0097108 hedgehog family protein binding | IDA PMID:16630821 The ihog cell-surface proteins bind Hedgehog and mediate pat... | ACCEPT | Summary: Cell-surface Hedgehog binding assays in which Ihog enhances binding of Hedgehog to cells co-expressing Patched, using the second fibronectin-III domain of Ihog. Reason: The cached record is abstract-only and the abstract is written around Ihog, so the Patched panels cannot be inspected here; the FlyBase curator read the full text and the claim that Patched binds Hedgehog is independently established (PMID:25231763). Accepted rather than downgraded. Supporting Evidence: PMID:16630821 the second FNIII domain is additionally required for in vivo signaling activity and for Ihog-enhanced binding of Hh protein to cells coexpressing Ptc PMID:25231763 Together, these results reinforce the central role for Ptc in Hh binding in vivo |
| GO:0097108 hedgehog family protein binding | IPI PMID:20048000 Genetic and biochemical definition of the Hedgehog receptor. | ACCEPT | Summary: Biochemical definition of the Drosophila Hedgehog receptor, showing that Patched and Ihog are both required for high-affinity binding of Hedgehog (FB:FBgn0004644) and that the three form a multimolecular complex. Reason: Accepted with the caveat that this paper found no physical evidence for Hedgehog binding to solubilised Patched alone, so on its own it supports a complex-level rather than an isolated binding claim. Later genetics resolved this in Patched's favour by showing that Patched-expressing cells retain and sequester ligand without Ihog or Boi (PMID:25231763), so annotating the binding to ptc is correct. Supporting Evidence: PMID:20048000 We demonstrate that Ihog interacts directly with Ptc, is required for presentation of Ptc on the cell surface, and that Ihog and Ptc are both required for high-affinity Hh binding. PMID:20048000 we observed that immobilized HhN fails to precipitate detergent-solubilized Ptc alone, but does so in the presence of detergent-solubilized Ihog PMID:25231763 cells expressing Ptc can retain and sequester the Hh ligand without Ihog and Boi, but that Ihog and Boi cannot do so without Ptc |
| GO:2000274 regulation of epithelial cell migration, open tracheal system | IMP PMID:24651658 Hedgehog is a positive regulator of FGF signalling during em... | KEEP AS NON CORE | Summary: ptc mutants were used to overactivate Hedgehog signalling in the embryo, which raises Branchless or FGF levels via the transcription factor Stripe and alters migration of the tracheal ganglionic branches. The authors state the effect on migration is non-autonomous, exerted from the surrounding tissues. Reason: Retained because loss of ptc does change tracheal migration and the underlying logic - ptc restrains Hedgehog signalling, which permissively sets bnl expression - is coherent. It is non-core and deliberately not promoted further: Patched performs none of the work of cell migration, the effect runs through at least two intermediate steps, and the paper is framed as a study of Hedgehog rather than of ptc. Supporting Evidence: PMID:24651658 By studying the cellular consequences of overactivated Hh signalling, using ptc mutants, we found that Hh positively regulates Bnl/FGF levels during embryonic stages. PMID:24651658 Our results show that Hh modulates cell migration non-autonomously in the tissues surrounding the action of its activity. |
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Download this section (compressed HTML)Q: Does Drosophila Patched move any lipid across or within the membrane, as vertebrate PTCH1 is proposed to do for cholesterol, or is its effect on Smoothened entirely a matter of binding and sequestering PI(4)P and phosphatidic acid in place? No Drosophila transport assay has been reported, and GO:0140303 intramembrane lipid carrier activity is currently asserted for the fly protein only by similarity to human PTCH1.
Q: Are the PI(4)P and phosphatidic acid interactions two readouts of one mechanism or two independent ones? They are localised to different parts of the protein - the sterol-sensing domain and the cytoplasmic tail - and both are reported to be reduced by Hedgehog, so an epistasis or double-mutant analysis would say whether either alone is sufficient.
Q: Does Patched ever contact Smoothened directly in vivo? The stoichiometric argument says the restraint is catalytic and indirect, but Patched and Smoothened do co-fractionate in a large complex; proximity labelling or crosslinking in wing discs would distinguish an incidental co-residence from a functional interaction.
Q: Is the lipophorin receptor activity of Patched ancestral to the family or a Drosophila elaboration, and does it contribute anything to Hedgehog gradient formation beyond the effect on lipid droplets? Its independence from signalling was shown with two separation-of-function alleles, but its normal physiological purpose is unknown.
Q: How much of Drosophila Hedgehog signalling runs through the ciliary route? Patched and Smoothened localise to the ciliary membrane in olfactory sensory neurons, but nearly all other fly cells are non-ciliated; whether the ciliary and cytoplasmic Costal-2 routes use Patched in the same way is untested.
Experiment: Reconstitute purified full-length Patched into proteoliposomes of defined composition and assay for transbilayer or intramembrane movement of cholesterol, PI(4)P and phosphatidic acid, comparing wild type with the sterol-sensing-domain mutant and the PA-motif mutant PtcM124. A binding-only protein will show saturable association with no flux; a carrier will show flux that the separation-of-function mutants lose.
Hypothesis: Drosophila Patched restrains Smoothened by sequestering phosphatidic acid and PI(4)P rather than by catalysing net lipid transport.
Experiment: Build wing-disc rescue lines carrying the sterol-sensing-domain mutation, the PA-motif mutations, and both together in a ptc null background, and score Smoothened accumulation, Ci processing and dpp and ptc reporter expression. Additivity would indicate two mechanisms; epistasis would indicate one.
Hypothesis: The PI(4)P and phosphatidic acid interactions are separable contributions to Smoothened restraint.
Experiment: Apply proximity-dependent biotinylation from tagged Patched in wing discs with and without Hedgehog and compare the labelling of Smoothened with that of known direct partners such as Ihog. A catalytic, indirect mechanism predicts that Smoothened is not preferentially labelled even though it co-fractionates.
Hypothesis: Patched and Smoothened do not contact each other directly in the pathway-off state.
patched (ptc) is a segment polarity gene that encodes a 12-pass transmembrane protein involved in Hh signalling regulation. ptc product contributes to the binding, internalization and degradation of the ligand encoded by hh, limiting its activity spatial range. ptc product also represses the constitutive signaling activity of the transmembrane protein encoded by smo.
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