Smoothened (Smo) is the class-F seven-transmembrane receptor that transduces Hedgehog signalling in Drosophila. In the absence of ligand, Patched (Ptc) keeps Smo inactive and destabilised; Hedgehog binding to Ptc relieves that inhibition and Smo accumulates at the plasma membrane in a progressively activated state. What distinguishes the fly protein from its vertebrate orthologue is an unusually long (~480-residue) C-terminal cytoplasmic tail. Hedgehog drives graded phosphorylation of this tail by protein kinase A, casein kinase 1 and G protein-coupled receptor kinase 2, which neutralises inhibitory arginine clusters, switches the tail from a closed to an open conformation, promotes its dimerisation, and converts it into a docking platform for the kinesin-related scaffold Costal-2 and the Ser/Thr kinase Fused. Recruiting the Costal-2/Fused complex to the membrane activates Fused, blocks proteolytic processing of the transcription factor Cubitus interruptus into its repressor form, and releases the Ci activator. Because this cytoplasmic complex performs the organising role that the primary cilium plays in vertebrates, Hedgehog transduction in fly epithelia such as the imaginal discs proceeds without a cilium; in the ciliated olfactory sensory neurons, however, Smo localises to the sensory cilium and signals from there in an intraflagellar-transport-dependent manner. Smo also behaves as a canonical GPCR, coupling to Galphai to lower cAMP, and its activation state is tuned by membrane lipids: phosphatidylinositol 4-phosphate binds an arginine motif in the C-tail and phosphatidic acid binds a pocket in the transmembrane core. Through these mechanisms Smo governs embryonic segment polarity, anterior/posterior patterning and growth of the imaginal discs, eye and head development, ovarian somatic stem cell maintenance and follicle cell development, and a Hedgehog-dependent arm of the gut epithelial immune response to bacterial uracil.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001745 compound eye morphogenesis | IMP PMID:16651542 Roadkill attenuates Hedgehog responses through degradation o... | KEEP AS NON CORE | Summary: Hedgehog signalling through Smo shapes the developing compound eye; manipulating the Hh-induced Cul3 adaptor Roadkill, which limits Ci levels, disorganises pigment and cone cells. Reason: Retained as non-core. Compound eye morphogenesis is a tissue-level developmental output of Hh/Smo signalling rather than an activity Smo itself performs. The molecular work Smo does here is the same receptor transduction captured by GO:0007224. Supporting Evidence: PMID:16651542 rdx manipulation in the eye revealed a novel role for Hh in the organization and survival of pigment and cone cells |
| 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) fails to form without Hedgehog signalling, which acts with eyes absent and sine oculis to drive atonal expression; notably this branch operates without Fused kinase or Cubitus interruptus. Reason: Retained as non-core. This is a developmental output downstream of Smo-mediated Hh reception, not a molecular function of Smo. The observation that the branch is Fu/Ci-independent is interesting for pathway architecture but does not change Smo's role as the transducer. Supporting Evidence: PMID:10704398 Neither Atonal expression nor Bolwig's organ formation occurred in the absence of hedgehog, eyes absent or sine oculis activity. |
| GO:0002385 mucosal immune response | IMP PMID:25639794 Bacterial uracil modulates Drosophila DUOX-dependent gut imm... | KEEP AS NON CORE | Summary: Bacterial uracil triggers a Hedgehog pathway in the adult gut epithelium that induces Cadherin 99C and Cad99C-dependent signalling endosomes, which are required for DUOX-dependent reactive oxygen species production; smo knockdown abolishes this response and reduces survival after infection. Reason: Retained as non-core. Smo genuinely transduces the Hh signal that initiates this epithelial immune response, and UniProt records it as an experimentally supported function, but the mucosal immune response itself is executed downstream by Cad99C, PLC-beta/PKC/Ca2+ and DUOX. This is a physiological output of Smo signalling rather than Smo's own activity. Supporting Evidence: PMID:25639794 Uracil-induced Hh signaling is required for intestinal expression of the calcium-dependent cell adhesion molecule Cadherin 99C (Cad99C) and subsequent Cad99C-dependent formation of endosomes. file:DROME/smo/smo-uniprot.txt Essential component of a hh-signaling pathway which CC regulates the Duox-dependent gut immune response to bacterial uracil |
| GO:0004888 transmembrane signaling receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: The InterPro-derived transmembrane signalling receptor activity term is directionally right but uninformatively broad: Smo is a class-F G protein-coupled receptor that signals through Galphai. Reason: Modify to GO:0004930 G protein-coupled receptor activity, which is the experimentally established specificity for fly Smo (IDA, PMID:18987629) and matches the action taken on the equivalent row in the human SMO review. Proposed replacements: G protein-coupled receptor activity Supporting Evidence: PMID:18987629 Our results demonstrate that Smo functions as a canonical GPCR, which signals through Galphai to regulate Hh pathway activation. |
| GO:0004930 G protein-coupled receptor activity | IDA PMID:18987629 G protein Galphai functions immediately downstream of Smooth... | ACCEPT | Summary: Drosophila Smo signals as a canonical GPCR: Hh stimulation activates Galphai in a Smo-dependent manner and lowers intracellular cAMP, and Galphai acts downstream of Smo and upstream of Fused and Ci. Reason: Accepted as a core molecular function. The seven-transmembrane architecture was recognised in the original cloning paper and heterotrimeric G protein coupling was demonstrated directly in fly cells and wing discs. Supporting Evidence: PMID:18987629 Our results demonstrate that Smo functions as a canonical GPCR, which signals through Galphai to regulate Hh pathway activation. PMID:18987629 Here we present in vitro and in vivo evidence in Drosophila that Smo activates a G protein to modulate intracellular cyclic AMP levels in response to Hh. PMID:8700230 Sequence analysis of the smoothened transcription unit reveals a single open reading frame encoding a protein with seven putative transmembrane domains. This structure is typical of G-protein-coupled receptors, suggesting that the Smoothened protein may act as a receptor for the Hedgehog ligand. |
| GO:0005113 patched binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Patched is the upstream negative regulator of Smo, and Ptc and Smo are recovered together in a large membrane complex in Drosophila, consistent with the phylogenetic assertion of patched binding at the Smoothened node. Reason: Retained as non-core, matching the human SMO review. The IBA rests on a node placement for which fly and vertebrate Smoothened are both descendants, and the physical association is reported in flies; but Ptc acts largely by controlling Smo's access to activating lipids rather than through a required stable receptor complex, so patched binding is not Smo's principal molecular activity. Supporting Evidence: PMID:17284519 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. PMID:8898207 Hh binds to Ptc, or a Ptc-Smo complex, and thereby induces Smo activity |
| GO:0005515 protein binding | IPI PMID:14597665 Smoothened transduces Hedgehog signal by physically interact... | MODIFY | Summary: The interaction recorded here is between the Smo C-terminal cytoplasmic tail and the kinesin-related scaffold Costal-2, the step that brings the Cos2/Fused/Ci complex to the activated receptor at the membrane. Reason: A bare protein binding annotation carries no functional information, but the cited evidence supports a specific one. Smo's phosphorylated tail recruits the Cos2/Fu complex to the plasma membrane, and deleting the Cos2-binding segment abolishes signalling without abolishing the rest of the receptor, so Smo is acting as the adaptor that couples the receptor to the cytoplasmic signalling complex. Modify to GO:0030674 protein-macromolecule adaptor activity, the molecular function assigned to this step in modules/hedgehog_signaling.yaml. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:14597665 Smo physically interacts with Costal2 (Cos2) and Fused (Fu) through its C-tail. Deletion of the Cos2/Fu-binding domain from Smo abolishes its signaling activity. PMID:21844892 Collectively, our data indicate that, in response to a Hh gradient and Smo activity, the Cos2/Fu complex is recruited to the cell membrane through an interaction between Smo and Cos2. |
| GO:0005515 protein binding | IPI PMID:14597665 Smoothened transduces Hedgehog signal by physically interact... | MODIFY | Summary: The interaction recorded here is between the Smo C-terminal cytoplasmic tail and the kinesin-related scaffold Costal-2, the step that brings the Cos2/Fused/Ci complex to the activated receptor at the membrane. Reason: A bare protein binding annotation carries no functional information, but the cited evidence supports a specific one. Smo's phosphorylated tail recruits the Cos2/Fu complex to the plasma membrane, and deleting the Cos2-binding segment abolishes signalling without abolishing the rest of the receptor, so Smo is acting as the adaptor that couples the receptor to the cytoplasmic signalling complex. Modify to GO:0030674 protein-macromolecule adaptor activity, the molecular function assigned to this step in modules/hedgehog_signaling.yaml. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:14597665 Smo physically interacts with Costal2 (Cos2) and Fused (Fu) through its C-tail. Deletion of the Cos2/Fu-binding domain from Smo abolishes its signaling activity. PMID:21844892 Our findings suggest that the phosphorylated C-terminus of Smo recruits the Cos2/Fu complex to the membrane through the interaction between Smo and Cos2, which further induces Fu dimerization. |
| GO:0005515 protein binding | IPI PMID:14614827 Identification of a functional interaction between the trans... | MODIFY | Summary: The interaction recorded here is between the Smo C-terminal cytoplasmic tail and the kinesin-related scaffold Costal-2, the step that brings the Cos2/Fused/Ci complex to the activated receptor at the membrane. Reason: A bare protein binding annotation carries no functional information, but the cited evidence supports a specific one. Smo's phosphorylated tail recruits the Cos2/Fu complex to the plasma membrane, and deleting the Cos2-binding segment abolishes signalling without abolishing the rest of the receptor, so Smo is acting as the adaptor that couples the receptor to the cytoplasmic signalling complex. Modify to GO:0030674 protein-macromolecule adaptor activity, the molecular function assigned to this step in modules/hedgehog_signaling.yaml. Here the association is shown to be direct by yeast two-hybrid and mapped to the intracellular portion of Smo. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:14614827 Combined with our immunoprecipitation and immunofluorescence data, our yeast two-hybrid results provide strong evidence that Smo and Cos2 directly associate and that the association occurs within the intracellular signaling portion of Smo. PMID:14614827 Both Cos2 and Fu coimmunoprecipitated specifically with both Smo antisera but were not detected in the control immunoprecipitation. |
| GO:0005515 protein binding | IPI PMID:15691767 Hedgehog-regulated Costal2-kinase complexes control phosphor... | MODIFY | Summary: The interaction recorded here is between the Smo C-terminal cytoplasmic tail and the kinesin-related scaffold Costal-2, the step that brings the Cos2/Fused/Ci complex to the activated receptor at the membrane. Reason: A bare protein binding annotation carries no functional information, but the cited evidence supports a specific one. Smo's phosphorylated tail recruits the Cos2/Fu complex to the plasma membrane, and deleting the Cos2-binding segment abolishes signalling without abolishing the rest of the receptor, so Smo is acting as the adaptor that couples the receptor to the cytoplasmic signalling complex. Modify to GO:0030674 protein-macromolecule adaptor activity, the molecular function assigned to this step in modules/hedgehog_signaling.yaml. The cached record for this paper is abstract-only and does not itself quote the Smo-Cos2 experiment, but UniProt cites it directly for the SUBUNIT statement that Smo interacts with cos, and the curator read the full text. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: file:DROME/smo/smo-uniprot.txt Interacts with cos. PMID:21844892 Collectively, our data indicate that, in response to a Hh gradient and Smo activity, the Cos2/Fu complex is recruited to the cell membrane through an interaction between Smo and Cos2. |
| GO:0005515 protein binding | IPI PMID:17284519 A large complex containing Patched and Smoothened initiates ... | REMOVE | Summary: Cubitus interruptus, Sex-lethal, Patched and Smoothened co-immunoprecipitate and co-fractionate, which the authors interpret as a single large complex containing both membrane and cytoplasmic pathway components. Reason: Removed because the generic term is uninformative and, unlike the Costal-2 rows, the evidence here does not support a more specific molecular function for Smo. The recovery of Sex-lethal with Smo is from a co-immunoprecipitation of a large multi-protein assembly, so it does not establish a direct Smo-Sxl contact or any activity Smo performs on Sxl; the authors' own model has Sxl acting on Ci and on endocytic cycling. Removal does not mean the reported co-purification is false. Supporting Evidence: PMID:17284519 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:22253573 USP8 promotes smoothened signaling by preventing its ubiquit... | REMOVE | Summary: Hedgehog promotes binding of the deubiquitinase USP8 to Smo residues 625-753, which span the three PKA/CK1 phosphorylation clusters; USP8 removes Smo ubiquitin and promotes its accumulation at the cell surface. Reason: Removed because the generic term is uninformative and the evidence does not support a more specific molecular function for Smo. In this interaction Smo is the substrate: USP8 is the deubiquitinase and Smo is the protein whose ubiquitination it removes, so the informative annotations belong on USP8 (its hydrolase activity) and on Smo's own trafficking, not on a bare binding row. Removal does not mean the interaction is false; it is well mapped, to Smo residues 625-753. Supporting Evidence: PMID:22253573 we show that Hh promotes the interaction of USP8 with Smo aa625-753, which covers the three PKA and CK1 phosphorylation clusters PMID:22253573 USP8 promotes the accumulation of Smo at the cell surface and prevents localization to the early endosomes, presumably by deubiquitinating Smo. |
| GO:0005515 protein binding | IPI PMID:22253574 Hedgehog-regulated ubiquitination controls smoothened traffi... | REMOVE | Summary: Smo is downregulated by ubiquitin-mediated endocytosis, and Hh-induced phosphorylation of the Smo autoinhibitory domain inhibits that ubiquitination; UBPY/USP8 counteracts it. Reason: Removed because the generic term is uninformative and the evidence does not support a more specific molecular function for Smo. In this interaction Smo is the substrate: USP8 is the deubiquitinase and Smo is the protein whose ubiquitination it removes, so the informative annotations belong on USP8 (its hydrolase activity) and on Smo's own trafficking, not on a bare binding row. Removal does not mean the interaction is false; it is well mapped, to Smo residues 625-753. Supporting Evidence: PMID:22253574 Hh inhibits Smo ubiquitination via PKA/CK1-mediated phosphorylation of SAID, leading to Smo cell surface accumulation. |
| GO:0005515 protein binding | IPI PMID:22537496 Hh-induced Smoothened conformational switch is mediated by d... | MODIFY | Summary: The interaction recorded here is between the Smo C-terminal cytoplasmic tail and the kinesin-related scaffold Costal-2, the step that brings the Cos2/Fused/Ci complex to the activated receptor at the membrane. Reason: A bare protein binding annotation carries no functional information, but the cited evidence supports a specific one. Smo's phosphorylated tail recruits the Cos2/Fu complex to the plasma membrane, and deleting the Cos2-binding segment abolishes signalling without abolishing the rest of the receptor, so Smo is acting as the adaptor that couples the receptor to the cytoplasmic signalling complex. Modify to GO:0030674 protein-macromolecule adaptor activity, the molecular function assigned to this step in modules/hedgehog_signaling.yaml. This study shows the interaction is graded: progressive phosphorylation of three serine clusters produces a graded conformational change that progressively promotes Cos2 binding. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:22537496 We propose a zipper-lock model in which the gradual phosphorylation at these clusters induces a gradual conformational change in the Smo cytoplasmic tail, which promotes the interaction between Smo and Costal2 (Cos2). PMID:22537496 The activation of Smoothened (Smo) requires phosphorylation at three clusters of Serine residues in Drosophila Hedgehog (Hh) signaling. |
| GO:0005515 protein binding | IPI PMID:26863604 PI(4)P Promotes Phosphorylation and Conformational Change of... | MODIFY | Summary: The interaction recorded here is between the Smo C-terminal cytoplasmic tail and the kinesin-related scaffold Costal-2, the step that brings the Cos2/Fused/Ci complex to the activated receptor at the membrane. Reason: A bare protein binding annotation carries no functional information, but the cited evidence supports a specific one. Smo's phosphorylated tail recruits the Cos2/Fu complex to the plasma membrane, and deleting the Cos2-binding segment abolishes signalling without abolishing the rest of the receptor, so Smo is acting as the adaptor that couples the receptor to the cytoplasmic signalling complex. Modify to GO:0030674 protein-macromolecule adaptor activity, the molecular function assigned to this step in modules/hedgehog_signaling.yaml. The arginine-motif mutant Smo-RA4 loses PI(4)P binding and the Cos2-Fu interaction together, linking lipid binding to adaptor function. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:26863604 we generated the Arg to Ala mutation in Smo full-length (Myc-SmoRA4) and found that Myc-SmoRA4 lost both the ability to bind PI(4)P (Fig 3J) and the interaction with Cos2-Fu complex (Fig 3K) PMID:26863604 We further found that PI(4)P directly binds Smo through an arginine motif, which then triggers Smo phosphorylation and activation. |
| GO:0005886 plasma membrane | EXP PMID:15616566 Hedgehog signalling activity of Smoothened requires phosphor... | ACCEPT | Summary: Smo is a multi-pass plasma membrane protein whose Hh-regulated accumulation at the cell surface is the central readout of pathway activation: Hh induces phosphorylation, stabilisation and surface accumulation of Smo, phosphorylation-deficient Smo fails to reach the surface and cannot signal, and the Cos2/Fu/Ci complex is recruited to Smo in membrane fractions. Reason: Accepted as a core location. Plasma membrane residence is established by imaging, surface-biotinylation and membrane-fractionation experiments in wing discs and S2 cells across many independent laboratories, and UniProt lists Cell membrane as the primary subcellular location. Supporting Evidence: PMID:15616566 phosphorylation-deficient forms of Smo fail to accumulate on the cell surface and are unable to transduce the Hh signal PMID:15616566 Our data indicate that Hh induces progressive Smo phosphorylation by PKA and CKI, leading to elevation of Smo cell-surface levels and signalling activity. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Smo is a multi-pass plasma membrane protein whose Hh-regulated accumulation at the cell surface is the central readout of pathway activation: Hh induces phosphorylation, stabilisation and surface accumulation of Smo, phosphorylation-deficient Smo fails to reach the surface and cannot signal, and the Cos2/Fu/Ci complex is recruited to Smo in membrane fractions. Reason: Accepted as a core location. Plasma membrane residence is established by imaging, surface-biotinylation and membrane-fractionation experiments in wing discs and S2 cells across many independent laboratories, and UniProt lists Cell membrane as the primary subcellular location. Supporting Evidence: PMID:10966113 Hedgehog causes phosphorylation, stabilization, and accumulation of Smoothened at the cell surface. PMID:15616566 phosphorylation-deficient forms of Smo fail to accumulate on the cell surface and are unable to transduce the Hh signal file:DROME/smo/smo-uniprot.txt Cell membrane |
| GO:0005886 plasma membrane | IDA PMID:10966113 Hedgehog induces opposite changes in turnover and subcellula... | ACCEPT | Summary: Smo is a multi-pass plasma membrane protein whose Hh-regulated accumulation at the cell surface is the central readout of pathway activation: Hh induces phosphorylation, stabilisation and surface accumulation of Smo, phosphorylation-deficient Smo fails to reach the surface and cannot signal, and the Cos2/Fu/Ci complex is recruited to Smo in membrane fractions. Reason: Accepted as a core location. Plasma membrane residence is established by imaging, surface-biotinylation and membrane-fractionation experiments in wing discs and S2 cells across many independent laboratories, and UniProt lists Cell membrane as the primary subcellular location. Supporting Evidence: PMID:10966113 Hedgehog causes phosphorylation, stabilization, and accumulation of Smoothened at the cell surface. |
| GO:0005886 plasma membrane | IDA PMID:17960137 Hedgehog regulates smoothened activity by inducing a conform... | ACCEPT | Summary: Smo is a multi-pass plasma membrane protein whose Hh-regulated accumulation at the cell surface is the central readout of pathway activation: Hh induces phosphorylation, stabilisation and surface accumulation of Smo, phosphorylation-deficient Smo fails to reach the surface and cannot signal, and the Cos2/Fu/Ci complex is recruited to Smo in membrane fractions. Reason: Accepted as a core location. Plasma membrane residence is established by imaging, surface-biotinylation and membrane-fractionation experiments in wing discs and S2 cells across many independent laboratories, and UniProt lists Cell membrane as the primary subcellular location. Supporting Evidence: PMID:17960137 The Arg clusters inhibit SMO by blocking its cell surface expression and keeping it in an inactive conformation that is maintained by intramolecular electrostatic interactions. |
| GO:0005886 plasma membrane | IDA PMID:22223683 The extracellular loops of Smoothened play a regulatory role... | ACCEPT | Summary: Smo is a multi-pass plasma membrane protein whose Hh-regulated accumulation at the cell surface is the central readout of pathway activation: Hh induces phosphorylation, stabilisation and surface accumulation of Smo, phosphorylation-deficient Smo fails to reach the surface and cannot signal, and the Cos2/Fu/Ci complex is recruited to Smo in membrane fractions. Reason: Accepted as a core location. Plasma membrane residence is established by imaging, surface-biotinylation and membrane-fractionation experiments in wing discs and S2 cells across many independent laboratories, and UniProt lists Cell membrane as the primary subcellular location. Supporting Evidence: PMID:22223683 We provide in vitro and in vivo evidence that EC1 cysteine mutation induces significant Hh-independent Smo signaling, triggering a level of pathway activation similar to that of a maximal Hh response in Drosophila and mammalian systems. |
| GO:0005886 plasma membrane | IDA PMID:22537496 Hh-induced Smoothened conformational switch is mediated by d... | ACCEPT | Summary: Smo is a multi-pass plasma membrane protein whose Hh-regulated accumulation at the cell surface is the central readout of pathway activation: Hh induces phosphorylation, stabilisation and surface accumulation of Smo, phosphorylation-deficient Smo fails to reach the surface and cannot signal, and the Cos2/Fu/Ci complex is recruited to Smo in membrane fractions. Reason: Accepted as a core location. Plasma membrane residence is established by imaging, surface-biotinylation and membrane-fractionation experiments in wing discs and S2 cells across many independent laboratories, and UniProt lists Cell membrane as the primary subcellular location. Supporting Evidence: PMID:22537496 The activation of Smoothened (Smo) requires phosphorylation at three clusters of Serine residues in Drosophila Hedgehog (Hh) signaling. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Smo is a multi-pass plasma membrane protein whose Hh-regulated accumulation at the cell surface is the central readout of pathway activation: Hh induces phosphorylation, stabilisation and surface accumulation of Smo, phosphorylation-deficient Smo fails to reach the surface and cannot signal, and the Cos2/Fu/Ci complex is recruited to Smo in membrane fractions. Reason: Accepted as a core location. Plasma membrane residence is established by imaging, surface-biotinylation and membrane-fractionation experiments in wing discs and S2 cells across many independent laboratories, and UniProt lists Cell membrane as the primary subcellular location. Supporting Evidence: PMID:10966113 Hedgehog causes phosphorylation, stabilization, and accumulation of Smoothened at the cell surface. PMID:15616566 phosphorylation-deficient forms of Smo fail to accumulate on the cell surface and are unable to transduce the Hh signal file:DROME/smo/smo-uniprot.txt Cell membrane |
| GO:0005886 plasma membrane | IMP PMID:19850026 Regulation of smoothened by Drosophila G-protein-coupled rec... | ACCEPT | Summary: Smo is a multi-pass plasma membrane protein whose Hh-regulated accumulation at the cell surface is the central readout of pathway activation: Hh induces phosphorylation, stabilisation and surface accumulation of Smo, phosphorylation-deficient Smo fails to reach the surface and cannot signal, and the Cos2/Fu/Ci complex is recruited to Smo in membrane fractions. Reason: Accepted as a core location. Plasma membrane residence is established by imaging, surface-biotinylation and membrane-fractionation experiments in wing discs and S2 cells across many independent laboratories, and UniProt lists Cell membrane as the primary subcellular location. Supporting Evidence: PMID:19850026 In response to Hh binding to Ptc, Ptc-mediated repression of Smo is relieved, leading to Smo activation, surface accumulation, and downstream signaling. PMID:19850026 we provide evidence that Gprk2 promotes Smo internalization subsequent to its activation, most likely by direct phosphorylation |
| GO:0005886 plasma membrane | TAS Reactome:R-DME-209168 | ACCEPT | Summary: Smo is a multi-pass plasma membrane protein whose Hh-regulated accumulation at the cell surface is the central readout of pathway activation: Hh induces phosphorylation, stabilisation and surface accumulation of Smo, phosphorylation-deficient Smo fails to reach the surface and cannot signal, and the Cos2/Fu/Ci complex is recruited to Smo in membrane fractions. Reason: Accepted. These Reactome reactions place Smo at the plasma membrane for the Drosophila Hedgehog pathway steps in which it is phosphorylated by PKA and CK1, changes conformation and binds Costal-2. The compartment assignment matches the primary experimental evidence on this gene. |
| GO:0005886 plasma membrane | TAS Reactome:R-DME-209220 | ACCEPT | Summary: Smo is a multi-pass plasma membrane protein whose Hh-regulated accumulation at the cell surface is the central readout of pathway activation: Hh induces phosphorylation, stabilisation and surface accumulation of Smo, phosphorylation-deficient Smo fails to reach the surface and cannot signal, and the Cos2/Fu/Ci complex is recruited to Smo in membrane fractions. Reason: Accepted. These Reactome reactions place Smo at the plasma membrane for the Drosophila Hedgehog pathway steps in which it is phosphorylated by PKA and CK1, changes conformation and binds Costal-2. The compartment assignment matches the primary experimental evidence on this gene. |
| GO:0005886 plasma membrane | TAS Reactome:R-DME-209253 | ACCEPT | Summary: Smo is a multi-pass plasma membrane protein whose Hh-regulated accumulation at the cell surface is the central readout of pathway activation: Hh induces phosphorylation, stabilisation and surface accumulation of Smo, phosphorylation-deficient Smo fails to reach the surface and cannot signal, and the Cos2/Fu/Ci complex is recruited to Smo in membrane fractions. Reason: Accepted. These Reactome reactions place Smo at the plasma membrane for the Drosophila Hedgehog pathway steps in which it is phosphorylated by PKA and CK1, changes conformation and binds Costal-2. The compartment assignment matches the primary experimental evidence on this gene. |
| GO:0005886 plasma membrane | TAS Reactome:R-DME-209341 | ACCEPT | Summary: Smo is a multi-pass plasma membrane protein whose Hh-regulated accumulation at the cell surface is the central readout of pathway activation: Hh induces phosphorylation, stabilisation and surface accumulation of Smo, phosphorylation-deficient Smo fails to reach the surface and cannot signal, and the Cos2/Fu/Ci complex is recruited to Smo in membrane fractions. Reason: Accepted. These Reactome reactions place Smo at the plasma membrane for the Drosophila Hedgehog pathway steps in which it is phosphorylated by PKA and CK1, changes conformation and binds Costal-2. The compartment assignment matches the primary experimental evidence on this gene. |
| GO:0005886 plasma membrane | TAS Reactome:R-DME-216133 | ACCEPT | Summary: Smo is a multi-pass plasma membrane protein whose Hh-regulated accumulation at the cell surface is the central readout of pathway activation: Hh induces phosphorylation, stabilisation and surface accumulation of Smo, phosphorylation-deficient Smo fails to reach the surface and cannot signal, and the Cos2/Fu/Ci complex is recruited to Smo in membrane fractions. Reason: Accepted. These Reactome reactions place Smo at the plasma membrane for the Drosophila Hedgehog pathway steps in which it is phosphorylated by PKA and CK1, changes conformation and binds Costal-2. The compartment assignment matches the primary experimental evidence on this gene. |
| GO:0005886 plasma membrane | TAS Reactome:R-DME-216202 | ACCEPT | Summary: Smo is a multi-pass plasma membrane protein whose Hh-regulated accumulation at the cell surface is the central readout of pathway activation: Hh induces phosphorylation, stabilisation and surface accumulation of Smo, phosphorylation-deficient Smo fails to reach the surface and cannot signal, and the Cos2/Fu/Ci complex is recruited to Smo in membrane fractions. Reason: Accepted. These Reactome reactions place Smo at the plasma membrane for the Drosophila Hedgehog pathway steps in which it is phosphorylated by PKA and CK1, changes conformation and binds Costal-2. The compartment assignment matches the primary experimental evidence on this gene. |
| GO:0005886 plasma membrane | TAS Reactome:R-DME-216222 | ACCEPT | Summary: Smo is a multi-pass plasma membrane protein whose Hh-regulated accumulation at the cell surface is the central readout of pathway activation: Hh induces phosphorylation, stabilisation and surface accumulation of Smo, phosphorylation-deficient Smo fails to reach the surface and cannot signal, and the Cos2/Fu/Ci complex is recruited to Smo in membrane fractions. Reason: Accepted. These Reactome reactions place Smo at the plasma membrane for the Drosophila Hedgehog pathway steps in which it is phosphorylated by PKA and CK1, changes conformation and binds Costal-2. The compartment assignment matches the primary experimental evidence on this gene. |
| GO:0005929 cilium | IBA GO_REF:0000033 | ACCEPT | Summary: Drosophila cells are largely non-ciliated during development, and imaginal-disc Hh transduction runs on the cytoplasmic Cos2/Fu complex without a cilium. In the ciliated olfactory sensory neurons, however, Smo localises to the sensory cilium, ciliary targeting requires the intraflagellar transport machinery together with Cos2 and Fused, and the cilium mediates expression of Hh target genes. Reason: Accepted as a genuine, cell-type-restricted signalling location. This annotation resolves the question of why fly smo appears among the seeds of the PAINT cilium row at node PTN000885245: the fly gene carries its own experimental ciliary annotation (IDA, PMID:24768000), so the eumetazoan placement is grounded in protostome as well as vertebrate evidence rather than being a vertebrate assertion propagated into flies. UniProt independently records Cell projection, cilium membrane on the strength of the same study. The cilium is not where the classical imaginal-disc pathway operates, but it is where Smo acts in olfactory sensory neurons, which is what the annotation asserts. Supporting Evidence: PMID:24768000 We demonstrate that several fundamental key aspects of the vertebrate cilia pathway, such as ciliary localization of Smoothened and the requirement of the intraflagellar transport system, are present in Drosophila. PMID:24768000 Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. PMID:24768000 We show that Cos2 and Fused are required for the ciliary transport of Smoothened and that cilia mediate the expression of the Hh pathway target genes. file:DROME/smo/smo-uniprot.txt Cell projection, cilium membrane |
| GO:0005929 cilium | IDA PMID:24768000 Cilia-mediated hedgehog signaling in Drosophila. | ACCEPT | Summary: Drosophila cells are largely non-ciliated during development, and imaginal-disc Hh transduction runs on the cytoplasmic Cos2/Fu complex without a cilium. In the ciliated olfactory sensory neurons, however, Smo localises to the sensory cilium, ciliary targeting requires the intraflagellar transport machinery together with Cos2 and Fused, and the cilium mediates expression of Hh target genes. Reason: Accepted as a genuine, cell-type-restricted signalling location. This annotation resolves the question of why fly smo appears among the seeds of the PAINT cilium row at node PTN000885245: the fly gene carries its own experimental ciliary annotation (IDA, PMID:24768000), so the eumetazoan placement is grounded in protostome as well as vertebrate evidence rather than being a vertebrate assertion propagated into flies. UniProt independently records Cell projection, cilium membrane on the strength of the same study. The cilium is not where the classical imaginal-disc pathway operates, but it is where Smo acts in olfactory sensory neurons, which is what the annotation asserts. Supporting Evidence: PMID:24768000 We demonstrate that several fundamental key aspects of the vertebrate cilia pathway, such as ciliary localization of Smoothened and the requirement of the intraflagellar transport system, are present in Drosophila. PMID:24768000 Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. PMID:24768000 We show that Cos2 and Fused are required for the ciliary transport of Smoothened and that cilia mediate the expression of the Hh pathway target genes. PMID:24768000 Drosophila cells are nonciliated during development, which has led to the assumption that cilia-mediated Hh signaling is restricted to vertebrates. |
| GO:0007166 cell surface receptor signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: The InterPro-derived cell surface receptor signalling pathway term is correct but far broader than the pathway Smo actually transduces. Reason: Modify to GO:0007224 smoothened signaling pathway, the specific cascade established for this gene by dozens of experimental annotations. This mirrors the action taken on the equivalent InterPro row in the human SMO review. Proposed replacements: smoothened signaling pathway Supporting Evidence: file:DROME/smo/smo-uniprot.txt G protein-coupled receptor, which transduces the smoothened CC signaling pathway and which is required for correct patterning of every CC segment |
| GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway | IMP PMID:18987629 G protein Galphai functions immediately downstream of Smooth... | ACCEPT | Summary: Hedgehog stimulation activates Galphai through Smo and lowers intracellular cAMP; genetic reduction of Galphai or of cAMP phosphodiesterase modifies smo wing phenotypes, placing the adenylate cyclase-inhibiting branch immediately downstream of Smo. Reason: Accepted as a core process annotation. This names the immediate biochemical branch in which Smo itself acts, not a remote developmental phenotype, and it is the fly counterpart of the same term accepted on human SMO. Supporting Evidence: PMID:18987629 Here we present in vitro and in vivo evidence in Drosophila that Smo activates a G protein to modulate intracellular cyclic AMP levels in response to Hh. PMID:18987629 Our results demonstrate that Smo functions as a canonical GPCR, which signals through Galphai to regulate Hh pathway activation. |
| GO:0007224 smoothened signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:15616566 Our data indicate that Hh induces progressive Smo phosphorylation by PKA and CKI, leading to elevation of Smo cell-surface levels and signalling activity. PMID:14597665 Smo physically interacts with Costal2 (Cos2) and Fused (Fu) through its C-tail. Deletion of the Cos2/Fu-binding domain from Smo abolishes its signaling activity. |
| GO:0007224 smoothened signaling pathway | IDA PMID:10966113 Hedgehog induces opposite changes in turnover and subcellula... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:10966113 Hedgehog causes phosphorylation, stabilization, and accumulation of Smoothened at the cell surface. |
| GO:0007224 smoothened signaling pathway | IDA PMID:14636583 Hedgehog signal transduction via Smoothened association with... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:14636583 Smo associates directly with a Ci-containing complex that is scaffolded and stabilized by the atypical kinesin, Costal-2 (Cos2) |
| GO:0007224 smoothened signaling pathway | IDA PMID:15616566 Hedgehog signalling activity of Smoothened requires phosphor... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:15616566 Our data indicate that Hh induces progressive Smo phosphorylation by PKA and CKI, leading to elevation of Smo cell-surface levels and signalling activity. |
| GO:0007224 smoothened signaling pathway | IDA PMID:15691767 Hedgehog-regulated Costal2-kinase complexes control phosphor... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: file:DROME/smo/smo-uniprot.txt Interacts with cos. |
| GO:0007224 smoothened signaling pathway | IDA PMID:17960137 Hedgehog regulates smoothened activity by inducing a conform... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:17960137 HH-induced phosphorylation disrupts the interaction, and induces a conformational switch and dimerization of SMO cytoplasmic tails, which is essential for pathway activation. |
| GO:0007224 smoothened signaling pathway | IDA PMID:18987629 G protein Galphai functions immediately downstream of Smooth... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:18987629 Our results demonstrate that Smo functions as a canonical GPCR, which signals through Galphai to regulate Hh pathway activation. |
| GO:0007224 smoothened signaling pathway | IDA PMID:21844892 Transduction of the Hedgehog signal through the dimerization... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:21844892 Our findings suggest that the phosphorylated C-terminus of Smo recruits the Cos2/Fu complex to the membrane through the interaction between Smo and Cos2, which further induces Fu dimerization. |
| GO:0007224 smoothened signaling pathway | IDA PMID:21852395 The Hedgehog-induced Smoothened conformational switch assemb... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:21852395 Here, we show that Hh-induced Smo conformational change recruits Costal2 (Cos2)/Fused (Fu) and promotes Fu kinase domain dimerization. |
| GO:0007224 smoothened signaling pathway | IDA PMID:22223683 The extracellular loops of Smoothened play a regulatory role... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:22223683 We provide in vitro and in vivo evidence that EC1 cysteine mutation induces significant Hh-independent Smo signaling, triggering a level of pathway activation similar to that of a maximal Hh response in Drosophila and mammalian systems. |
| GO:0007224 smoothened signaling pathway | IDA PMID:22306085 Distinct phosphorylations on kinesin costal-2 mediate differ... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:22306085 within the Hh gradient field, low- and high-magnitude Smo activations control differentially the phosphorylation of Cos2 on two distinct serines |
| GO:0007224 smoothened signaling pathway | IDA PMID:22537496 Hh-induced Smoothened conformational switch is mediated by d... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:22537496 We propose a zipper-lock model in which the gradual phosphorylation at these clusters induces a gradual conformational change in the Smo cytoplasmic tail, which promotes the interaction between Smo and Costal2 (Cos2). |
| GO:0007224 smoothened signaling pathway | IDA PMID:24985345 Hedgehog induces formation of PKA-Smoothened complexes to pr... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:24985345 We found that in cells exposed to Hh, the catalytic subunit of PKA (PKAc) bound to the juxtamembrane region of the carboxyl terminus of Smo. |
| GO:0007224 smoothened signaling pathway | IDA PMID:25289679 Switch of PKA substrates from Cubitus interruptus to Smoothe... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:25289679 Here we show that Hh signalling activation causes PKA to switch its substrates from Ci to Smo within the Hh signalling complex (HSC). |
| GO:0007224 smoothened signaling pathway | IDA PMID:36083801 High hedgehog signaling is transduced by a multikinase-depen... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:36083801 We provide evidence that HH promotes the stabilization of SMO by switching its fate after endocytosis toward recycling. PMID:36083801 Moreover, in the presence of very high levels of HH, the second effect of FU leads to the local enrichment of SMO in the most basal domain of the cell membrane. |
| GO:0007224 smoothened signaling pathway | IGI PMID:16386907 Processing of the Drosophila hedgehog signaling effector Ci-... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. The IGI partner is cubitus interruptus, and the cached abstract centres on Slimb-dependent processing of Ci-155 to Ci-75; the curator read the full text. Smo's role in this chain is to block that processing, so the genetic interaction is coherent. Supporting Evidence: PMID:16423832 Smo signals to the Hh signaling complex, which consists of the kinesin-related protein Costal2 (Cos2), the protein kinase Fused (Fu), and the Drosophila Gli homolog cubitus interruptus (Ci), in two distinct manners |
| GO:0007224 smoothened signaling pathway | IGI PMID:17182028 The last 59 amino acids of Smoothened cytoplasmic tail direc... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:17182028 we show that the regulatory domain of FU physically interacts with the last 52 amino acids of SMO and that the two proteins colocalize in vivo to vesicles |
| GO:0007224 smoothened signaling pathway | IGI PMID:26271100 A Comparison of Ci/Gli Activity as Regulated by Sufu in Dros... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:26271100 Fu kinase-dependent Ci activation in response to HhN occurs in the context of a Hh-responsive complex comprising Smo, Cos2, Fu and Ci. |
| GO:0007224 smoothened signaling pathway | IMP PMID:14523402 Stability and association of Smoothened, Costal2 and Fused w... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:14523402 we find that the Cos2-Fu-Ci protein complex is associated with Smo in membrane fractions both in vitro and in vivo |
| GO:0007224 smoothened signaling pathway | IMP PMID:14597665 Smoothened transduces Hedgehog signal by physically interact... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:14597665 Smo physically interacts with Costal2 (Cos2) and Fused (Fu) through its C-tail. Deletion of the Cos2/Fu-binding domain from Smo abolishes its signaling activity. |
| GO:0007224 smoothened signaling pathway | IMP PMID:14614827 Identification of a functional interaction between the trans... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:14614827 Combined with our immunoprecipitation and immunofluorescence data, our yeast two-hybrid results provide strong evidence that Smo and Cos2 directly associate and that the association occurs within the intracellular signaling portion of Smo. |
| GO:0007224 smoothened signaling pathway | IMP PMID:15592457 Drosophila Smoothened phosphorylation sites essential for He... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:15592457 a cluster of protein kinase A and protein kinase A-primed casein kinase 1 phosphorylation sites in Smoothened, similarly distributed to those regulating Ci, are essential for Smoothened to transduce a Hh signal |
| GO:0007224 smoothened signaling pathway | IMP PMID:15598741 Extensive phosphorylation of Smoothened in Hedgehog pathway ... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:15598741 we identify here 26 serine/threonine residues within the Smo C-terminal cytoplasmic tail that are phosphorylated in Hh-stimulated cells |
| GO:0007224 smoothened signaling pathway | IMP PMID:15616566 Hedgehog signalling activity of Smoothened requires phosphor... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:15616566 Our data indicate that Hh induces progressive Smo phosphorylation by PKA and CKI, leading to elevation of Smo cell-surface levels and signalling activity. |
| GO:0007224 smoothened signaling pathway | IMP PMID:16423832 Smoothened regulates activator and repressor functions of He... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:16423832 Smo signals to the Hh signaling complex, which consists of the kinesin-related protein Costal2 (Cos2), the protein kinase Fused (Fu), and the Drosophila Gli homolog cubitus interruptus (Ci), in two distinct manners |
| GO:0007224 smoothened signaling pathway | IMP PMID:17671093 Fused-Costal2 protein complex regulates Hedgehog-induced Smo... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:17671093 Our data suggest that Cos2-Smo interaction blocks Hh-induced Smo phosphorylation, and that Fu promotes Smo phosphorylation by antagonizing Cos2. PMID:17671093 we found that Hh-induced Smo accumulation is inhibited in fu mutant clones or by expressing a dominant-negative form of Fu, and such inhibition is alleviated by removal of Cos2 |
| GO:0007224 smoothened signaling pathway | IMP PMID:19850026 Regulation of smoothened by Drosophila G-protein-coupled rec... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:19850026 In response to Hh binding to Ptc, Ptc-mediated repression of Smo is relieved, leading to Smo activation, surface accumulation, and downstream signaling. |
| GO:0007224 smoothened signaling pathway | IMP PMID:20435030 Dynamic phosphorylation of the kinesin Costal-2 in vivo reve... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. The cached record for this study is abstract-only and centres on Cos2 phosphorylation as an in situ readout of signalling; the curator read the full text. Graded Fu kinase activity is the immediate downstream consequence of Smo activation, so the annotation is consistent. Supporting Evidence: PMID:21664578 Here we show that the Fused (Fu) protein kinase is activated by Smo and Cos2 via Fu- and CK1-dependent phosphorylation. |
| GO:0007224 smoothened signaling pathway | IMP PMID:20844016 G protein-coupled receptor kinase 2 promotes high-level Hedg... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:20844016 Gprk2 promotes Smo activation by phosphorylating Smo C-terminal tail (C-tail) at Ser741/Thr742, which is facilitated by PKA and CK1 phosphorylation at adjacent Ser residues. |
| GO:0007224 smoothened signaling pathway | IMP PMID:21664578 Hedgehog activates fused through phosphorylation to elicit a... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:21664578 Here we show that the Fused (Fu) protein kinase is activated by Smo and Cos2 via Fu- and CK1-dependent phosphorylation. |
| GO:0007224 smoothened signaling pathway | IMP PMID:22096079 Drosophila G-protein-coupled receptor kinase 2 regulates cAM... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:22096079 loss of Gprk2 resulted in a decrease in cellular cAMP concentrations to a level that was limiting for Hh target gene activation |
| GO:0007224 smoothened signaling pathway | IMP PMID:25512501 Hedgehog-induced phosphorylation by CK1 sustains the activit... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. The cached record is abstract-only and centres on CK1-dependent protection of the Ci activator; the curator read the full text. The step assayed lies downstream of Smo within the same pathway, so the annotation is coherent even though the abstract does not name Smo. Supporting Evidence: PMID:21852395 Here, we show that Hh-induced Smo conformational change recruits Costal2 (Cos2)/Fused (Fu) and promotes Fu kinase domain dimerization. |
| GO:0007224 smoothened signaling pathway | IMP PMID:28360132 Dose-dependent transduction of Hedgehog relies on phosphoryl... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:28360132 we identified new SMO phosphosites that enhance the effects of the PKA/CKI kinases on SMO accumulation, its localization at the plasma membrane and its activity |
| GO:0007224 smoothened signaling pathway | IMP PMID:30541874 Protein association changes in the Hedgehog signaling comple... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:30541874 we show that the last amino acids of the cytoplasmic tail of Smo, in combination with G protein-coupled receptor kinase 2 (Gprk2), bind to the regulatory domain of Fused (Fu) and highly activate its kinase activity |
| GO:0007224 smoothened signaling pathway | IMP PMID:31279575 Phosphorylation of Ci/Gli by Fused Family Kinases Promotes H... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. The cached record is abstract-only and centres on Fused-mediated phosphorylation of Ci; the curator read the full text. Fused activation is the immediate output of Smo C-tail engagement, so the annotation is coherent. Supporting Evidence: PMID:21852395 Here, we show that Hh-induced Smo conformational change recruits Costal2 (Cos2)/Fused (Fu) and promotes Fu kinase domain dimerization. |
| GO:0007224 smoothened signaling pathway | IMP PMID:35037619 The NDNF-like factor Nord is a Hedgehog-induced extracellula... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:35037619 Through genome-wide expression profiling of the Drosophila wing imaginal discs, we identify nord as a novel target gene of the Hh signaling pathway. |
| GO:0007224 smoothened signaling pathway | IMP PMID:35573695 Dissection of the microRNA Network Regulating Hedgehog Signa... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:35573695 we used the miRNA sensor toolbox to show that miR-10 and miR-958 directly target fu and smo, respectively |
| GO:0007224 smoothened signaling pathway | IMP PMID:8898207 Dual roles for patched in sequestering and transducing Hedge... | ACCEPT | Summary: Smo is the obligate membrane transducer of the Drosophila Hedgehog pathway. Hh relieves Ptc-mediated inhibition; PKA, CK1 and Gprk2 progressively phosphorylate the long C-terminal tail; the tail opens, dimerises, and recruits the Costal-2/Fused complex to the membrane, activating Fused and switching Cubitus interruptus from repressor to activator. Reason: Accepted as the core process. This is the single best-supported annotation on the gene, resting on mutant clone analysis in embryos and imaginal discs, structure-function dissection of the C-tail, phosphosite mapping, conformational FRET reporters and biochemical reconstitution. Supporting Evidence: PMID:8898207 Hh binds to Ptc, or a Ptc-Smo complex, and thereby induces Smo activity |
| GO:0007346 regulation of mitotic cell cycle | IMP PMID:11279500 Hedgehog acts as a somatic stem cell factor in the Drosophil... | KEEP AS NON CORE | Summary: Hedgehog acts as a somatic stem cell factor in the Drosophila ovary: somatic cells cannot proliferate as stem cells without Hh signalling, and excess signalling produces supernumerary stem cells. Reason: Retained as non-core. Control of the mitotic cell cycle is a cellular consequence of Ci-driven transcription downstream of Smo, not a step Smo executes. Smo's own contribution is the receptor transduction already captured by GO:0007224. Supporting Evidence: PMID:11279500 Hh acts specifically on stem cells in the Drosophila ovary. These cells cannot proliferate as stem cells in the absence of Hh signalling, whereas excessive Hh signalling produces supernumerary stem cells. |
| GO:0007350 blastoderm segmentation | IMP PMID:8700230 smoothened encodes a receptor-like serpentine protein requir... | KEEP AS NON CORE | Summary: smoothened is a segment-polarity gene: it is required for cells to respond to Hedgehog during development of the embryonic segments. Reason: Retained as non-core. Blastoderm segmentation is an embryonic patterning output of Hh/Smo signalling. It is a genuine requirement, established by the founding genetic analysis, but it is a developmental phenotype rather than a molecular role of Smo. Supporting Evidence: PMID:8700230 the segment-polarity gene smoothened is required for the response of cells to hedgehog signalling during the development of both the embryonic segments and imaginal discs |
| GO:0007367 segment polarity determination | IMP PMID:8700230 smoothened encodes a receptor-like serpentine protein requir... | KEEP AS NON CORE | Summary: Mutations in smoothened disrupt the pattern and polarity of individual embryonic segments, the defining segment-polarity phenotype. Reason: Retained as non-core, on the same basis as blastoderm segmentation: this is the organismal readout of Smo-dependent Hh reception rather than an activity Smo performs. Supporting Evidence: PMID:8700230 the segment-polarity gene smoothened is required for the response of cells to hedgehog signalling during the development of both the embryonic segments and imaginal discs |
| GO:0007389 pattern specification process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Positional patterning is the shared developmental output of Hedgehog signalling in flies and vertebrates, which is why the PAINT Smoothened node carries pattern specification. Reason: Retained as non-core, matching both the human SMO review and the SOUND assessment recorded for this row at node PTN000885245 in the PTHR11309 family review. The node is seeded by fly, mouse and zebrafish Smoothened, so the eumetazoan placement is well supported; the term is simply broader than Smo's molecular activity. |
| GO:0007455 eye-antennal disc morphogenesis | IGI PMID:11934850 A positive role for patched-smoothened signaling in promotin... | KEEP AS NON CORE | Summary: Patched and Smoothened act together to promote cell proliferation in the eye-antennal disc during head development; loss of either affects proliferation and produces adult head capsule defects. Reason: Retained as non-core. Eye-antennal disc morphogenesis is a tissue-level output. The paper reports an unusual configuration in which Ptc and Smo act positively together, which is worth flagging, but it does not make disc morphogenesis a molecular function of Smo. Supporting Evidence: PMID:11934850 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:20844016 G protein-coupled receptor kinase 2 promotes high-level Hedg... | KEEP AS NON CORE | Summary: Gprk2-dependent tuning of the Smo active state is required for high-level Hh signalling in the wing disc, and perturbing it produces wing patterning defects. Reason: Retained as non-core. Wing morphogenesis is the classic assay used to read out Smo activity, but the morphogenetic process itself is carried out by the many Ci target genes downstream, not by Smo. Supporting Evidence: PMID:20844016 Gprk2 promotes Smo activation by phosphorylating Smo C-terminal tail (C-tail) at Ser741/Thr742, which is facilitated by PKA and CK1 phosphorylation at adjacent Ser residues. |
| GO:0010628 positive regulation of gene expression | IMP PMID:35037619 The NDNF-like factor Nord is a Hedgehog-induced extracellula... | KEEP AS NON CORE | Summary: nord, which encodes a secreted NDNF-like BMP modulator, was identified as a Hedgehog target gene in the wing disc, so Smo signalling is required upstream of its expression. Reason: Retained as non-core. The acts_upstream_of qualifier is honest about the indirection: Smo does not regulate transcription itself, it transduces the signal that converts Ci into an activator. The term is also very general; the informative annotation for this chain of events is GO:0007224, which the gene already carries. Supporting Evidence: PMID:35037619 Through genome-wide expression profiling of the Drosophila wing imaginal discs, we identify nord as a novel target gene of the Hh signaling pathway. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: The InterPro-derived generic membrane term is correct but less specific than the locations experimentally established for fly Smo. Reason: Modify to GO:0005886 plasma membrane and GO:0060170 ciliary membrane. Both replacements are independently supported on this gene: plasma membrane by surface-accumulation and fractionation experiments, ciliary membrane by imaging in olfactory sensory neurons (PMID:24768000) and by the corresponding UniProt subcellular location. Proposed replacements: plasma membrane ciliary membrane Supporting Evidence: file:DROME/smo/smo-uniprot.txt Cell membrane file:DROME/smo/smo-uniprot.txt Cell projection, cilium membrane |
| GO:0019901 protein kinase binding | IPI PMID:21844892 Transduction of the Hedgehog signal through the dimerization... | ACCEPT | Summary: The Smo C-terminal tail is a direct binding site for pathway kinases: the regulatory domain of Fused binds the last ~52 residues of Smo, the last residues of the tail together with Gprk2 bind the Fused regulatory domain and strongly activate its kinase activity, and the PKA catalytic subunit binds the juxtamembrane region of the tail in Hh-stimulated cells. Reason: Accepted as a core molecular function. Unlike a bare protein-binding row, this term names the class of partner and the interactions are mapped to defined segments of the tail by deletion and co-immunoprecipitation. Binding and concentrating Fused at the membrane is how Smo activates the kinase, so this is mechanistically central rather than incidental. Supporting Evidence: PMID:21844892 Our findings suggest that the phosphorylated C-terminus of Smo recruits the Cos2/Fu complex to the membrane through the interaction between Smo and Cos2, which further induces Fu dimerization. PMID:17182028 we show that the regulatory domain of FU physically interacts with the last 52 amino acids of SMO and that the two proteins colocalize in vivo to vesicles PMID:24985345 We found that in cells exposed to Hh, the catalytic subunit of PKA (PKAc) bound to the juxtamembrane region of the carboxyl terminus of Smo. PMID:30541874 we show that the last amino acids of the cytoplasmic tail of Smo, in combination with G protein-coupled receptor kinase 2 (Gprk2), bind to the regulatory domain of Fused (Fu) and highly activate its kinase activity |
| GO:0030424 axon | IDA PMID:24768000 Cilia-mediated hedgehog signaling in Drosophila. | KEEP AS NON CORE | Summary: In olfactory sensory neurons Smo is detected in the axon as well as in the dendrite, cell body and sensory cilium. Reason: Retained as non-core. The colocalizes_with qualifier already marks this as a weaker claim than located_in, and the axon is not a compartment where Smo is known to transduce Hh. It is a real cell-type-specific distribution, reported in the same study that established ciliary Smo, but it is peripheral to the receptor's activity. Supporting Evidence: PMID:24768000 Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. |
| GO:0030425 dendrite | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Smo is present in the dendrites of Drosophila olfactory sensory neurons, at whose distal tip the sensory cilium is elaborated; the PAINT Smoothened node also asserts dendrite for eumetazoan descendants, seeded by fly smo and rat Smo. Reason: Retained as non-core, matching the human SMO review. The fly IDA row is what grounds the protostome side of the PAINT dendrite assertion at PTN000885245, so the node is better supported than the family review could establish offline. Even so, the dendrite is a compartment of one differentiated cell type rather than the general site of Smo activity, which is the plasma membrane. Supporting Evidence: PMID:24768000 Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. file:DROME/smo/smo-uniprot.txt Expressed in olfactory sensory neurons (at protein CC level). |
| GO:0030425 dendrite | IDA PMID:24768000 Cilia-mediated hedgehog signaling in Drosophila. | KEEP AS NON CORE | Summary: Smo is present in the dendrites of Drosophila olfactory sensory neurons, at whose distal tip the sensory cilium is elaborated; the PAINT Smoothened node also asserts dendrite for eumetazoan descendants, seeded by fly smo and rat Smo. Reason: Retained as non-core, matching the human SMO review. The fly IDA row is what grounds the protostome side of the PAINT dendrite assertion at PTN000885245, so the node is better supported than the family review could establish offline. Even so, the dendrite is a compartment of one differentiated cell type rather than the general site of Smo activity, which is the plasma membrane. Supporting Evidence: PMID:24768000 Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. file:DROME/smo/smo-uniprot.txt Expressed in olfactory sensory neurons (at protein CC level). |
| GO:0030707 follicle cell of egg chamber development | IGI PMID:29093440 Quantitative microscopy of the Drosophila ovary shows multip... | KEEP AS NON CORE | Summary: Hedgehog signalling from the ovarian niche controls the proliferation-to-differentiation transition of follicle stem cell progeny, acting in parallel with Wnt and Notch inputs; somatic stem cell behaviour in the germarium also depends on BMP signalling. Reason: Retained as non-core. Follicle cell development is an organ-level developmental process driven by Ci target genes and several parallel pathways; Smo's contribution is Hh reception. Supporting Evidence: PMID:29093440 Hh signalling independently controls the proliferation to differentiation transition. |
| GO:0030707 follicle cell of egg chamber development | IMP PMID:16256740 BMP signaling is required for controlling somatic stem cell ... | KEEP AS NON CORE | Summary: Hedgehog signalling from the ovarian niche controls the proliferation-to-differentiation transition of follicle stem cell progeny, acting in parallel with Wnt and Notch inputs; somatic stem cell behaviour in the germarium also depends on BMP signalling. Reason: Retained as non-core. Follicle cell development is an organ-level developmental process driven by Ci target genes and several parallel pathways; Smo's contribution is Hh reception. The cached abstract for this study centres on BMP signalling in ovarian somatic stem cells; the curator read the full text. A smo requirement in the same cells is independently established (PMID:11279500), so there is no basis for second-guessing the annotation. Supporting Evidence: PMID:11279500 Hh acts specifically on stem cells in the Drosophila ovary. These cells cannot proliferate as stem cells in the absence of Hh signalling, whereas excessive Hh signalling produces supernumerary stem cells. |
| GO:0035019 somatic stem cell population maintenance | IMP PMID:16256740 BMP signaling is required for controlling somatic stem cell ... | KEEP AS NON CORE | Summary: Somatic stem cells of the Drosophila ovary depend on Hedgehog signalling for maintenance, alongside a direct BMP requirement for self-renewal. Reason: Retained as non-core. Stem cell population maintenance is a tissue-homeostatic output of the pathway. The cited study is centred on BMP signalling, and the curator will have read the full text; the smo requirement in this tissue is independently established (PMID:11279500), so there is no reason to second-guess the annotation. Supporting Evidence: PMID:11279500 Hh acts specifically on stem cells in the Drosophila ovary. These cells cannot proliferate as stem cells in the absence of Hh signalling, whereas excessive Hh signalling produces supernumerary stem cells. |
| GO:0042802 identical protein binding | IPI PMID:17960137 Hedgehog regulates smoothened activity by inducing a conform... | ACCEPT | Summary: Hh-induced phosphorylation of the Smo C-tail antagonises inhibitory arginine clusters and drives dimerisation of the cytoplasmic tails, which is essential for pathway activation; PI(4)P binding to the same arginine motif likewise promotes Smo phosphorylation and dimerisation. Reason: Accepted as a core molecular function. Self-association here is not an incidental interaction but the conformational switch that converts a silent receptor into an active one, and it is supported by independent co-immunoprecipitation and fluorescence-complementation evidence in two laboratories. Supporting Evidence: PMID:17960137 HH-induced phosphorylation disrupts the interaction, and induces a conformational switch and dimerization of SMO cytoplasmic tails, which is essential for pathway activation. PMID:17960137 The Arg clusters inhibit SMO by blocking its cell surface expression and keeping it in an inactive conformation that is maintained by intramolecular electrostatic interactions. |
| GO:0042802 identical protein binding | IPI PMID:26863604 PI(4)P Promotes Phosphorylation and Conformational Change of... | ACCEPT | Summary: Hh-induced phosphorylation of the Smo C-tail antagonises inhibitory arginine clusters and drives dimerisation of the cytoplasmic tails, which is essential for pathway activation; PI(4)P binding to the same arginine motif likewise promotes Smo phosphorylation and dimerisation. Reason: Accepted as a core molecular function. Self-association here is not an incidental interaction but the conformational switch that converts a silent receptor into an active one, and it is supported by independent co-immunoprecipitation and fluorescence-complementation evidence in two laboratories. Supporting Evidence: PMID:26863604 Upon Hh stimulation, PI(4)P production is increased and PI(4)P is also released from Ptc, allowing PI(4)P to bind and activate Smo by promoting Smo phosphorylation and dimerization. |
| GO:0042803 protein homodimerization activity | IDA PMID:21852395 The Hedgehog-induced Smoothened conformational switch assemb... | ACCEPT | Summary: Smo homodimerisation through its phosphorylated C-terminal tail accompanies cell-surface accumulation and the active conformation, and is required for assembly of the active Smo-Cos2-Fu complex. Reason: Accepted, consistent with the identical protein binding rows on the same gene. The cited study documents the Hh-induced conformational change of Smo and the resulting Smo-Cos2-Fu assembly and states the dose-dependent dimerisation/oligomerisation of the Smo C tails; the dimerisation itself is demonstrated most directly in PMID:17960137 and PMID:26863604. Supporting Evidence: PMID:21852395 Phosphorylation promotes Smo cell surface accumulation and active conformation in a dose-dependent manner, leading to dimerization/oligomerization of its C tails PMID:17960137 HH-induced phosphorylation disrupts the interaction, and induces a conformational switch and dimerization of SMO cytoplasmic tails, which is essential for pathway activation. |
| 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 deregulated Hedgehog signalling are reported not to protect themselves from apoptosis; instead they promote survival of neighbouring wild-type cells, and that effect is mediated by Hh-induced Notch signalling raising Diap-1 levels. Reason: Marked as over-annotated. The cited study explicitly establishes that the anti-apoptotic effect is non-cell-autonomous and is executed by Notch and Diap-1 in cells other than the Hh-responding ones. Smo transduces the signal that sets this in motion, but attaching regulation of apoptotic process to Smo makes a second-order, indirect consequence look like a function of the receptor. The IGI partner is head involution defective, a pro-apoptotic effector acting well downstream. The annotation is not false, but it over-reaches. 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:0043025 neuronal cell body | IDA PMID:24768000 Cilia-mediated hedgehog signaling in Drosophila. | KEEP AS NON CORE | Summary: Smo protein is detected in the cell bodies of Drosophila olfactory sensory neurons in addition to their dendrites and sensory cilia. Reason: Retained as non-core. This is a distribution observed in one differentiated cell type and most likely reflects the biosynthetic and trafficking pool of the receptor rather than a site of signalling. Supporting Evidence: PMID:24768000 Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. file:DROME/smo/smo-uniprot.txt Expressed in olfactory sensory neurons (at protein CC level). |
| 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: Hedgehog signalling across the anterior/posterior compartment boundary of imaginal discs, which requires Smo in the receiving anterior cells, contributes to the lineage restriction that keeps the two compartments separate. Reason: Retained as non-core. Compartmental lineage restriction is a tissue-level property produced by differential cell affinity downstream of Hh target gene expression, not something Smo executes. The supporting citation is a review article (TAS), so the annotation reflects author statement rather than primary data, but the underlying requirement for Smo in anterior cells is not in doubt. |
| 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: Anterior/posterior pattern formation in the wing disc depends on Hedgehog signalling received through Smo by anterior compartment cells. Reason: Retained as non-core. The biology is well established for this gene, but it is a developmental output rather than a molecular activity. The cited reference is a general review about adhesion as a patterning force and is only tangentially about Smo; the annotation would be better anchored to one of the primary wing-disc studies already cited in this review. Supporting Evidence: 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:0060170 ciliary membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt records Smo at the cilium membrane on the strength of its localisation to the sensory cilium of Drosophila olfactory sensory neurons. Reason: Accepted. The electronic subcellular-location mapping is grounded in an experimental observation for this very gene (PMID:24768000), and it is the membrane-specific counterpart of the cilium annotation accepted above. Supporting Evidence: file:DROME/smo/smo-uniprot.txt Cell projection, cilium membrane PMID:24768000 We demonstrate that several fundamental key aspects of the vertebrate cilia pathway, such as ciliary localization of Smoothened and the requirement of the intraflagellar transport system, are present in Drosophila. |
| GO:0070273 phosphatidylinositol-4-phosphate binding | IDA PMID:26863604 PI(4)P Promotes Phosphorylation and Conformational Change of... | ACCEPT | Summary: Hedgehog raises PI(4)P levels, and PI(4)P binds Smo directly through an arginine motif in the C-terminal tail, triggering Smo phosphorylation and activation; mutating that motif abolishes both PI(4)P binding and recruitment of the Cos2-Fu complex. Reason: Accepted as a core molecular function. This is direct lipid binding measured on purified protein and in cells, mapped to a defined motif, with a separation-of-function mutant that loses both the binding and the downstream consequence. Supporting Evidence: PMID:26863604 We further found that PI(4)P directly binds Smo through an arginine motif, which then triggers Smo phosphorylation and activation. PMID:26863604 we generated the Arg to Ala mutation in Smo full-length (Myc-SmoRA4) and found that Myc-SmoRA4 lost both the ability to bind PI(4)P (Fig 3J) and the interaction with Cos2-Fu complex (Fig 3K) |
| GO:0070300 phosphatidic acid binding | IDA PMID:37847757 Phosphatidic acid binding to Patched contributes to the inhi... | ACCEPT | Summary: Phosphatidic acid binds a pocket in the transmembrane region of Smo; mutating residues in that pocket reduces Smo activity in vivo and in cultured cells, and Patched appears to control the local availability of PA to Smo. Reason: Accepted as a core molecular function. Direct in vitro binding plus pocket mutants with a matching in vivo signalling defect meet the bar for a molecular function, and PA binding sits in the same lipid-regulation logic as the PI(4)P site and the sterol regulation established for vertebrate SMO. Supporting Evidence: PMID:37847757 Smo also interacted with PA in vitro through a binding pocket located in the transmembrane region, and mutating residues in this pocket reduced Smo activity in vivo and in cells. |
| GO:0071679 commissural neuron axon guidance | IBA GO_REF:0000033 | REMOVE | Summary: Commissural neuron axon guidance is asserted for all eumetazoan descendants of the Smoothened node PTN000885245, but both descendant evidences behind it are vertebrate (rat and zebrafish Smo), and the process presupposes a centralised nervous system with a midline that axons cross. Reason: Removed as an over-propagation, in agreement with the TOO_DEEP assessment recorded for this row in interpro/panther/PTHR11309/PTHR11309-review.yaml. This is not a complaint about donor count: the objection is to the node placement. Drosophila smo is absent from the WITH/FROM list, no Hh/Smo commissural guidance role of this kind is described in the fly, and a vertebrate-scoped sibling node (PTN002601731) already exists that would carry the same evidence without reaching into protostomes. Contrast the cilium and dendrite rows at the same node, where fly smo is itself a seed and the assertion therefore stands. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN000885245 · PTN000885245 SUPPORTS SOURCE BUT NOT TARGET Smoothened node placed at Eumetazoa; the descendant evidence behind this row is vertebrate only. RGD:3726 · Smo SUPPORTS SOURCE BUT NOT TARGET Rat Smo; vertebrate spinal-cord midline context with no Drosophila counterpart. ZFIN:ZDB-GENE-980526-89 · smo SUPPORTS SOURCE BUT NOT TARGET Zebrafish smo; same vertebrate midline context as the rat seed. |
| GO:1903078 positive regulation of protein localization to plasma membrane | IDA PMID:17658259 Evidence for a novel feedback loop in the Hedgehog pathway i... | ACCEPT | Summary: Hedgehog drives targeting of the Fused kinase to the plasma membrane, and this depends on Smo; membrane-anchored Fused becomes a potent Ptc-resistant pathway activator, and Smo and Gprk2 together bind the Fused regulatory domain. Reason: Accepted as a core process annotation. Concentrating Fused at the membrane is not an indirect downstream consequence but the direct mechanism by which Smo activates the kinase, and it is executed by Smo's own C-terminal tail acting with Cos2. Supporting Evidence: PMID:17658259 We show here that HH induces FU targeting to the plasma membrane in a SMO-dependent fashion and that, reciprocally, FU controls SMO stability and phosphorylation. PMID:21844892 Collectively, our data indicate that, in response to a Hh gradient and Smo activity, the Cos2/Fu complex is recruited to the cell membrane through an interaction between Smo and Cos2. PMID:30541874 we show that the last amino acids of the cytoplasmic tail of Smo, in combination with G protein-coupled receptor kinase 2 (Gprk2), bind to the regulatory domain of Fused (Fu) and highly activate its kinase activity |
| GO:2000134 negative regulation of G1/S transition of mitotic cell cycle | IMP PMID:15809036 Extracellular signals responsible for spatially regulated pr... | KEEP AS NON CORE | Summary: In the differentiating Drosophila eye, all cells arrest in G1 ahead of the morphogenetic furrow, and this arrest depends redundantly on Dpp and Hedgehog signalling. Reason: Retained as non-core. The G1/S block is imposed by cell cycle regulators such as Dacapo and Rbf/E2F acting downstream; Hh/Smo is one of two redundant extracellular inputs. This is a cellular consequence of Smo signalling, not a step Smo performs. Supporting Evidence: PMID:15809036 All cells arrest in G1 prior to the start of neurogenesis. Arrest depends on Dpp and Hh, acting redundantly. |
| GO:2000736 regulation of stem cell differentiation | IMP PMID:28619819 Yorkie and Hedgehog independently restrict BMP production in... | KEEP AS NON CORE | Summary: In escort cells of the germarium, Hedgehog signalling limits BMP ligand production so that germline cysts can differentiate; Hh and Yorkie do this through separate outputs. Reason: Retained as non-core. Regulation of stem cell differentiation here is a niche-level effect produced by Ci-dependent changes in BMP ligand expression. Smo's role is reception of the Hh signal. Supporting Evidence: PMID:28619819 Here, we show that in ECs both Hh and Yki limit production of BMP ligands to allow germline differentiation. |
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Download this section (compressed HTML)Q: Drosophila Smo localises to the sensory cilium of olfactory sensory neurons and signals there, yet imaginal-disc Hedgehog transduction is cilium-independent. Do the ciliary and cytoplasmic routes use the same Smo C-tail phosphorylation code, or does ciliary signalling read a different set of sites?
Q: How much of fly Hedgehog signalling output actually flows through Galphai and cAMP, as opposed to the Cos2/Fused route, and can the two be separated genetically in the wing disc?
Q: Vertebrate SMO is activated by sterols binding the cysteine-rich domain and a transmembrane channel, whereas the demonstrated lipid ligands of fly Smo are PI(4)P and phosphatidic acid. Is sterol regulation conserved in Drosophila, or has the fly receptor switched to a different lipid code?
Q: Should the PAINT commissural neuron axon guidance assertion at node PTN000885245 be moved to the vertebrate-scoped sibling node PTN002601731, given that both descendant evidences are vertebrate?
Experiment: Generate an allelic series of endogenous smo knock-ins in which each of the three PKA/CK1 serine clusters, the Gprk2 site Ser741/Thr742 and the distal Fused-binding segment are mutated individually to alanine. Score, in the same animals, Hedgehog target gene induction in the wing disc (cilium-independent) and in olfactory sensory neurons (cilium-dependent), together with Smo localisation to the sensory cilium and to the disc plasma membrane.
Hypothesis: Ciliary and non-ciliary Hedgehog transduction in Drosophila require different subsets of the C-terminal tail phosphorylation clusters of Smo.
Type: CRISPR knock-in allelic series with tissue-paired reporter and imaging readouts
Experiment: Introduce endogenous separation-of-function smo alleles that delete the Cos2-binding segment while leaving the transmembrane core intact, and, separately, that disrupt the predicted Galphai coupling surface. Measure Cos2/Fu recruitment to the membrane by FRET, Fused activation-loop phosphorylation, cellular cAMP, Ci-155 processing and target gene expression, with wild-type rescue controls.
Hypothesis: The Smo C-terminal tail acts as the adaptor that recruits the Costal-2/Fused complex, and this adaptor role is separable from Galphai coupling.
Type: Separation-of-function knock-in with FRET, phospho-specific immunoblot and cAMP readouts
smoothened (smo) encodes a critical component of the Hedgehog signaling pathway. It is regulated by phosphorylation, dimerization, and cell-surface accumulation upon Hedgehog stimulation. The product of smo is also regulated by ubiquitin and other small molecules such as phospholipids.
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