SMO (Smoothened) is a 787-amino-acid, seven-pass class-F G protein-coupled receptor and the obligate signal-transducing membrane component of vertebrate Hedgehog signaling. In the pathway-off state, PTCH1 or PTCH2 restricts SMO access to activating sterols. Hedgehog binding to Patched relieves this inhibition, allowing cholesterol and oxysterols to bind SMO's extracellular cysteine-rich domain and transmembrane sterol-binding sites, stabilize an active conformation, and promote accumulation of SMO in the primary-cilium membrane. Active SMO can couple to heterotrimeric Gi, lowering cAMP, and also directly binds and inhibits the catalytic subunit of protein kinase A through a C-terminal pseudosubstrate/PKI motif. These mechanisms prevent inhibitory phosphorylation and processing of GLI transcription factors and permit GLI-dependent transcription. SMO therefore functions principally at the plasma membrane and the membrane of non-motile primary cilia, with context-dependent roles in embryonic patterning, organogenesis, tissue homeostasis, and cell proliferation. Germline biallelic loss-of-function variants cause pleiotropic developmental anomalies through impaired Hedgehog signaling, whereas activating somatic or mosaic variants drive tumors and Curry-Jones syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The plasma membrane annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. Supporting Evidence: file:human/SMO/SMO-uniprot.txt Cell membrane |
| GO:0005929 cilium | IBA GO_REF:0000033 | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The cilium annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. Supporting Evidence: file:human/SMO/SMO-uniprot.txt Cell projection, cilium membrane |
| GO:0007224 smoothened signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: SMO is the membrane transducer of the smoothened signaling pathway; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This phylogenetic inference is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. Supporting Evidence: file:human/SMO/SMO-uniprot.txt G protein-coupled receptor, which transduces the smoothened signaling pathway |
| GO:0007417 central nervous system development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The central nervous system development annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The phylogenetic inference (GO_REF:0000033) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0007389 pattern specification process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The pattern specification process annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The phylogenetic inference (GO_REF:0000033) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0030425 dendrite | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The dendrite annotation is compatible with a context-specific localization, trafficking state, or downstream role of SMO, but it does not define SMO's core receptor/transducer activity. Reason: Retained as non-core on the basis of phylogenetic inference (GO_REF:0000033); it is secondary to SMO's sterol-regulated signaling activity at the plasma and primary-cilium membranes. |
| GO:0071679 commissural neuron axon guidance | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The commissural neuron axon guidance annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The phylogenetic inference (GO_REF:0000033) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0005113 patched binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Patched proteins negatively regulate SMO and older biochemical experiments reported PTCH-SMO complexes. Current mechanistic work emphasizes control of SMO sterol access rather than a required stable receptor complex. Reason: Retained as non-core because the physical association is reported by PMID:9811851 and supported phylogenetically, but patched binding is not the principal molecular activity of SMO. |
| GO:0004888 transmembrane signaling receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: The transmembrane signaling receptor activity annotation is directionally correct but too broad to represent SMO's established function. SMO is a sterol-regulated class-F GPCR that transduces the smoothened pathway at plasma and ciliary membranes. Reason: Modify to the more informative G protein-coupled receptor activity (GO:0004930). The replacement preserves the source inference (GO_REF:0000002) while matching the experimentally established specificity of SMO. Proposed replacements: G protein-coupled receptor activity |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The plasma membrane annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. |
| GO:0007166 cell surface receptor signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: The cell surface receptor signaling pathway annotation is directionally correct but too broad to represent SMO's established function. SMO is a sterol-regulated class-F GPCR that transduces the smoothened pathway at plasma and ciliary membranes. Reason: Modify to the more informative smoothened signaling pathway (GO:0007224). The replacement preserves the source inference (GO_REF:0000002) while matching the experimentally established specificity of SMO. Proposed replacements: smoothened signaling pathway |
| GO:0009888 tissue development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: The tissue development phenotype can occur downstream of altered SMO/Hedgehog signaling, but the annotation makes an indirect cellular or organismal output appear to be a direct activity of SMO. Reason: Marked as over-annotated. The source (GO_REF:0000117; electronic inference) supports pathway perturbation or a downstream phenotype, whereas SMO directly performs receptor/transducer, sterol-binding, Gi-coupling, and PKA-inhibitory functions. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: The membrane annotation is directionally correct but too broad to represent SMO's established function. SMO is a sterol-regulated class-F GPCR that transduces the smoothened pathway at plasma and ciliary membranes. Reason: Modify to the more informative plasma membrane (GO:0005886) and ciliary membrane (GO:0060170). The replacement preserves the source inference (GO_REF:0000002) while matching the experimentally established specificity of SMO. Proposed replacements: plasma membrane ciliary membrane |
| GO:0060170 ciliary membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The ciliary membrane annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. |
| GO:0120025 plasma membrane bounded cell projection | IEA GO_REF:0000117 | MODIFY | Summary: The plasma membrane bounded cell projection annotation is directionally correct but too broad to represent SMO's established function. SMO is a sterol-regulated class-F GPCR that transduces the smoothened pathway at plasma and ciliary membranes. Reason: Modify to the more informative cilium (GO:0005929). The replacement preserves the source inference (GO_REF:0000117) while matching the experimentally established specificity of SMO. Proposed replacements: cilium |
| GO:0001947 heart looping | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The heart looping annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The electronic inference (GO_REF:0000107) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0003140 determination of left/right asymmetry in lateral mesoderm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The determination of left/right asymmetry in lateral mesoderm annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The electronic inference (GO_REF:0000107) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: The G protein-coupled receptor activity annotation captures a directly established molecular activity of SMO. Sterol-regulated class-F GPCR signaling and direct PKA-C engagement are supported by structural, biochemical, and cellular studies; this electronic inference is concordant with that mechanism. Reason: Accepted as part of SMO's core molecular mechanism. The source (GO_REF:0000107) is consistent with direct human SMO evidence summarized in PMID:27437577, PMID:31168089, PMID:32929279, PMID:36202993, and PMID:39138140, as applicable to this activity. Supporting Evidence: file:human/SMO/SMO-uniprot.txt G protein-coupled receptor, which transduces the smoothened signaling pathway |
| GO:0005929 cilium | IEA GO_REF:0000107 | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The cilium annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. Supporting Evidence: file:human/SMO/SMO-uniprot.txt Cell projection, cilium membrane |
| GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: SMO is the membrane transducer of the adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This electronic inference is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. Supporting Evidence: file:human/SMO/SMO-uniprot.txt G protein-coupled receptor, which transduces the smoothened signaling pathway |
| GO:0007224 smoothened signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: SMO is the membrane transducer of the smoothened signaling pathway; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This electronic inference is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. Supporting Evidence: file:human/SMO/SMO-uniprot.txt G protein-coupled receptor, which transduces the smoothened signaling pathway |
| GO:0007371 ventral midline determination | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The ventral midline determination annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The electronic inference (GO_REF:0000107) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0007494 midgut development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The midgut development annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The electronic inference (GO_REF:0000107) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0008142 oxysterol binding | IEA GO_REF:0000107 | ACCEPT | Summary: The oxysterol binding annotation captures a directly established molecular activity of SMO. Sterol-regulated class-F GPCR signaling and direct PKA-C engagement are supported by structural, biochemical, and cellular studies; this electronic inference is concordant with that mechanism. Reason: Accepted as part of SMO's core molecular mechanism. The source (GO_REF:0000107) is consistent with direct human SMO evidence summarized in PMID:27437577, PMID:31168089, PMID:32929279, PMID:36202993, and PMID:39138140, as applicable to this activity. Supporting Evidence: file:human/SMO/SMO-uniprot.txt In addition to cholesterol, SMO is also activated by various oxysterols |
| GO:0015485 cholesterol binding | IEA GO_REF:0000107 | ACCEPT | Summary: The cholesterol binding annotation captures a directly established molecular activity of SMO. Sterol-regulated class-F GPCR signaling and direct PKA-C engagement are supported by structural, biochemical, and cellular studies; this electronic inference is concordant with that mechanism. Reason: Accepted as part of SMO's core molecular mechanism. The source (GO_REF:0000107) is consistent with direct human SMO evidence summarized in PMID:27437577, PMID:31168089, PMID:32929279, PMID:36202993, and PMID:39138140, as applicable to this activity. Supporting Evidence: file:human/SMO/SMO-uniprot.txt G protein-coupled receptor, which transduces the smoothened signaling pathway |
| GO:0021513 spinal cord dorsal/ventral patterning | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The spinal cord dorsal/ventral patterning annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The electronic inference (GO_REF:0000107) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0034236 protein kinase A catalytic subunit binding | IEA GO_REF:0000107 | ACCEPT | Summary: The protein kinase A catalytic subunit binding annotation captures a directly established molecular activity of SMO. Sterol-regulated class-F GPCR signaling and direct PKA-C engagement are supported by structural, biochemical, and cellular studies; this electronic inference is concordant with that mechanism. Reason: Accepted as part of SMO's core molecular mechanism. The source (GO_REF:0000107) is consistent with direct human SMO evidence summarized in PMID:27437577, PMID:31168089, PMID:32929279, PMID:36202993, and PMID:39138140, as applicable to this activity. Supporting Evidence: file:human/SMO/SMO-uniprot.txt Interacts (via PKI motif) with protein kinase A catalytic subunit PRKACA |
| GO:0040018 positive regulation of multicellular organism growth | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The positive regulation of multicellular organism growth phenotype can occur downstream of altered SMO/Hedgehog signaling, but the annotation makes an indirect cellular or organismal output appear to be a direct activity of SMO. Reason: Marked as over-annotated. The source (GO_REF:0000107; electronic inference) supports pathway perturbation or a downstream phenotype, whereas SMO directly performs receptor/transducer, sterol-binding, Gi-coupling, and PKA-inhibitory functions. |
| GO:0045880 positive regulation of smoothened signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: SMO is the membrane transducer of the positive regulation of smoothened signaling pathway; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This electronic inference is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. Supporting Evidence: file:human/SMO/SMO-uniprot.txt G protein-coupled receptor, which transduces the smoothened signaling pathway |
| GO:0045892 negative regulation of DNA-templated transcription | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The negative regulation of DNA-templated transcription phenotype can occur downstream of altered SMO/Hedgehog signaling, but the annotation makes an indirect cellular or organismal output appear to be a direct activity of SMO. Reason: Marked as over-annotated. The source (GO_REF:0000107; electronic inference) supports pathway perturbation or a downstream phenotype, whereas SMO directly performs receptor/transducer, sterol-binding, Gi-coupling, and PKA-inhibitory functions. |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The positive regulation of DNA-templated transcription phenotype can occur downstream of altered SMO/Hedgehog signaling, but the annotation makes an indirect cellular or organismal output appear to be a direct activity of SMO. Reason: Marked as over-annotated. The source (GO_REF:0000107; electronic inference) supports pathway perturbation or a downstream phenotype, whereas SMO directly performs receptor/transducer, sterol-binding, Gi-coupling, and PKA-inhibitory functions. |
| GO:0046622 positive regulation of organ growth | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The positive regulation of organ growth phenotype can occur downstream of altered SMO/Hedgehog signaling, but the annotation makes an indirect cellular or organismal output appear to be a direct activity of SMO. Reason: Marked as over-annotated. The source (GO_REF:0000107; electronic inference) supports pathway perturbation or a downstream phenotype, whereas SMO directly performs receptor/transducer, sterol-binding, Gi-coupling, and PKA-inhibitory functions. |
| GO:0048853 forebrain morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The forebrain morphogenesis annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The electronic inference (GO_REF:0000107) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0061053 somite development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The somite development annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The electronic inference (GO_REF:0000107) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0071397 cellular response to cholesterol | IEA GO_REF:0000107 | ACCEPT | Summary: SMO is the membrane transducer of the cellular response to cholesterol; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This electronic inference is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. Supporting Evidence: file:human/SMO/SMO-uniprot.txt G protein-coupled receptor, which transduces the smoothened signaling pathway |
| GO:0072285 mesenchymal to epithelial transition involved in metanephric renal vesicle formation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The mesenchymal to epithelial transition involved in metanephric renal vesicle formation annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The electronic inference (GO_REF:0000107) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0090190 positive regulation of branching involved in ureteric bud morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The positive regulation of branching involved in ureteric bud morphogenesis annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The electronic inference (GO_REF:0000107) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0098804 non-motile cilium membrane | IEA GO_REF:0000107 | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The non-motile cilium membrane annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. Supporting Evidence: file:human/SMO/SMO-uniprot.txt Cell projection, cilium membrane |
| GO:0140311 protein sequestering activity | IEA GO_REF:0000107 | ACCEPT | Summary: The protein sequestering activity annotation captures a directly established molecular activity of SMO. Sterol-regulated class-F GPCR signaling and direct PKA-C engagement are supported by structural, biochemical, and cellular studies; this electronic inference is concordant with that mechanism. Reason: Accepted as part of SMO's core molecular mechanism. The source (GO_REF:0000107) is consistent with direct human SMO evidence summarized in PMID:27437577, PMID:31168089, PMID:32929279, PMID:36202993, and PMID:39138140, as applicable to this activity. Supporting Evidence: file:human/SMO/SMO-uniprot.txt Interacts (via PKI motif) with protein kinase A catalytic subunit PRKACA |
| GO:2000826 regulation of heart morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The regulation of heart morphogenesis annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The electronic inference (GO_REF:0000107) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0004930 G protein-coupled receptor activity | IDA PMID:27437577 Structural basis of Smoothened regulation by its extracellul... | ACCEPT | Summary: The G protein-coupled receptor activity annotation captures a directly established molecular activity of SMO. Sterol-regulated class-F GPCR signaling and direct PKA-C engagement are supported by structural, biochemical, and cellular studies; this IDA experimental evidence is concordant with that mechanism. Reason: Accepted as part of SMO's core molecular mechanism. The source (PMID:27437577) is consistent with direct human SMO evidence summarized in PMID:27437577, PMID:31168089, PMID:32929279, PMID:36202993, and PMID:39138140, as applicable to this activity. Supporting Evidence: PMID:27437577 Unexpectedly, we find a cholesterol molecule bound to Smoothened in the CRD binding site. |
| GO:0004930 G protein-coupled receptor activity | IDA PMID:31168089 Cryo-EM structure of oxysterol-bound human Smoothened couple... | ACCEPT | Summary: The G protein-coupled receptor activity annotation captures a directly established molecular activity of SMO. Sterol-regulated class-F GPCR signaling and direct PKA-C engagement are supported by structural, biochemical, and cellular studies; this IDA experimental evidence is concordant with that mechanism. Reason: Accepted as part of SMO's core molecular mechanism. The source (PMID:31168089) is consistent with direct human SMO evidence summarized in PMID:27437577, PMID:31168089, PMID:32929279, PMID:36202993, and PMID:39138140, as applicable to this activity. Supporting Evidence: PMID:31168089 The oncoprotein Smoothened (SMO), a G-protein-coupled receptor (GPCR) of the Frizzled-class (class-F), transduces the Hedgehog signal |
| GO:0004930 G protein-coupled receptor activity | IDA PMID:32929279 Sterols in an intramolecular channel of Smoothened mediate H... | ACCEPT | Summary: The G protein-coupled receptor activity annotation captures a directly established molecular activity of SMO. Sterol-regulated class-F GPCR signaling and direct PKA-C engagement are supported by structural, biochemical, and cellular studies; this IDA experimental evidence is concordant with that mechanism. Reason: Accepted as part of SMO's core molecular mechanism. The source (PMID:32929279) is consistent with direct human SMO evidence summarized in PMID:27437577, PMID:31168089, PMID:32929279, PMID:36202993, and PMID:39138140, as applicable to this activity. Supporting Evidence: PMID:32929279 Smoothened (SMO), a class Frizzled G protein-coupled receptor (class F GPCR), transduces the Hedgehog signal across the cell membrane. |
| GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway | IDA PMID:32929279 Sterols in an intramolecular channel of Smoothened mediate H... | ACCEPT | Summary: SMO is the membrane transducer of the adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This IDA experimental evidence is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. Supporting Evidence: PMID:32929279 Smoothened (SMO), a class Frizzled G protein-coupled receptor (class F GPCR), transduces the Hedgehog signal across the cell membrane. |
| GO:0007224 smoothened signaling pathway | IDA PMID:31168089 Cryo-EM structure of oxysterol-bound human Smoothened couple... | ACCEPT | Summary: SMO is the membrane transducer of the smoothened signaling pathway; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This IDA experimental evidence is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. Supporting Evidence: PMID:31168089 The oncoprotein Smoothened (SMO), a G-protein-coupled receptor (GPCR) of the Frizzled-class (class-F), transduces the Hedgehog signal |
| GO:0007224 smoothened signaling pathway | IDA PMID:32929279 Sterols in an intramolecular channel of Smoothened mediate H... | ACCEPT | Summary: SMO is the membrane transducer of the smoothened signaling pathway; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This IDA experimental evidence is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. Supporting Evidence: PMID:32929279 Smoothened (SMO), a class Frizzled G protein-coupled receptor (class F GPCR), transduces the Hedgehog signal across the cell membrane. |
| GO:0007224 smoothened signaling pathway | IDA PMID:39138140 GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA s... | ACCEPT | Summary: SMO is the membrane transducer of the smoothened signaling pathway; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This IDA experimental evidence is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. Supporting Evidence: PMID:39138140 GRK2 phosphorylation enables active SMO to bind PKA-C directly. |
| GO:0015485 cholesterol binding | IDA PMID:27437577 Structural basis of Smoothened regulation by its extracellul... | ACCEPT | Summary: The cholesterol binding annotation captures a directly established molecular activity of SMO. Sterol-regulated class-F GPCR signaling and direct PKA-C engagement are supported by structural, biochemical, and cellular studies; this IDA experimental evidence is concordant with that mechanism. Reason: Accepted as part of SMO's core molecular mechanism. The source (PMID:27437577) is consistent with direct human SMO evidence summarized in PMID:27437577, PMID:31168089, PMID:32929279, PMID:36202993, and PMID:39138140, as applicable to this activity. Supporting Evidence: PMID:27437577 Unexpectedly, we find a cholesterol molecule bound to Smoothened in the CRD binding site. |
| GO:0015485 cholesterol binding | IDA PMID:31168089 Cryo-EM structure of oxysterol-bound human Smoothened couple... | ACCEPT | Summary: The cholesterol binding annotation captures a directly established molecular activity of SMO. Sterol-regulated class-F GPCR signaling and direct PKA-C engagement are supported by structural, biochemical, and cellular studies; this IDA experimental evidence is concordant with that mechanism. Reason: Accepted as part of SMO's core molecular mechanism. The source (PMID:31168089) is consistent with direct human SMO evidence summarized in PMID:27437577, PMID:31168089, PMID:32929279, PMID:36202993, and PMID:39138140, as applicable to this activity. Supporting Evidence: PMID:31168089 The oncoprotein Smoothened (SMO), a G-protein-coupled receptor (GPCR) of the Frizzled-class (class-F), transduces the Hedgehog signal |
| GO:0015485 cholesterol binding | IDA PMID:32929279 Sterols in an intramolecular channel of Smoothened mediate H... | ACCEPT | Summary: The cholesterol binding annotation captures a directly established molecular activity of SMO. Sterol-regulated class-F GPCR signaling and direct PKA-C engagement are supported by structural, biochemical, and cellular studies; this IDA experimental evidence is concordant with that mechanism. Reason: Accepted as part of SMO's core molecular mechanism. The source (PMID:32929279) is consistent with direct human SMO evidence summarized in PMID:27437577, PMID:31168089, PMID:32929279, PMID:36202993, and PMID:39138140, as applicable to this activity. Supporting Evidence: PMID:32929279 Smoothened (SMO), a class Frizzled G protein-coupled receptor (class F GPCR), transduces the Hedgehog signal across the cell membrane. |
| GO:0140311 protein sequestering activity | IDA PMID:39138140 GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA s... | ACCEPT | Summary: The protein sequestering activity annotation captures a directly established molecular activity of SMO. Sterol-regulated class-F GPCR signaling and direct PKA-C engagement are supported by structural, biochemical, and cellular studies; this IDA experimental evidence is concordant with that mechanism. Reason: Accepted as part of SMO's core molecular mechanism. The source (PMID:39138140) is consistent with direct human SMO evidence summarized in PMID:27437577, PMID:31168089, PMID:32929279, PMID:36202993, and PMID:39138140, as applicable to this activity. Supporting Evidence: PMID:39138140 GRK2 phosphorylation enables active SMO to bind PKA-C directly. |
| GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway | IDA PMID:31168089 Cryo-EM structure of oxysterol-bound human Smoothened couple... | ACCEPT | Summary: SMO is the membrane transducer of the adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This IDA experimental evidence is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. Supporting Evidence: PMID:31168089 The oncoprotein Smoothened (SMO), a G-protein-coupled receptor (GPCR) of the Frizzled-class (class-F), transduces the Hedgehog signal |
| GO:0098804 non-motile cilium membrane | IDA PMID:31168089 Cryo-EM structure of oxysterol-bound human Smoothened couple... | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The non-motile cilium membrane annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. Supporting Evidence: PMID:31168089 The oncoprotein Smoothened (SMO), a G-protein-coupled receptor (GPCR) of the Frizzled-class (class-F), transduces the Hedgehog signal |
| GO:0140311 protein sequestering activity | IDA PMID:36202993 A PKA inhibitor motif within SMOOTHENED controls Hedgehog si... | ACCEPT | Summary: The protein sequestering activity annotation captures a directly established molecular activity of SMO. Sterol-regulated class-F GPCR signaling and direct PKA-C engagement are supported by structural, biochemical, and cellular studies; this IDA experimental evidence is concordant with that mechanism. Reason: Accepted as part of SMO's core molecular mechanism. The source (PMID:36202993) is consistent with direct human SMO evidence summarized in PMID:27437577, PMID:31168089, PMID:32929279, PMID:36202993, and PMID:39138140, as applicable to this activity. Supporting Evidence: PMID:36202993 SMO uses a decoy substrate sequence to physically block the active site of the cAMP-dependent protein kinase (PKA) catalytic subunit (PKA-C) and extinguish its enzymatic activity. |
| GO:0098804 non-motile cilium membrane | IDA PMID:22072986 A novel protein LZTFL1 regulates ciliary trafficking of the ... | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The non-motile cilium membrane annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. Supporting Evidence: PMID:22072986 In control siRNA transfected cells, SMO localizes to the cilia in response to SMO agonist (SAG) but not in SAG-untreated cells |
| GO:0005929 cilium | IDA GO_REF:0000052 | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The cilium annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The plasma membrane annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. Supporting Evidence: file:human/SMO/SMO-uniprot.txt Cell membrane |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: The positive regulation of transcription by RNA polymerase II phenotype can occur downstream of altered SMO/Hedgehog signaling, but the annotation makes an indirect cellular or organismal output appear to be a direct activity of SMO. Reason: Marked as over-annotated. The source (GO_REF:0000024; curator-reviewed orthology transfer) supports pathway perturbation or a downstream phenotype, whereas SMO directly performs receptor/transducer, sterol-binding, Gi-coupling, and PKA-inhibitory functions. |
| GO:0007224 smoothened signaling pathway | IDA PMID:36202993 A PKA inhibitor motif within SMOOTHENED controls Hedgehog si... | ACCEPT | Summary: SMO is the membrane transducer of the smoothened signaling pathway; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This IDA experimental evidence is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. Supporting Evidence: PMID:36202993 SMO uses a decoy substrate sequence to physically block the active site of the cAMP-dependent protein kinase (PKA) catalytic subunit (PKA-C) and extinguish its enzymatic activity. |
| GO:0007224 smoothened signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: SMO is the membrane transducer of the smoothened signaling pathway; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This curator-reviewed orthology transfer is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. Supporting Evidence: file:human/SMO/SMO-uniprot.txt G protein-coupled receptor, which transduces the smoothened signaling pathway |
| GO:0034236 protein kinase A catalytic subunit binding | ISS GO_REF:0000024 | ACCEPT | Summary: The protein kinase A catalytic subunit binding annotation captures a directly established molecular activity of SMO. Sterol-regulated class-F GPCR signaling and direct PKA-C engagement are supported by structural, biochemical, and cellular studies; this curator-reviewed orthology transfer is concordant with that mechanism. Reason: Accepted as part of SMO's core molecular mechanism. The source (GO_REF:0000024) is consistent with direct human SMO evidence summarized in PMID:27437577, PMID:31168089, PMID:32929279, PMID:36202993, and PMID:39138140, as applicable to this activity. Supporting Evidence: file:human/SMO/SMO-uniprot.txt Interacts (via PKI motif) with protein kinase A catalytic subunit PRKACA |
| GO:0008142 oxysterol binding | ISS GO_REF:0000024 | ACCEPT | Summary: The oxysterol binding annotation captures a directly established molecular activity of SMO. Sterol-regulated class-F GPCR signaling and direct PKA-C engagement are supported by structural, biochemical, and cellular studies; this curator-reviewed orthology transfer is concordant with that mechanism. Reason: Accepted as part of SMO's core molecular mechanism. The source (GO_REF:0000024) is consistent with direct human SMO evidence summarized in PMID:27437577, PMID:31168089, PMID:32929279, PMID:36202993, and PMID:39138140, as applicable to this activity. Supporting Evidence: file:human/SMO/SMO-uniprot.txt In addition to cholesterol, SMO is also activated by various oxysterols |
| GO:0005929 cilium | IDA PMID:32413283 Bi-allelic Variations of SMO in Humans Cause a Broad Spectru... | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The cilium annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. Supporting Evidence: PMID:32413283 Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction as a result of either altered PC trafficking or abnormal activation of the pathway downstream of SMO. |
| GO:0007224 smoothened signaling pathway | IMP PMID:32413283 Bi-allelic Variations of SMO in Humans Cause a Broad Spectru... | ACCEPT | Summary: SMO is the membrane transducer of the smoothened signaling pathway; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This IMP experimental evidence is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. Supporting Evidence: PMID:32413283 Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction as a result of either altered PC trafficking or abnormal activation of the pathway downstream of SMO. |
| GO:0005929 cilium | IDA PMID:27727273 Zfp423 Regulates Sonic Hedgehog Signaling via Primary Cilium... | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The cilium annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. Supporting Evidence: PMID:27727273 loss of Zfp423 in these precursors leads to cell-intrinsic reduction in proliferation, loss of response to Shh, and primary cilia abnormalities that include diminished frequency of both Smoothened and IFT88 localization. |
| GO:0048745 smooth muscle tissue development | IEP PMID:17850284 Immunohistochemical analysis of Sonic hedgehog signalling in... | KEEP AS NON CORE | Summary: The smooth muscle tissue development annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The expression-pattern evidence (PMID:17850284) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. Supporting Evidence: PMID:17850284 The expression patterns of the SHH-transducing proteins Patched (PTCH) and Smoothened (SMO) were consistent with long-range paracrine signalling associated with detrusor smooth muscle differentiation in the urogenital sinus. |
| GO:0010628 positive regulation of gene expression | IMP PMID:21671467 miR-338-3p suppresses invasion of liver cancer cell by targe... | MARK AS OVER ANNOTATED | Summary: The positive regulation of gene expression phenotype can occur downstream of altered SMO/Hedgehog signaling, but the annotation makes an indirect cellular or organismal output appear to be a direct activity of SMO. Reason: Marked as over-annotated. The source (PMID:21671467; IMP experimental evidence) supports pathway perturbation or a downstream phenotype, whereas SMO directly performs receptor/transducer, sterol-binding, Gi-coupling, and PKA-inhibitory functions. Supporting Evidence: PMID:21671467 small interfering RNA targeted SMO reversed the effects induced by blockade of miR-338-3p. |
| GO:0030335 positive regulation of cell migration | IMP PMID:21671467 miR-338-3p suppresses invasion of liver cancer cell by targe... | MARK AS OVER ANNOTATED | Summary: The positive regulation of cell migration phenotype can occur downstream of altered SMO/Hedgehog signaling, but the annotation makes an indirect cellular or organismal output appear to be a direct activity of SMO. Reason: Marked as over-annotated. The source (PMID:21671467; IMP experimental evidence) supports pathway perturbation or a downstream phenotype, whereas SMO directly performs receptor/transducer, sterol-binding, Gi-coupling, and PKA-inhibitory functions. Supporting Evidence: PMID:21671467 small interfering RNA targeted SMO reversed the effects induced by blockade of miR-338-3p. |
| GO:0005515 protein binding | IPI PMID:21659505 Growth Arrest Specific 8 (Gas8) and G protein-coupled recept... | MARK AS OVER ANNOTATED | Summary: The protein binding phenotype can occur downstream of altered SMO/Hedgehog signaling, but the annotation makes an indirect cellular or organismal output appear to be a direct activity of SMO. Reason: Marked as over-annotated. The source (PMID:21659505; IPI experimental evidence) supports pathway perturbation or a downstream phenotype, whereas SMO directly performs receptor/transducer, sterol-binding, Gi-coupling, and PKA-inhibitory functions. Supporting Evidence: PMID:21659505 Here we demonstrate that Growth Arrest Specific 8 (Gas8), a microtubule associated subunit of the Dynein Regulatory Complex (DRC), interacts with Smo to modulate this process. |
| GO:0005929 cilium | ISS GO_REF:0000024 | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The cilium annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. Supporting Evidence: file:human/SMO/SMO-uniprot.txt Cell projection, cilium membrane |
| GO:0005901 caveola | IDA PMID:11278759 The sonic hedgehog receptor patched associates with caveolin... | KEEP AS NON CORE | Summary: The caveola annotation is compatible with a context-specific localization, trafficking state, or downstream role of SMO, but it does not define SMO's core receptor/transducer activity. Reason: Retained as non-core on the basis of IDA experimental evidence (PMID:11278759); it is secondary to SMO's sterol-regulated signaling activity at the plasma and primary-cilium membranes. Supporting Evidence: PMID:11278759 both Smoothened and Patched are in caveolin-1-enriched/raft microdomains. |
| GO:0060170 ciliary membrane | TAS Reactome:R-HSA-5633040 | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The ciliary membrane annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. |
| GO:0060170 ciliary membrane | TAS Reactome:R-HSA-5632668 | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The ciliary membrane annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. |
| GO:0097542 ciliary tip | TAS Reactome:R-HSA-5610763 | KEEP AS NON CORE | Summary: The ciliary tip annotation is compatible with a context-specific localization, trafficking state, or downstream role of SMO, but it does not define SMO's core receptor/transducer activity. Reason: Retained as non-core on the basis of traceable-author-statement curation (Reactome:R-HSA-5610763); it is secondary to SMO's sterol-regulated signaling activity at the plasma and primary-cilium membranes. |
| GO:0030666 endocytic vesicle membrane | TAS Reactome:R-HSA-5610763 | KEEP AS NON CORE | Summary: The endocytic vesicle membrane annotation is compatible with a context-specific localization, trafficking state, or downstream role of SMO, but it does not define SMO's core receptor/transducer activity. Reason: Retained as non-core on the basis of traceable-author-statement curation (Reactome:R-HSA-5610763); it is secondary to SMO's sterol-regulated signaling activity at the plasma and primary-cilium membranes. |
| GO:0030666 endocytic vesicle membrane | TAS Reactome:R-HSA-5632668 | KEEP AS NON CORE | Summary: The endocytic vesicle membrane annotation is compatible with a context-specific localization, trafficking state, or downstream role of SMO, but it does not define SMO's core receptor/transducer activity. Reason: Retained as non-core on the basis of traceable-author-statement curation (Reactome:R-HSA-5632668); it is secondary to SMO's sterol-regulated signaling activity at the plasma and primary-cilium membranes. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: The extracellular exosome annotation is compatible with a context-specific localization, trafficking state, or downstream role of SMO, but it does not define SMO's core receptor/transducer activity. Reason: Retained as non-core on the basis of high-throughput direct assay (PMID:23533145); it is secondary to SMO's sterol-regulated signaling activity at the plasma and primary-cilium membranes. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: The extracellular exosome annotation is compatible with a context-specific localization, trafficking state, or downstream role of SMO, but it does not define SMO's core receptor/transducer activity. Reason: Retained as non-core on the basis of high-throughput direct assay (PMID:19056867); it is secondary to SMO's sterol-regulated signaling activity at the plasma and primary-cilium membranes. |
| GO:0005794 Golgi apparatus | IDA PMID:11278759 The sonic hedgehog receptor patched associates with caveolin... | KEEP AS NON CORE | Summary: The Golgi apparatus annotation is compatible with a context-specific localization, trafficking state, or downstream role of SMO, but it does not define SMO's core receptor/transducer activity. Reason: Retained as non-core on the basis of IDA experimental evidence (PMID:11278759); it is secondary to SMO's sterol-regulated signaling activity at the plasma and primary-cilium membranes. Supporting Evidence: PMID:11278759 both Smoothened and Patched are in caveolin-1-enriched/raft microdomains. |
| GO:0071397 cellular response to cholesterol | ISS GO_REF:0000024 | ACCEPT | Summary: SMO is the membrane transducer of the cellular response to cholesterol; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This curator-reviewed orthology transfer is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. Supporting Evidence: file:human/SMO/SMO-uniprot.txt G protein-coupled receptor, which transduces the smoothened signaling pathway |
| GO:0005929 cilium | TAS PMID:21931618 The hedgehog receptor patched is involved in cholesterol tra... | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The cilium annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. |
| GO:0005113 patched binding | IPI PMID:9811851 Characterization of two patched receptors for the vertebrate... | KEEP AS NON CORE | Summary: Patched proteins negatively regulate SMO and older biochemical experiments reported PTCH-SMO complexes. Current mechanistic work emphasizes control of SMO sterol access rather than a required stable receptor complex. Reason: Retained as non-core because the physical association is reported by PMID:9811851 and supported phylogenetically, but patched binding is not the principal molecular activity of SMO. Supporting Evidence: PMID:9811851 they can form a complex with SMO. |
| GO:0007371 ventral midline determination | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The ventral midline determination annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The curator-reviewed orthology transfer (GO_REF:0000024) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:2000826 regulation of heart morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The regulation of heart morphogenesis annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The curator-reviewed orthology transfer (GO_REF:0000024) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0005886 plasma membrane | IDA PMID:19304771 Evidence for allosteric interactions of antagonist binding t... | ACCEPT | Summary: SMO functions as a multi-pass receptor at the plasma membrane and undergoes activation-dependent accumulation in the membrane of the non-motile primary cilium. The plasma membrane annotation is consistent with this established trafficking and signaling cycle. Reason: Accepted as a functionally relevant location. Human cell imaging and biochemical work place SMO at the plasma membrane and primary-cilium membrane, where sterol activation and PKA-C regulation occur. Supporting Evidence: PMID:19304771 Binding of two radioligands |
| GO:0007224 smoothened signaling pathway | IMP PMID:19304771 Evidence for allosteric interactions of antagonist binding t... | ACCEPT | Summary: SMO is the membrane transducer of the smoothened signaling pathway; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This IMP experimental evidence is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. Supporting Evidence: PMID:19304771 Binding of two radioligands |
| GO:0007224 smoothened signaling pathway | IMP PMID:21177415 Identification and mechanism of action of the acylguanidine ... | ACCEPT | Summary: SMO is the membrane transducer of the smoothened signaling pathway; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This IMP experimental evidence is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. |
| GO:0072285 mesenchymal to epithelial transition involved in metanephric renal vesicle formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The mesenchymal to epithelial transition involved in metanephric renal vesicle formation annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The curator-reviewed orthology transfer (GO_REF:0000024) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0090190 positive regulation of branching involved in ureteric bud morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The positive regulation of branching involved in ureteric bud morphogenesis annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The curator-reviewed orthology transfer (GO_REF:0000024) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0001947 heart looping | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The heart looping annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The curator-reviewed orthology transfer (GO_REF:0000024) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0003140 determination of left/right asymmetry in lateral mesoderm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The determination of left/right asymmetry in lateral mesoderm annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The curator-reviewed orthology transfer (GO_REF:0000024) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0007224 smoothened signaling pathway | IEP PMID:17850284 Immunohistochemical analysis of Sonic hedgehog signalling in... | ACCEPT | Summary: Expression of SMO in the developing human urogenital sinus is consistent with operation of the smoothened signaling pathway during detrusor differentiation. Although IEP is weaker than a functional perturbation, the annotated pathway is the core signaling cascade directly transduced by SMO. Reason: Accepted for consistency with the extensive direct biochemical and genetic evidence that SMO transduces this pathway. PMID:17850284 provides human developmental expression context rather than the sole basis for the mechanistic assignment. Supporting Evidence: PMID:17850284 The expression patterns of the SHH-transducing proteins Patched (PTCH) and Smoothened (SMO) were consistent with long-range paracrine signalling associated with detrusor smooth muscle differentiation in the urogenital sinus. |
| GO:0007494 midgut development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The midgut development annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The curator-reviewed orthology transfer (GO_REF:0000024) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0048853 forebrain morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The forebrain morphogenesis annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The curator-reviewed orthology transfer (GO_REF:0000024) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0061053 somite development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The somite development annotation records a conserved, context-specific developmental output of Hedgehog/SMO signaling. SMO is required broadly for morphogen interpretation, but this tissue-level process is not the molecular activity that defines the protein. Reason: Retained as non-core. The curator-reviewed orthology transfer (GO_REF:0000024) is biologically plausible and consistent with SMO's pleiotropic developmental role, while the core function remains sterol-regulated ciliary signal transduction. |
| GO:0007224 smoothened signaling pathway | IMP PMID:9422511 Activating Smoothened mutations in sporadic basal-cell carci... | ACCEPT | Summary: SMO is the membrane transducer of the smoothened signaling pathway; activation by sterols couples SMO to Gi and/or direct PKA-C inhibition and thereby permits GLI activation. This IMP experimental evidence is mechanistically concordant with direct human SMO studies. Reason: Accepted as a core process annotation. The annotation names the signaling cascade or an immediate biochemical branch in which SMO directly acts, rather than a remote developmental phenotype. Supporting Evidence: PMID:9422511 These findings support the role of SMO as a signalling component of the SHH-receptor complex |
| GO:0060242 contact inhibition | IMP PMID:9422511 Activating Smoothened mutations in sporadic basal-cell carci... | UNDECIDED | Summary: The cited experimental annotation may be valid, but the cached publication record does not expose enough assay detail to verify the exact contact inhibition claim for human SMO. Reason: Undecided because the relevant full text is unavailable locally. In accordance with the project policy, the experimental curator is not overruled from title/abstract-level evidence alone. |
| GO:0005515 protein binding | IPI PMID:19592253 The mammalian Cos2 homolog Kif7 plays an essential role in m... | UNDECIDED | Summary: The cited experimental annotation may be valid, but the cached publication record does not expose enough assay detail to verify the exact protein binding claim for human SMO. Reason: Undecided because the relevant full text is unavailable locally. In accordance with the project policy, the experimental curator is not overruled from title/abstract-level evidence alone. |
| GO:0004862 cAMP-dependent protein kinase inhibitor activity | IDA PMID:36202993 A PKA inhibitor motif within SMOOTHENED controls Hedgehog si... | NEW | Summary: SMO contains a C-terminal PKI pseudosubstrate motif that directly occupies the PKA catalytic-subunit active site and inhibits its kinase activity, preventing inhibitory GLI phosphorylation. Reason: Proposed because this specific molecular function is directly demonstrated in biochemical, cellular, and organismal assays in PMID:36202993 and is more informative than generic protein sequestering activity or PKA catalytic-subunit binding. Supporting Evidence: PMID:36202993 SMO uses a decoy substrate sequence to physically block the active site of the cAMP-dependent protein kinase (PKA) catalytic subunit (PKA-C) and extinguish its enzymatic activity. PMID:39138140 GRK2 phosphorylation enables active SMO to bind PKA-C directly. |
Loading supporting content…
Download this section (compressed HTML)Q: In which human cell types does SMO signal predominantly through heterotrimeric Gi versus direct PKA-C inhibition, and how are these two immediate effector routes integrated?
Q: Which endogenous cholesterol or oxysterol species occupies each SMO sterol-binding site in specific physiological tissues?
Experiment: Introduce endogenous separation-of-function SMO alleles that selectively disrupt Gi coupling or the PKI pseudosubstrate motif in human ciliated neural and mesenchymal organoids. Measure ciliary SMO trafficking, local and whole-cell cAMP, PKA substrate phosphorylation, GLI processing, and GLI target transcription after defined SHH and sterol stimulation, with wild-type rescue controls.
Hypothesis: Gi coupling and PKI-motif-dependent PKA inhibition make separable, cell-context-dependent contributions to human SMO-to-GLI signaling.
Type: CRISPR knock-in with live-cell signaling and organoid phenotyping
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)