SHH encodes Sonic hedgehog, a secreted morphogen synthesized as a 462-amino-acid precursor. In the endoplasmic reticulum, its C-terminal HINT domain catalyzes autocleavage coupled to covalent transfer of cholesterol onto the C terminus of the N-terminal signaling product; HHAT subsequently palmitoylates the new N terminus. The mature, dually lipidated SHH-N product is retained at and released from producing-cell membranes and acts locally or over a distance. SHH-N binds PTCH1 or PTCH2, relieving Patched-mediated inhibition of SMO and changing GLI activator/repressor output in target cells. Spatial concentration and duration of this signal control cell-fate specification, proliferation, and tissue patterning across the developing nervous system, limb, somites, and multiple epithelial-mesenchymal organs. Heterozygous loss-of-function variants in human SHH are a cause of holoprosencephaly and related midline developmental defects.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: The processed signaling product SHH-N is released into the extracellular region and acts there as a morphogen. This GOA record uses phylogenetic inference (IBA) from GO_REF:0000033. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The extracellular region annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. |
| GO:0007224 smoothened signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: SHH is the extracellular ligand that initiates canonical PTCH-SMO Hedgehog signaling. This GOA record uses phylogenetic inference (IBA) from GO_REF:0000033. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The smoothened signaling pathway annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:30139912 Activation occurs when the lipid-modified HH-N binds to its receptor, Patched-1 (PTCH1) protein (15). PMID:30139912 In the absence of HH-N binding, PTCH1 represses the HH pathway presumably by regulating the transport of a ligand of its downstream protein, Smoothened (SMO) (2, 17, 18). |
| GO:0010468 regulation of gene expression | IBA GO_REF:0000033 | ACCEPT | Summary: SHH-PTCH-SMO signaling changes GLI activator/repressor balance and thereby regulates target-gene expression. This GOA record uses phylogenetic inference (IBA) from GO_REF:0000033. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The regulation of gene expression annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:30139912 Activation occurs when the lipid-modified HH-N binds to its receptor, Patched-1 (PTCH1) protein (15). PMID:30139912 In the absence of HH-N binding, PTCH1 represses the HH pathway presumably by regulating the transport of a ligand of its downstream protein, Smoothened (SMO) (2, 17, 18). |
| GO:0005113 patched binding | IBA GO_REF:0000033 | ACCEPT | Summary: Processed SHH-N directly binds PTCH1/PTCH2, relieving PTCH-mediated inhibition of SMO. This GOA record uses phylogenetic inference (IBA) from GO_REF:0000033. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The patched binding annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:30139912 Activation occurs when the lipid-modified HH-N binds to its receptor, Patched-1 (PTCH1) protein (15). PMID:30139912 In the absence of HH-N binding, PTCH1 represses the HH pathway presumably by regulating the transport of a ligand of its downstream protein, Smoothened (SMO) (2, 17, 18). |
| GO:0001708 cell fate specification | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cell-fate specification is a canonical consequence of graded SHH morphogen signaling. This GOA record uses phylogenetic inference (IBA) from GO_REF:0000033. Reason: Retained because the cell fate specification annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0048709 oligodendrocyte differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference supports a conserved role in oligodendrocyte differentiation. This GOA record uses phylogenetic inference (IBA) from GO_REF:0000033. Reason: Retained because the oligodendrocyte differentiation annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005509 calcium ion binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Calcium stabilizes the SHH signaling domain and participates in one PTCH-binding interface. This GOA record uses phylogenetic inference (IBA) from GO_REF:0000033. Reason: Retained because the calcium ion binding annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: A biosynthetic membrane compartment traversed by the SHH precursor during processing and lipidation. This GOA record uses electronic inference (IEA) from GO_REF:0000044. Reason: Retained because the Golgi membrane annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Calcium stabilizes the SHH signaling domain and participates in one PTCH-binding interface. This GOA record uses electronic inference (IEA) from GO_REF:0000117. Reason: Retained because the calcium ion binding annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: The processed signaling product SHH-N is released into the extracellular region and acts there as a morphogen. This GOA record uses electronic inference (IEA) from GO_REF:0000044. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The extracellular region annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The precursor is associated with the ER membrane during biosynthetic processing. This GOA record uses electronic inference (IEA) from GO_REF:0000044. Reason: Retained because the endoplasmic reticulum membrane annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Dually lipidated SHH-N is tethered at the producing-cell plasma membrane before carrier-mediated release. This GOA record uses electronic inference (IEA) from GO_REF:0000044. Reason: Retained because the plasma membrane annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0007267 cell-cell signaling | IEA GO_REF:0000002 | ACCEPT | Summary: Secreted or cell-surface SHH conveys a signal from producing cells to responding cells. This GOA record uses electronic inference (IEA) from GO_REF:0000002. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The cell-cell signaling annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. |
| GO:0007389 pattern specification process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Pattern specification is a canonical but context-dependent developmental consequence of graded SHH signaling. This GOA record uses electronic inference (IEA) from GO_REF:0000117. Reason: Retained because the pattern specification process annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0007417 central nervous system development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: SHH has broad, conserved patterning roles in central nervous system development. This GOA record uses electronic inference (IEA) from GO_REF:0000117. Reason: Retained because the central nervous system development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0009888 tissue development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This umbrella term is true but less informative than the many specific tissue and patterning annotations. This GOA record uses electronic inference (IEA) from GO_REF:0000117. Reason: The tissue development term is not false, but it is an uninformative umbrella consequence of SHH signaling and is superseded by multiple more specific developmental annotations. |
| GO:0016539 intein-mediated protein splicing | IEA GO_REF:0000002 | REMOVE | Summary: The HINT-related C-terminal domain catalyzes a single self-cleavage/cholesterol-transfer reaction; SHH does not excise and splice an intein from a host protein. This GOA record uses electronic inference (IEA) from GO_REF:0000002. Reason: Remove the InterPro-derived intein-splicing annotation. Homology of the SHH C-terminal HINT domain to inteins does not mean that SHH performs intein excision/protein splicing; its supported reaction is autocleavage coupled to cholesterol transfer. |
| GO:0016540 protein autoprocessing | IEA GO_REF:0000120 | ACCEPT | Summary: The SHH precursor autocatalytically cleaves into N-terminal signaling and C-terminal processing products. This GOA record uses electronic inference (IEA) from GO_REF:0000120. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The protein autoprocessing annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:24342078 This preproprotein is composed of a 23aa signal peptide ER targeting sequence, a 174 amino acid N-terminal signaling domain, and a 265aa C-terminal autoprocessing domain endowed with autoproteolysis and cholesterol transferase activity. |
| GO:0030182 neuron differentiation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: A broad, context-dependent neural differentiation outcome of SHH signaling. This GOA record uses electronic inference (IEA) from GO_REF:0000117. Reason: Retained because the neuron differentiation annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0035295 tube development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This umbrella term is too broad to add information beyond specific neural, limb, lung, kidney, and vascular annotations. This GOA record uses electronic inference (IEA) from GO_REF:0000117. Reason: The tube development term is not false, but it is an uninformative umbrella consequence of SHH signaling and is superseded by multiple more specific developmental annotations. |
| GO:0042127 regulation of cell population proliferation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Regulation of proliferation is a recurring downstream outcome of SHH signaling in several target tissues. This GOA record uses electronic inference (IEA) from GO_REF:0000117. Reason: Retained because the regulation of cell population proliferation annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0045165 cell fate commitment | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Cell-fate commitment is a broad downstream consequence of graded SHH signaling. This GOA record uses electronic inference (IEA) from GO_REF:0000117. Reason: Retained because the cell fate commitment annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0045880 positive regulation of smoothened signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: SHH binding to PTCH relieves PTCH inhibition of SMO and positively regulates pathway activation. This GOA record uses electronic inference (IEA) from GO_REF:0000117. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The positive regulation of smoothened signaling pathway annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:30139912 Activation occurs when the lipid-modified HH-N binds to its receptor, Patched-1 (PTCH1) protein (15). PMID:30139912 In the absence of HH-N binding, PTCH1 represses the HH pathway presumably by regulating the transport of a ligand of its downstream protein, Smoothened (SMO) (2, 17, 18). |
| GO:0048468 cell development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This generic term adds little beyond specific cell-fate, proliferation, and differentiation annotations. This GOA record uses electronic inference (IEA) from GO_REF:0000117. Reason: The cell development term is not false, but it is an uninformative umbrella consequence of SHH signaling and is superseded by multiple more specific developmental annotations. |
| GO:0048513 animal organ development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This generic umbrella term adds little beyond the specific organ-development annotations. This GOA record uses electronic inference (IEA) from GO_REF:0000117. Reason: The animal organ development term is not false, but it is an uninformative umbrella consequence of SHH signaling and is superseded by multiple more specific developmental annotations. |
| GO:0050793 regulation of developmental process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This umbrella term adds little beyond specific cell-fate, patterning, and morphogenesis annotations. This GOA record uses electronic inference (IEA) from GO_REF:0000117. Reason: The regulation of developmental process term is not false, but it is an uninformative umbrella consequence of SHH signaling and is superseded by multiple more specific developmental annotations. |
| GO:0005515 protein binding | IPI PMID:19561609 The structure of SHH in complex with HHIP reveals a recognit... | REMOVE | Summary: The cited experiments establish a physical SHH complex, but generic protein binding is not an informative GO molecular function. This GOA record uses physical-interaction evidence (IPI) from PMID:19561609. Reason: Remove the generic protein-binding annotation as uninformative. The HHIP-SHH complex is real, but the interaction is better retained in the mechanistic narrative and reference findings; no specific HHIP-binding GO molecular-function term is available here. |
| GO:0005515 protein binding | IPI PMID:29954986 Structural basis for the recognition of Sonic Hedgehog by hu... | MODIFY | Summary: The cited experiments establish a physical SHH complex, but generic protein binding is not an informative GO molecular function. This GOA record uses physical-interaction evidence (IPI) from PMID:29954986. Reason: Generic protein binding is uninformative. The cited human structural/interaction study specifically demonstrates SHH-N engagement of PTCH1, so patched binding is the precise replacement term. Proposed replacements: patched binding |
| GO:0005515 protein binding | IPI PMID:29995851 Structures of human Patched and its complex with native palm... | MODIFY | Summary: The cited experiments establish a physical SHH complex, but generic protein binding is not an informative GO molecular function. This GOA record uses physical-interaction evidence (IPI) from PMID:29995851. Reason: Generic protein binding is uninformative. The cited human structural/interaction study specifically demonstrates SHH-N engagement of PTCH1, so patched binding is the precise replacement term. Proposed replacements: patched binding |
| GO:0005515 protein binding | IPI PMID:30139912 Two Patched molecules engage distinct sites on Hedgehog yiel... | MODIFY | Summary: The cited experiments establish a physical SHH complex, but generic protein binding is not an informative GO molecular function. This GOA record uses physical-interaction evidence (IPI) from PMID:30139912. Reason: Generic protein binding is uninformative. The cited human structural/interaction study specifically demonstrates SHH-N engagement of PTCH1, so patched binding is the precise replacement term. Proposed replacements: patched binding |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A downstream, context-dependent transcriptional outcome of SHH-PTCH-SMO-GLI signaling. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the negative regulation of transcription by RNA polymerase II annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0001656 metanephros development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A context-specific urinary-system developmental role inferred from the mouse ortholog. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the metanephros development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0001947 heart looping | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A context-specific embryonic left-right/heart morphogenesis role inferred from the mouse ortholog. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the heart looping annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0002320 lymphoid progenitor cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse loss-of-function evidence supports a role in early thymocyte expansion and differentiation. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the lymphoid progenitor cell differentiation annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0003140 determination of left/right asymmetry in lateral mesoderm | IEA GO_REF:0000107 | UNDECIDED | Summary: A context-specific role in vertebrate left-right patterning rather than SHH's defining molecular activity. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: The determination of left/right asymmetry in lateral mesoderm claim was electronically transferred from mouse, but its underlying source experiment is not exposed in this GOA record and independent causal evidence was not available in the cached sources. It is left undecided rather than overruled. |
| GO:0004175 endopeptidase activity | IEA GO_REF:0000107 | MODIFY | Summary: SHH cleavage is coupled to cholesterol transfer; the precise current activity term is cholesterol-protein transferase activity. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Replace broad endopeptidase activity with the mechanistically precise cholesterol-protein transferase activity. SHH self-cleavage is a cholesterolysis reaction, not ordinary peptide bond hydrolysis. Proposed replacements: cholesterol-protein transferase activity Supporting Evidence: PMID:24342078 This preproprotein is composed of a 23aa signal peptide ER targeting sequence, a 174 amino acid N-terminal signaling domain, and a 265aa C-terminal autoprocessing domain endowed with autoproteolysis and cholesterol transferase activity. |
| GO:0005113 patched binding | IEA GO_REF:0000120 | ACCEPT | Summary: Processed SHH-N directly binds PTCH1/PTCH2, relieving PTCH-mediated inhibition of SMO. This GOA record uses electronic inference (IEA) from GO_REF:0000120. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The patched binding annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:30139912 Activation occurs when the lipid-modified HH-N binds to its receptor, Patched-1 (PTCH1) protein (15). PMID:30139912 In the absence of HH-N binding, PTCH1 represses the HH pathway presumably by regulating the transport of a ligand of its downstream protein, Smoothened (SMO) (2, 17, 18). |
| GO:0007224 smoothened signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: SHH is the extracellular ligand that initiates canonical PTCH-SMO Hedgehog signaling. This GOA record uses electronic inference (IEA) from GO_REF:0000120. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The smoothened signaling pathway annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:30139912 Activation occurs when the lipid-modified HH-N binds to its receptor, Patched-1 (PTCH1) protein (15). PMID:30139912 In the absence of HH-N binding, PTCH1 represses the HH pathway presumably by regulating the transport of a ligand of its downstream protein, Smoothened (SMO) (2, 17, 18). |
| GO:0009949 polarity specification of anterior/posterior axis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A context-specific anterior-posterior patterning role, prominently in the limb bud. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the polarity specification of anterior/posterior axis annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A downstream transcriptional consequence of pathway activation, rather than direct transcription-factor activity by SHH. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the positive regulation of gene expression annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0010629 negative regulation of gene expression | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A context-dependent downstream transcriptional consequence of SHH signaling. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the negative regulation of gene expression annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0021904 dorsal/ventral neural tube patterning | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SHH is a canonical ventralizing signal in dorsal-ventral neural-tube patterning. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the dorsal/ventral neural tube patterning annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0021930 cerebellar granule cell precursor proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Purkinje-cell-derived Shh stimulates cerebellar granule-cell-precursor proliferation in mouse, supporting orthology transfer to human SHH. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the cerebellar granule cell precursor proliferation annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. Supporting Evidence: PMID:10226030 treatment of dissociated granule neuron cultures with recombinant Shh stimulated |
| GO:0033077 T cell differentiation in thymus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse knockout and pathway-activation experiments support context-specific roles in thymocyte development. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the T cell differentiation in thymus annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0033089 positive regulation of T cell differentiation in thymus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse genetic evidence supports a context-specific positive influence on early thymocyte differentiation. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the positive regulation of T cell differentiation in thymus annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0033092 positive regulation of immature T cell proliferation in thymus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse Shh loss-of-function supports a context-specific role in early thymocyte expansion. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the positive regulation of immature T cell proliferation in thymus annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0042481 regulation of odontogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A context-specific role in tooth development inferred from the mouse ortholog. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the regulation of odontogenesis annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0042733 embryonic digit morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A well-established context-specific role of SHH signaling in digit patterning. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the embryonic digit morphogenesis annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SHH binding can suppress PTCH-dependent pro-apoptotic signaling in specific contexts. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the negative regulation of apoptotic process annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0043369 CD4-positive or CD8-positive, alpha-beta T cell lineage commitment | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse genetic studies support a context-specific effect on alpha-beta T-cell lineage progression. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the CD4-positive or CD8-positive, alpha-beta T cell lineage commitment annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0045059 positive thymic T cell selection | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse genetic evidence supports involvement in positive thymic selection, but this is a peripheral developmental context. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the positive thymic T cell selection annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0045060 negative thymic T cell selection | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse genetic evidence supports involvement in negative thymic selection, but this is a peripheral developmental context. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the negative thymic T cell selection annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A downstream transcriptional consequence of SHH signaling rather than direct DNA-binding activity. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the positive regulation of DNA-templated transcription annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A downstream GLI-mediated transcriptional consequence of SHH pathway activation. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the positive regulation of transcription by RNA polymerase II annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0046638 positive regulation of alpha-beta T cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A context-specific immune-development outcome supported by mouse genetics. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the positive regulation of alpha-beta T cell differentiation annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0048538 thymus development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse genetic evidence supports a context-specific role in thymus development. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the thymus development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0048864 stem cell development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A broad, context-dependent role in stem/progenitor-cell development inferred from mouse. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the stem cell development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0061053 somite development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SHH is a conserved ventralizing signal during somite development. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the somite development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0072136 metanephric mesenchymal cell proliferation involved in metanephros development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A context-specific metanephric proliferation outcome inferred from the mouse ortholog. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the metanephric mesenchymal cell proliferation involved in metanephros development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0090370 negative regulation of cholesterol efflux | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SHH binding modulates PTCH sterol-transport behavior; this context-specific process was transferred from mouse. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the negative regulation of cholesterol efflux annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0097190 apoptotic signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SHH can suppress the pro-apoptotic dependence-receptor activity of unliganded PTCH in specific contexts. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the apoptotic signaling pathway annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0140853 cholesterol-protein transferase activity | IEA GO_REF:0000107 | ACCEPT | Summary: The precursor's C-terminal HINT domain catalyzes cleavage coupled to transfer of cholesterol onto SHH-N. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The cholesterol-protein transferase activity annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:24342078 This preproprotein is composed of a 23aa signal peptide ER targeting sequence, a 174 amino acid N-terminal signaling domain, and a 265aa C-terminal autoprocessing domain endowed with autoproteolysis and cholesterol transferase activity. |
| GO:1904339 negative regulation of dopaminergic neuron differentiation | IEA GO_REF:0000107 | UNDECIDED | Summary: This narrow mouse-transfer annotation was not independently verified from an underlying source publication. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: The narrow negative regulation of dopaminergic neuron differentiation claim is transferred from another organism or high-throughput source, but its underlying source experiment is not exposed in this GOA record and independent corroboration was not found. It is left undecided rather than overruled. |
| GO:2000062 negative regulation of ureter smooth muscle cell differentiation | IEA GO_REF:0000107 | UNDECIDED | Summary: The narrow negative ureter-smooth-muscle claim was transferred from mouse without an exposed source publication. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: The narrow negative regulation of ureter smooth muscle cell differentiation claim is transferred from another organism or high-throughput source, but its underlying source experiment is not exposed in this GOA record and independent corroboration was not found. It is left undecided rather than overruled. |
| GO:2000063 positive regulation of ureter smooth muscle cell differentiation | IEA GO_REF:0000107 | UNDECIDED | Summary: The narrow positive ureter-smooth-muscle claim was transferred from mouse without an exposed source publication. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: The narrow positive regulation of ureter smooth muscle cell differentiation claim is transferred from another organism or high-throughput source, but its underlying source experiment is not exposed in this GOA record and independent corroboration was not found. It is left undecided rather than overruled. |
| GO:2000357 negative regulation of kidney smooth muscle cell differentiation | IEA GO_REF:0000107 | UNDECIDED | Summary: The narrow negative kidney-smooth-muscle claim was transferred from mouse without an exposed source publication. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: The narrow negative regulation of kidney smooth muscle cell differentiation claim is transferred from another organism or high-throughput source, but its underlying source experiment is not exposed in this GOA record and independent corroboration was not found. It is left undecided rather than overruled. |
| GO:2000358 positive regulation of kidney smooth muscle cell differentiation | IEA GO_REF:0000107 | UNDECIDED | Summary: The narrow positive kidney-smooth-muscle claim was transferred from mouse without an exposed source publication. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: The narrow positive regulation of kidney smooth muscle cell differentiation claim is transferred from another organism or high-throughput source, but its underlying source experiment is not exposed in this GOA record and independent corroboration was not found. It is left undecided rather than overruled. |
| GO:2000729 positive regulation of mesenchymal cell proliferation involved in ureter development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A context-specific ureteric mesenchymal proliferation outcome inferred from the mouse ortholog. This GOA record uses electronic inference (IEA) from GO_REF:0000107. Reason: Retained because the positive regulation of mesenchymal cell proliferation involved in ureter development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0004175 endopeptidase activity | ISS GO_REF:0000024 | MODIFY | Summary: SHH cleavage is coupled to cholesterol transfer; the precise current activity term is cholesterol-protein transferase activity. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Replace broad endopeptidase activity with the mechanistically precise cholesterol-protein transferase activity. SHH self-cleavage is a cholesterolysis reaction, not ordinary peptide bond hydrolysis. Proposed replacements: cholesterol-protein transferase activity Supporting Evidence: PMID:24342078 This preproprotein is composed of a 23aa signal peptide ER targeting sequence, a 174 amino acid N-terminal signaling domain, and a 265aa C-terminal autoprocessing domain endowed with autoproteolysis and cholesterol transferase activity. |
| GO:0016540 protein autoprocessing | ISS GO_REF:0000024 | ACCEPT | Summary: The SHH precursor autocatalytically cleaves into N-terminal signaling and C-terminal processing products. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The protein autoprocessing annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:24342078 This preproprotein is composed of a 23aa signal peptide ER targeting sequence, a 174 amino acid N-terminal signaling domain, and a 265aa C-terminal autoprocessing domain endowed with autoproteolysis and cholesterol transferase activity. |
| GO:0005576 extracellular region | EXP PMID:24342078 A new role for Hedgehogs in juxtacrine signaling. | ACCEPT | Summary: The processed signaling product SHH-N is released into the extracellular region and acts there as a morphogen. This GOA record uses experimental evidence (EXP) from PMID:24342078. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The extracellular region annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Dually lipidated SHH-N is tethered at the producing-cell plasma membrane before carrier-mediated release. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the plasma membrane annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0140853 cholesterol-protein transferase activity | ISS GO_REF:0000024 | ACCEPT | Summary: The precursor's C-terminal HINT domain catalyzes cleavage coupled to transfer of cholesterol onto SHH-N. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The cholesterol-protein transferase activity annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:24342078 This preproprotein is composed of a 23aa signal peptide ER targeting sequence, a 174 amino acid N-terminal signaling domain, and a 265aa C-terminal autoprocessing domain endowed with autoproteolysis and cholesterol transferase activity. |
| GO:1900107 regulation of nodal signaling pathway | NAS PMID:17507406 Cerberus is a feedback inhibitor of Nodal asymmetric signali... | UNDECIDED | Summary: The cited abstract concerns chick Cerberus feedback on Nodal and does not expose the basis for an SHH annotation; full text is unavailable. This GOA record uses non-traceable author-statement evidence (NAS) from PMID:17507406. Reason: Evidence in the cached publication is insufficient to verify the specific regulation of nodal signaling pathway claim. The annotation is left undecided rather than removed because the curator may have had access to information not present in the cached abstract/full text. |
| GO:0007224 smoothened signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: SHH is the extracellular ligand that initiates canonical PTCH-SMO Hedgehog signaling. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The smoothened signaling pathway annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:30139912 Activation occurs when the lipid-modified HH-N binds to its receptor, Patched-1 (PTCH1) protein (15). PMID:30139912 In the absence of HH-N binding, PTCH1 represses the HH pathway presumably by regulating the transport of a ligand of its downstream protein, Smoothened (SMO) (2, 17, 18). |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A downstream GLI-mediated transcriptional consequence of SHH pathway activation. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the positive regulation of transcription by RNA polymerase II annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0003140 determination of left/right asymmetry in lateral mesoderm | NAS PMID:17507406 Cerberus is a feedback inhibitor of Nodal asymmetric signali... | UNDECIDED | Summary: A context-specific role in vertebrate left-right patterning rather than SHH's defining molecular activity. This GOA record uses non-traceable author-statement evidence (NAS) from PMID:17507406. Reason: Evidence in the cached publication is insufficient to verify the specific determination of left/right asymmetry in lateral mesoderm claim. The annotation is left undecided rather than removed because the curator may have had access to information not present in the cached abstract/full text. |
| GO:0060684 epithelial-mesenchymal cell signaling | IDA PMID:12221011 Sonic hedgehog activates mesenchymal Gli1 expression during ... | KEEP AS NON CORE | Summary: Prostate explant experiments support epithelial SHH signaling to adjacent mesenchyme. This GOA record uses direct assay (IDA) from PMID:12221011. Reason: Retained because the epithelial-mesenchymal cell signaling annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0045880 positive regulation of smoothened signaling pathway | IDA PMID:24342078 A new role for Hedgehogs in juxtacrine signaling. | ACCEPT | Summary: SHH binding to PTCH relieves PTCH inhibition of SMO and positively regulates pathway activation. This GOA record uses direct assay (IDA) from PMID:24342078. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The positive regulation of smoothened signaling pathway annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:30139912 Activation occurs when the lipid-modified HH-N binds to its receptor, Patched-1 (PTCH1) protein (15). PMID:30139912 In the absence of HH-N binding, PTCH1 represses the HH pathway presumably by regulating the transport of a ligand of its downstream protein, Smoothened (SMO) (2, 17, 18). |
| GO:0005113 patched binding | IDA PMID:11472839 Comparative biological responses to human Sonic, Indian, and... | ACCEPT | Summary: Processed SHH-N directly binds PTCH1/PTCH2, relieving PTCH-mediated inhibition of SMO. This GOA record uses direct assay (IDA) from PMID:11472839. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The patched binding annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:30139912 Activation occurs when the lipid-modified HH-N binds to its receptor, Patched-1 (PTCH1) protein (15). PMID:30139912 In the absence of HH-N binding, PTCH1 represses the HH pathway presumably by regulating the transport of a ligand of its downstream protein, Smoothened (SMO) (2, 17, 18). |
| GO:0005783 endoplasmic reticulum | IDA PMID:18534984 Hhat is a palmitoylacyltransferase with specificity for N-pa... | ACCEPT | Summary: The SHH precursor enters the endoplasmic reticulum for autocatalytic processing and lipid modification. This GOA record uses direct assay (IDA) from PMID:18534984. Reason: The endoplasmic reticulum is the active site of the precursor's defining cholesterol-transfer/autoprocessing reaction and is therefore a core functional location, not merely a generic biosynthetic compartment. |
| GO:0005794 Golgi apparatus | IDA PMID:18534984 Hhat is a palmitoylacyltransferase with specificity for N-pa... | KEEP AS NON CORE | Summary: SHH traverses the Golgi/secretory pathway during maturation and palmitoylation. This GOA record uses direct assay (IDA) from PMID:18534984. Reason: Retained because the Golgi apparatus annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0007224 smoothened signaling pathway | IDA PMID:31279575 Phosphorylation of Ci/Gli by Fused Family Kinases Promotes H... | ACCEPT | Summary: SHH is the extracellular ligand that initiates canonical PTCH-SMO Hedgehog signaling. This GOA record uses direct assay (IDA) from PMID:31279575. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The smoothened signaling pathway annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:30139912 Activation occurs when the lipid-modified HH-N binds to its receptor, Patched-1 (PTCH1) protein (15). PMID:30139912 In the absence of HH-N binding, PTCH1 represses the HH pathway presumably by regulating the transport of a ligand of its downstream protein, Smoothened (SMO) (2, 17, 18). |
| GO:0004175 endopeptidase activity | TAS Reactome:R-HSA-5358460 | MODIFY | Summary: SHH cleavage is coupled to cholesterol transfer; the precise current activity term is cholesterol-protein transferase activity. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5358460. Reason: Replace broad endopeptidase activity with the mechanistically precise cholesterol-protein transferase activity. SHH self-cleavage is a cholesterolysis reaction, not ordinary peptide bond hydrolysis. Proposed replacements: cholesterol-protein transferase activity Supporting Evidence: PMID:24342078 This preproprotein is composed of a 23aa signal peptide ER targeting sequence, a 174 amino acid N-terminal signaling domain, and a 265aa C-terminal autoprocessing domain endowed with autoproteolysis and cholesterol transferase activity. |
| GO:0048745 smooth muscle tissue development | IEP PMID:17850284 Immunohistochemical analysis of Sonic hedgehog signalling in... | KEEP AS NON CORE | Summary: Human fetal expression patterns are consistent with a role in urinary-tract smooth-muscle development, but the study is descriptive. This GOA record uses expression-pattern evidence (IEP) from PMID:17850284. Reason: Retained because the smooth muscle tissue development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0072205 metanephric collecting duct development | IEP PMID:17850284 Immunohistochemical analysis of Sonic hedgehog signalling in... | KEEP AS NON CORE | Summary: Human fetal expression supports association with collecting-duct development, but the cited study is descriptive rather than causal. This GOA record uses expression-pattern evidence (IEP) from PMID:17850284. Reason: Retained because the metanephric collecting duct development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0031012 extracellular matrix | HDA PMID:28344315 Proteomic characterization of human multiple myeloma bone ma... | UNDECIDED | Summary: The HDA call derives from a multiple-myeloma bone-marrow ECM proteome, but the abstract does not identify SHH and the full text is unavailable in cache. This GOA record uses high-throughput direct-assay evidence (HDA) from PMID:28344315. Reason: Evidence in the cached publication is insufficient to verify the specific extracellular matrix claim. The annotation is left undecided rather than removed because the curator may have had access to information not present in the cached abstract/full text. |
| GO:0016015 morphogen activity | TAS PMID:24431302 Wnt signaling in midbrain dopaminergic neuron development an... | ACCEPT | Summary: Processed SHH-N forms spatial and concentration-dependent signals that specify developmental outcomes. This GOA record uses traceable-author-statement evidence (TAS) from PMID:24431302. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The morphogen activity annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:30139912 Activation occurs when the lipid-modified HH-N binds to its receptor, Patched-1 (PTCH1) protein (15). PMID:30139912 In the absence of HH-N binding, PTCH1 represses the HH pathway presumably by regulating the transport of a ligand of its downstream protein, Smoothened (SMO) (2, 17, 18). |
| GO:0071542 dopaminergic neuron differentiation | TAS PMID:24431302 Wnt signaling in midbrain dopaminergic neuron development an... | UNDECIDED | Summary: The cited Wnt-focused review's cached abstract does not verify this SHH annotation and full text is unavailable. This GOA record uses traceable-author-statement evidence (TAS) from PMID:24431302. Reason: Evidence in the cached publication is insufficient to verify the specific dopaminergic neuron differentiation claim. The annotation is left undecided rather than removed because the curator may have had access to information not present in the cached abstract/full text. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5387389 | KEEP AS NON CORE | Summary: The SHH precursor and processing intermediates occupy the ER lumen during maturation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5387389. Reason: Retained because the endoplasmic reticulum lumen annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5483238 | KEEP AS NON CORE | Summary: The SHH precursor and processing intermediates occupy the ER lumen during maturation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5483238. Reason: Retained because the endoplasmic reticulum lumen annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5387389 | KEEP AS NON CORE | Summary: This Reactome localization concerns transient retrotranslocated C-terminal or processing-defective fragments destined for degradation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5387389. Reason: Retained because the cytosol annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5387392 | KEEP AS NON CORE | Summary: This Reactome localization concerns transient retrotranslocated C-terminal or processing-defective fragments destined for degradation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5387392. Reason: Retained because the cytosol annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0045880 positive regulation of smoothened signaling pathway | IDA PMID:19561609 The structure of SHH in complex with HHIP reveals a recognit... | ACCEPT | Summary: SHH binding to PTCH relieves PTCH inhibition of SMO and positively regulates pathway activation. This GOA record uses direct assay (IDA) from PMID:19561609. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The positive regulation of smoothened signaling pathway annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:30139912 Activation occurs when the lipid-modified HH-N binds to its receptor, Patched-1 (PTCH1) protein (15). PMID:30139912 In the absence of HH-N binding, PTCH1 represses the HH pathway presumably by regulating the transport of a ligand of its downstream protein, Smoothened (SMO) (2, 17, 18). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-445448 | ACCEPT | Summary: The processed signaling product SHH-N is released into the extracellular region and acts there as a morphogen. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-445448. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The extracellular region annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5632649 | ACCEPT | Summary: The processed signaling product SHH-N is released into the extracellular region and acts there as a morphogen. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5632649. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The extracellular region annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5632652 | ACCEPT | Summary: The processed signaling product SHH-N is released into the extracellular region and acts there as a morphogen. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5632652. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The extracellular region annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5358336 | KEEP AS NON CORE | Summary: The SHH precursor and processing intermediates occupy the ER lumen during maturation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5358336. Reason: Retained because the endoplasmic reticulum lumen annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5358340 | KEEP AS NON CORE | Summary: The SHH precursor and processing intermediates occupy the ER lumen during maturation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5358340. Reason: Retained because the endoplasmic reticulum lumen annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5358343 | KEEP AS NON CORE | Summary: The SHH precursor and processing intermediates occupy the ER lumen during maturation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5358343. Reason: Retained because the endoplasmic reticulum lumen annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5362386 | KEEP AS NON CORE | Summary: The SHH precursor and processing intermediates occupy the ER lumen during maturation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5362386. Reason: Retained because the endoplasmic reticulum lumen annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5362412 | KEEP AS NON CORE | Summary: The SHH precursor and processing intermediates occupy the ER lumen during maturation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5362412. Reason: Retained because the endoplasmic reticulum lumen annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5362437 | KEEP AS NON CORE | Summary: The SHH precursor and processing intermediates occupy the ER lumen during maturation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5362437. Reason: Retained because the endoplasmic reticulum lumen annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5362441 | KEEP AS NON CORE | Summary: The SHH precursor and processing intermediates occupy the ER lumen during maturation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5362441. Reason: Retained because the endoplasmic reticulum lumen annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5362459 | KEEP AS NON CORE | Summary: The SHH precursor and processing intermediates occupy the ER lumen during maturation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5362459. Reason: Retained because the endoplasmic reticulum lumen annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5362549 | KEEP AS NON CORE | Summary: The SHH precursor and processing intermediates occupy the ER lumen during maturation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5362549. Reason: Retained because the endoplasmic reticulum lumen annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5362448 | KEEP AS NON CORE | Summary: This Reactome localization concerns transient retrotranslocated C-terminal or processing-defective fragments destined for degradation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5362448. Reason: Retained because the cytosol annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5362459 | KEEP AS NON CORE | Summary: This Reactome localization concerns transient retrotranslocated C-terminal or processing-defective fragments destined for degradation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5362459. Reason: Retained because the cytosol annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5362427 | KEEP AS NON CORE | Summary: Dually lipidated SHH-N is tethered at the producing-cell plasma membrane before carrier-mediated release. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5362427. Reason: Retained because the plasma membrane annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5362549 | KEEP AS NON CORE | Summary: Dually lipidated SHH-N is tethered at the producing-cell plasma membrane before carrier-mediated release. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5362549. Reason: Retained because the plasma membrane annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5362551 | KEEP AS NON CORE | Summary: Dually lipidated SHH-N is tethered at the producing-cell plasma membrane before carrier-mediated release. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5362551. Reason: Retained because the plasma membrane annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5362553 | KEEP AS NON CORE | Summary: Dually lipidated SHH-N is tethered at the producing-cell plasma membrane before carrier-mediated release. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5362553. Reason: Retained because the plasma membrane annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005886 plasma membrane | TAS Reactome:R-NUL-5362406 | KEEP AS NON CORE | Summary: Dually lipidated SHH-N is tethered at the producing-cell plasma membrane before carrier-mediated release. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-NUL-5362406. Reason: Retained because the plasma membrane annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0009949 polarity specification of anterior/posterior axis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific anterior-posterior patterning role, prominently in the limb bud. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the polarity specification of anterior/posterior axis annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0043066 negative regulation of apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SHH binding can suppress PTCH-dependent pro-apoptotic signaling in specific contexts. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the negative regulation of apoptotic process annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0097190 apoptotic signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SHH can suppress the pro-apoptotic dependence-receptor activity of unliganded PTCH in specific contexts. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the apoptotic signaling pathway annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5358460 | KEEP AS NON CORE | Summary: The SHH precursor and processing intermediates occupy the ER lumen during maturation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5358460. Reason: Retained because the endoplasmic reticulum lumen annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5362450 | KEEP AS NON CORE | Summary: The SHH precursor and processing intermediates occupy the ER lumen during maturation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5362450. Reason: Retained because the endoplasmic reticulum lumen annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5387386 | KEEP AS NON CORE | Summary: The SHH precursor and processing intermediates occupy the ER lumen during maturation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5387386. Reason: Retained because the endoplasmic reticulum lumen annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5483229 | KEEP AS NON CORE | Summary: The SHH precursor and processing intermediates occupy the ER lumen during maturation. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5483229. Reason: Retained because the endoplasmic reticulum lumen annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0021930 cerebellar granule cell precursor proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Purkinje-cell-derived Shh stimulates cerebellar granule-cell-precursor proliferation in mouse, supporting orthology transfer to human SHH. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the cerebellar granule cell precursor proliferation annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. Supporting Evidence: PMID:10226030 treatment of dissociated granule neuron cultures with recombinant Shh stimulated |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5362551 | ACCEPT | Summary: The processed signaling product SHH-N is released into the extracellular region and acts there as a morphogen. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5362551. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The extracellular region annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5362553 | ACCEPT | Summary: The processed signaling product SHH-N is released into the extracellular region and acts there as a morphogen. This GOA record uses traceable-author-statement evidence (TAS) from Reactome:R-HSA-5362553. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The extracellular region annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A downstream, context-dependent transcriptional outcome of SHH-PTCH-SMO-GLI signaling. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the negative regulation of transcription by RNA polymerase II annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0042481 regulation of odontogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific role in tooth development inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the regulation of odontogenesis annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A downstream GLI-mediated transcriptional consequence of SHH pathway activation. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the positive regulation of transcription by RNA polymerase II annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:1900180 regulation of protein localization to nucleus | IDA PMID:11331587 Patched1 interacts with cyclin B1 to regulate cell cycle pro... | KEEP AS NON CORE | Summary: SHH relieves PTCH1-mediated cyclin-B1 sequestration, permitting nuclear localization in cultured cells. This GOA record uses direct assay (IDA) from PMID:11331587. Reason: Retained because the regulation of protein localization to nucleus annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0061189 positive regulation of sclerotome development | IDA PMID:10654605 SHH-N upregulates Sfrp2 to mediate its competitive interacti... | KEEP AS NON CORE | Summary: Somite explant experiments support positive regulation of sclerotome development by SHH-N. This GOA record uses direct assay (IDA) from PMID:10654605. Reason: Retained because the positive regulation of sclerotome development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0090370 negative regulation of cholesterol efflux | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SHH binding modulates PTCH sterol-transport behavior; this context-specific process was transferred from mouse. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the negative regulation of cholesterol efflux annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0007418 ventral midline development | TAS PMID:11001584 The sonic hedgehog-patched-gli pathway in human development ... | KEEP AS NON CORE | Summary: Human SHH loss-of-function and vertebrate developmental evidence support a ventral-midline role. This GOA record uses traceable-author-statement evidence (TAS) from PMID:11001584. Reason: Retained because the ventral midline development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0008284 positive regulation of cell population proliferation | IDA PMID:11331587 Patched1 interacts with cyclin B1 to regulate cell cycle pro... | KEEP AS NON CORE | Summary: SHH promotes proliferation in multiple developmental contexts, including neural precursors. This GOA record uses direct assay (IDA) from PMID:11331587. Reason: Retained because the positive regulation of cell population proliferation annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0009880 embryonic pattern specification | TAS PMID:11001584 The sonic hedgehog-patched-gli pathway in human development ... | KEEP AS NON CORE | Summary: Embryonic pattern specification is a broad developmental consequence of SHH morphogen signaling. This GOA record uses traceable-author-statement evidence (TAS) from PMID:11001584. Reason: Retained because the embryonic pattern specification annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0016015 morphogen activity | NAS PMID:8647801 A mammalian patched homolog is expressed in target tissues o... | ACCEPT | Summary: Processed SHH-N forms spatial and concentration-dependent signals that specify developmental outcomes. This GOA record uses non-traceable author-statement evidence (NAS) from PMID:8647801. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The morphogen activity annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:30139912 Activation occurs when the lipid-modified HH-N binds to its receptor, Patched-1 (PTCH1) protein (15). PMID:30139912 In the absence of HH-N binding, PTCH1 represses the HH pathway presumably by regulating the transport of a ligand of its downstream protein, Smoothened (SMO) (2, 17, 18). |
| GO:0051781 positive regulation of cell division | IDA PMID:11331587 Patched1 interacts with cyclin B1 to regulate cell cycle pro... | KEEP AS NON CORE | Summary: SHH relieves PTCH1-mediated sequestration of cyclin B1 in a cultured-cell system, linking signaling to cell division. This GOA record uses direct assay (IDA) from PMID:11331587. Reason: Retained because the positive regulation of cell division annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0001947 heart looping | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific embryonic left-right/heart morphogenesis role inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the heart looping annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0003140 determination of left/right asymmetry in lateral mesoderm | ISS GO_REF:0000024 | UNDECIDED | Summary: A context-specific role in vertebrate left-right patterning rather than SHH's defining molecular activity. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: The determination of left/right asymmetry in lateral mesoderm claim was transferred from mouse by curator judgment, but its underlying source experiment is not exposed in this GOA record and independent causal evidence was not available in the cached sources. It is left undecided rather than overruled. |
| GO:0007224 smoothened signaling pathway | IEP PMID:17850284 Immunohistochemical analysis of Sonic hedgehog signalling in... | ACCEPT | Summary: SHH is the extracellular ligand that initiates canonical PTCH-SMO Hedgehog signaling. This GOA record uses expression-pattern evidence (IEP) from PMID:17850284. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The smoothened signaling pathway annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:30139912 Activation occurs when the lipid-modified HH-N binds to its receptor, Patched-1 (PTCH1) protein (15). PMID:30139912 In the absence of HH-N binding, PTCH1 represses the HH pathway presumably by regulating the transport of a ligand of its downstream protein, Smoothened (SMO) (2, 17, 18). |
| GO:0061053 somite development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SHH is a conserved ventralizing signal during somite development. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the somite development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005113 patched binding | IDA PMID:8906787 The tumour-suppressor gene patched encodes a candidate recep... | ACCEPT | Summary: Processed SHH-N directly binds PTCH1/PTCH2, relieving PTCH-mediated inhibition of SMO. This GOA record uses direct assay (IDA) from PMID:8906787. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The patched binding annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. Supporting Evidence: PMID:30139912 Activation occurs when the lipid-modified HH-N binds to its receptor, Patched-1 (PTCH1) protein (15). PMID:30139912 In the absence of HH-N binding, PTCH1 represses the HH pathway presumably by regulating the transport of a ligand of its downstream protein, Smoothened (SMO) (2, 17, 18). |
| GO:2000729 positive regulation of mesenchymal cell proliferation involved in ureter development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific ureteric mesenchymal proliferation outcome inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the positive regulation of mesenchymal cell proliferation involved in ureter development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0033089 positive regulation of T cell differentiation in thymus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse genetic evidence supports a context-specific positive influence on early thymocyte differentiation. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the positive regulation of T cell differentiation in thymus annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0045059 positive thymic T cell selection | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse genetic evidence supports involvement in positive thymic selection, but this is a peripheral developmental context. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the positive thymic T cell selection annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0045060 negative thymic T cell selection | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse genetic evidence supports involvement in negative thymic selection, but this is a peripheral developmental context. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the negative thymic T cell selection annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0046638 positive regulation of alpha-beta T cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific immune-development outcome supported by mouse genetics. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the positive regulation of alpha-beta T cell differentiation annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0048538 thymus development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse genetic evidence supports a context-specific role in thymus development. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the thymus development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0048864 stem cell development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A broad, context-dependent role in stem/progenitor-cell development inferred from mouse. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the stem cell development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0072136 metanephric mesenchymal cell proliferation involved in metanephros development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific metanephric proliferation outcome inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the metanephric mesenchymal cell proliferation involved in metanephros development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:2000062 negative regulation of ureter smooth muscle cell differentiation | ISS GO_REF:0000024 | UNDECIDED | Summary: The narrow negative ureter-smooth-muscle claim was transferred from mouse without an exposed source publication. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: The narrow negative regulation of ureter smooth muscle cell differentiation claim is transferred from another organism or high-throughput source, but its underlying source experiment is not exposed in this GOA record and independent corroboration was not found. It is left undecided rather than overruled. |
| GO:2000063 positive regulation of ureter smooth muscle cell differentiation | ISS GO_REF:0000024 | UNDECIDED | Summary: The narrow positive ureter-smooth-muscle claim was transferred from mouse without an exposed source publication. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: The narrow positive regulation of ureter smooth muscle cell differentiation claim is transferred from another organism or high-throughput source, but its underlying source experiment is not exposed in this GOA record and independent corroboration was not found. It is left undecided rather than overruled. |
| GO:2000357 negative regulation of kidney smooth muscle cell differentiation | ISS GO_REF:0000024 | UNDECIDED | Summary: The narrow negative kidney-smooth-muscle claim was transferred from mouse without an exposed source publication. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: The narrow negative regulation of kidney smooth muscle cell differentiation claim is transferred from another organism or high-throughput source, but its underlying source experiment is not exposed in this GOA record and independent corroboration was not found. It is left undecided rather than overruled. |
| GO:2000358 positive regulation of kidney smooth muscle cell differentiation | ISS GO_REF:0000024 | UNDECIDED | Summary: The narrow positive kidney-smooth-muscle claim was transferred from mouse without an exposed source publication. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: The narrow positive regulation of kidney smooth muscle cell differentiation claim is transferred from another organism or high-throughput source, but its underlying source experiment is not exposed in this GOA record and independent corroboration was not found. It is left undecided rather than overruled. |
| GO:0033077 T cell differentiation in thymus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse knockout and pathway-activation experiments support context-specific roles in thymocyte development. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the T cell differentiation in thymus annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0033092 positive regulation of immature T cell proliferation in thymus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse Shh loss-of-function supports a context-specific role in early thymocyte expansion. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the positive regulation of immature T cell proliferation in thymus annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0002320 lymphoid progenitor cell differentiation | IMP PMID:14764698 Reduced thymocyte development in sonic hedgehog knockout emb... | KEEP AS NON CORE | Summary: Mouse loss-of-function evidence supports a role in early thymocyte expansion and differentiation. This GOA record uses mutant-phenotype evidence (IMP) from PMID:14764698. Reason: Retained because the lymphoid progenitor cell differentiation annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0043369 CD4-positive or CD8-positive, alpha-beta T cell lineage commitment | IDA PMID:17227833 Activation of the Hedgehog signaling pathway in T-lineage ce... | KEEP AS NON CORE | Summary: Mouse genetic studies support a context-specific effect on alpha-beta T-cell lineage progression. This GOA record uses direct assay (IDA) from PMID:17227833. Reason: Retained because the CD4-positive or CD8-positive, alpha-beta T cell lineage commitment annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:10654605 SHH-N upregulates Sfrp2 to mediate its competitive interacti... | KEEP AS NON CORE | Summary: A downstream transcriptional consequence of SHH signaling rather than direct DNA-binding activity. This GOA record uses direct assay (IDA) from PMID:10654605. Reason: Retained because the positive regulation of DNA-templated transcription annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005509 calcium ion binding | IDA PMID:19561609 The structure of SHH in complex with HHIP reveals a recognit... | KEEP AS NON CORE | Summary: Calcium stabilizes the SHH signaling domain and participates in one PTCH-binding interface. This GOA record uses direct assay (IDA) from PMID:19561609. Reason: Retained because the calcium ion binding annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005576 extracellular region | IDA PMID:19561609 The structure of SHH in complex with HHIP reveals a recognit... | ACCEPT | Summary: The processed signaling product SHH-N is released into the extracellular region and acts there as a morphogen. This GOA record uses direct assay (IDA) from PMID:19561609. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The extracellular region annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. |
| GO:0008270 zinc ion binding | IDA PMID:19561609 The structure of SHH in complex with HHIP reveals a recognit... | KEEP AS NON CORE | Summary: The SHH signaling domain coordinates zinc; the ion contributes to receptor/antagonist recognition rather than defining a separate signaling output. This GOA record uses direct assay (IDA) from PMID:19561609. Reason: Retained because the zinc ion binding annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. Supporting Evidence: PMID:19561609 groove of SHH and directly coordinates its Zn2+ cation. |
| GO:0001569 branching involved in blood vessel morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific morphogenetic outcome inferred from the experimentally studied mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the branching involved in blood vessel morphogenesis annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0001570 vasculogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific vascular-development outcome inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the vasculogenesis annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0001656 metanephros development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific urinary-system developmental role inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the metanephros development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0001658 branching involved in ureteric bud morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific urinary tract branching phenotype inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the branching involved in ureteric bud morphogenesis annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0001708 cell fate specification | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cell-fate specification is a canonical consequence of graded SHH morphogen signaling. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the cell fate specification annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0001755 neural crest cell migration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific neural-crest migration outcome inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the neural crest cell migration annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005576 extracellular region | ISS GO_REF:0000024 | ACCEPT | Summary: The processed signaling product SHH-N is released into the extracellular region and acts there as a morphogen. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The extracellular region annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. |
| GO:0007267 cell-cell signaling | ISS GO_REF:0000024 | ACCEPT | Summary: Secreted or cell-surface SHH conveys a signal from producing cells to responding cells. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained as a defining SHH activity, pathway role, or active extracellular location. The cell-cell signaling annotation is consistent with the processed ligand's established PTCH-SMO signaling mechanism or the precursor's intrinsic maturation chemistry. |
| GO:0007389 pattern specification process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Pattern specification is a canonical but context-dependent developmental consequence of graded SHH signaling. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the pattern specification process annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0007405 neuroblast proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific neural precursor proliferation outcome inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the neuroblast proliferation annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0007411 axon guidance | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific axon-guidance role inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the axon guidance annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0007417 central nervous system development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SHH has broad, conserved patterning roles in central nervous system development. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the central nervous system development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0007507 heart development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific cardiac developmental role inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the heart development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0008209 androgen metabolic process | ISS GO_REF:0000024 | UNDECIDED | Summary: The annotation was transferred from mouse SHH, but no underlying source publication is exposed in the GOA record and the narrow metabolic claim was not independently verified. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: The narrow androgen metabolic process claim is transferred from another organism or high-throughput source, but its underlying source experiment is not exposed in this GOA record and independent corroboration was not found. It is left undecided rather than overruled. |
| GO:0008284 positive regulation of cell population proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SHH promotes proliferation in multiple developmental contexts, including neural precursors. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the positive regulation of cell population proliferation annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0009953 dorsal/ventral pattern formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific dorsal-ventral patterning role, prominently in neural tube and somites. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the dorsal/ventral pattern formation annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0009986 cell surface | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Lipidated SHH-N is retained at the producing-cell surface before local or long-range delivery. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the cell surface annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0030162 regulation of proteolysis | ISS GO_REF:0000024 | UNDECIDED | Summary: The broad proteolysis-regulation claim lacks an exposed source experiment and is not equivalent to SHH's own well-supported autoprocessing reaction. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: The narrow regulation of proteolysis claim is transferred from another organism or high-throughput source, but its underlying source experiment is not exposed in this GOA record and independent corroboration was not found. It is left undecided rather than overruled. |
| GO:0030324 lung development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific organogenesis role inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the lung development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0030326 embryonic limb morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SHH has a conserved role in embryonic limb patterning and morphogenesis. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the embryonic limb morphogenesis annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0030336 negative regulation of cell migration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-dependent cell-migration outcome inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the negative regulation of cell migration annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0030539 male genitalia development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific reproductive-system developmental role inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the male genitalia development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0030850 prostate gland development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Epithelial SHH signals to adjacent mesenchyme during prostate development. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the prostate gland development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0030900 forebrain development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Human loss-of-function and vertebrate studies support a major role in forebrain patterning. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the forebrain development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0030901 midbrain development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific midbrain developmental role inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the midbrain development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0030902 hindbrain development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific hindbrain developmental role inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the hindbrain development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0042127 regulation of cell population proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Regulation of proliferation is a recurring downstream outcome of SHH signaling in several target tissues. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the regulation of cell population proliferation annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0042733 embryonic digit morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A well-established context-specific role of SHH signaling in digit patterning. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the embryonic digit morphogenesis annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0043237 laminin-1 binding | ISS GO_REF:0000024 | UNDECIDED | Summary: The laminin-1-binding claim was transferred from mouse without an exposed supporting publication and was not independently verified. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: The narrow laminin-1 binding claim is transferred from another organism or high-throughput source, but its underlying source experiment is not exposed in this GOA record and independent corroboration was not found. It is left undecided rather than overruled. |
| GO:0045121 membrane raft | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cholesterylation and palmitoylation enrich mature SHH-N in membrane-raft-like domains before release. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the membrane raft annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0045596 negative regulation of cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-dependent differentiation outcome inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the negative regulation of cell differentiation annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0048468 cell development | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: This generic term adds little beyond specific cell-fate, proliferation, and differentiation annotations. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: The cell development term is not false, but it is an uninformative umbrella consequence of SHH signaling and is superseded by multiple more specific developmental annotations. |
| GO:0048663 neuron fate commitment | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A context-specific neural cell-fate outcome inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the neuron fate commitment annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0048754 branching morphogenesis of an epithelial tube | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A broad epithelial branching role inferred from the mouse ortholog. This GOA record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024. Reason: Retained because the branching morphogenesis of an epithelial tube annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0007418 ventral midline development | TAS PMID:8896572 Mutations in the human Sonic Hedgehog gene cause holoprosenc... | KEEP AS NON CORE | Summary: Human SHH loss-of-function and vertebrate developmental evidence support a ventral-midline role. This GOA record uses traceable-author-statement evidence (TAS) from PMID:8896572. Reason: Retained because the ventral midline development annotation is biologically consistent with SHH evidence, but it describes a biosynthetic location, structural cofactor, downstream effect, or tissue-specific developmental context rather than the gene product's defining activities. |
| GO:0005515 protein binding | IPI PMID:19561609 The structure of SHH in complex with HHIP reveals a recognit... | PENDING | Summary: TODO: Review this GOA annotation |
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Download this section (compressed HTML)Q: How do the two PTCH-binding interfaces, SHH calcium/zinc coordination, and dual lipidation quantitatively determine signaling potency and tissue range in human developmental contexts?
Q: Which human tissues use predominantly paracrine versus producing-cell-surface/juxtacrine SHH signaling, and how do DISP1, SCUBE2, glypicans, CDON, BOC, and GAS1 partition those modes?
Q: How closely does Purkinje-cell SHH output and granule-cell-precursor response in human fetal cerebellum or organoids recapitulate the causal circuit established in mouse?
Q: Which developmental phenotypes of human SHH variants arise primarily from defective precursor cholesterolysis, impaired secretion/range, or altered PTCH/co-receptor engagement?
Experiment: Engineer isogenic human cells with SHH variants that separately disrupt the HINT catalytic residues, cholesterol acceptor site, palmitoylation site, calcium/zinc interface, or PTCH-binding surfaces; quantify precursor processing, lipidation, secretion, PTCH binding, ciliary SMO accumulation, and GLI reporter output.
Experiment: Use spatially resolved human neural-tube, forebrain, limb-bud, and cerebellar organoids with inducible SHH source cells and live GLI reporters to measure how SHH concentration, exposure duration, lipidation, and carrier proteins determine cell-fate thresholds.
Experiment: In human cerebellar organoids, selectively delete or restore SHH in Purkinje-lineage cells and quantify granule-cell-precursor EdU incorporation, cell-cycle state, differentiation, and foliation-like tissue architecture, with SMO inhibition as an epistasis control.
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