SHH

Existing Annotations Review

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.

📄 View Raw YAML

id: Q15465
gene_symbol: SHH
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: '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.'
existing_annotations:
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: is_active_in
    review:
      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.
      action: ACCEPT
      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.
  - term:
      id: GO:0007224
      label: smoothened signaling pathway
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: involved_in
    review:
      summary: SHH is the extracellular ligand that initiates canonical PTCH-SMO Hedgehog signaling.
        This GOA record uses phylogenetic inference (IBA) from GO_REF:0000033.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30139912
          supporting_text: Activation occurs when the lipid-modified HH-N binds to its receptor,
            Patched-1 (PTCH1) protein (15).
        - reference_id: PMID:30139912
          supporting_text: 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).
      additional_reference_ids:
        - PMID:30139912
  - term:
      id: GO:0010468
      label: regulation of gene expression
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: involved_in
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30139912
          supporting_text: Activation occurs when the lipid-modified HH-N binds to its receptor,
            Patched-1 (PTCH1) protein (15).
        - reference_id: PMID:30139912
          supporting_text: 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).
      additional_reference_ids:
        - PMID:30139912
  - term:
      id: GO:0005113
      label: patched binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: enables
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30139912
          supporting_text: Activation occurs when the lipid-modified HH-N binds to its receptor,
            Patched-1 (PTCH1) protein (15).
        - reference_id: PMID:30139912
          supporting_text: 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).
      additional_reference_ids:
        - PMID:30139912
  - term:
      id: GO:0001708
      label: cell fate specification
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: involved_in
    review:
      summary: Cell-fate specification is a canonical consequence of graded SHH morphogen signaling.
        This GOA record uses phylogenetic inference (IBA) from GO_REF:0000033.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0048709
      label: oligodendrocyte differentiation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: involved_in
    review:
      summary: Phylogenetic inference supports a conserved role in oligodendrocyte differentiation.
        This GOA record uses phylogenetic inference (IBA) from GO_REF:0000033.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005509
      label: calcium ion binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: enables
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0000139
      label: Golgi membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005509
      label: calcium ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    qualifier: enables
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    qualifier: located_in
    review:
      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.
      action: ACCEPT
      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.
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    qualifier: located_in
    review:
      summary: The precursor is associated with the ER membrane during biosynthetic processing. This
        GOA record uses electronic inference (IEA) from GO_REF:0000044.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0007267
      label: cell-cell signaling
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    qualifier: involved_in
    review:
      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.
      action: ACCEPT
      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.
  - term:
      id: GO:0007389
      label: pattern specification process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0007417
      label: central nervous system development
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    qualifier: involved_in
    review:
      summary: SHH has broad, conserved patterning roles in central nervous system development. This
        GOA record uses electronic inference (IEA) from GO_REF:0000117.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0009888
      label: tissue development
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    qualifier: involved_in
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
  - term:
      id: GO:0016539
      label: intein-mediated protein splicing
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    qualifier: involved_in
    review:
      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.
      action: REMOVE
      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.
  - term:
      id: GO:0016540
      label: protein autoprocessing
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    qualifier: involved_in
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:24342078
          supporting_text: 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.
      additional_reference_ids:
        - PMID:24342078
  - term:
      id: GO:0030182
      label: neuron differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    qualifier: involved_in
    review:
      summary: A broad, context-dependent neural differentiation outcome of SHH signaling. This GOA
        record uses electronic inference (IEA) from GO_REF:0000117.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0035295
      label: tube development
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    qualifier: involved_in
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
  - term:
      id: GO:0042127
      label: regulation of cell population proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0045165
      label: cell fate commitment
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    qualifier: involved_in
    review:
      summary: Cell-fate commitment is a broad downstream consequence of graded SHH signaling. This
        GOA record uses electronic inference (IEA) from GO_REF:0000117.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0045880
      label: positive regulation of smoothened signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    qualifier: involved_in
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30139912
          supporting_text: Activation occurs when the lipid-modified HH-N binds to its receptor,
            Patched-1 (PTCH1) protein (15).
        - reference_id: PMID:30139912
          supporting_text: 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).
      additional_reference_ids:
        - PMID:30139912
  - term:
      id: GO:0048468
      label: cell development
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    qualifier: involved_in
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
  - term:
      id: GO:0048513
      label: animal organ development
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    qualifier: involved_in
    review:
      summary: This generic umbrella term adds little beyond the specific organ-development
        annotations. This GOA record uses electronic inference (IEA) from GO_REF:0000117.
      action: MARK_AS_OVER_ANNOTATED
      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.
  - term:
      id: GO:0050793
      label: regulation of developmental process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    qualifier: involved_in
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19561609
    qualifier: enables
    supporting_entities:
      - UniProtKB:Q96QV1
    review:
      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.
      action: REMOVE
      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.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29954986
    qualifier: enables
    review:
      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.
      action: MODIFY
      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_replacement_terms:
        - id: GO:0005113
          label: patched binding
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29995851
    qualifier: enables
    review:
      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.
      action: MODIFY
      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_replacement_terms:
        - id: GO:0005113
          label: patched binding
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:30139912
    qualifier: enables
    review:
      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.
      action: MODIFY
      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_replacement_terms:
        - id: GO:0005113
          label: patched binding
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: A downstream, context-dependent transcriptional outcome of SHH-PTCH-SMO-GLI
        signaling. This GOA record uses electronic inference (IEA) from GO_REF:0000107.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0001656
      label: metanephros development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: A context-specific urinary-system developmental role inferred from the mouse
        ortholog. This GOA record uses electronic inference (IEA) from GO_REF:0000107.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0001947
      label: heart looping
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0002320
      label: lymphoid progenitor cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0003140
      label: determination of left/right asymmetry in lateral mesoderm
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:0004175
      label: endopeptidase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: enables
    review:
      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.
      action: MODIFY
      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_replacement_terms:
        - &id001
          id: GO:0140853
          label: cholesterol-protein transferase activity
      supported_by:
        - reference_id: PMID:24342078
          supporting_text: 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.
      additional_reference_ids:
        - PMID:24342078
  - term:
      id: GO:0005113
      label: patched binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    qualifier: enables
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30139912
          supporting_text: Activation occurs when the lipid-modified HH-N binds to its receptor,
            Patched-1 (PTCH1) protein (15).
        - reference_id: PMID:30139912
          supporting_text: 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).
      additional_reference_ids:
        - PMID:30139912
  - term:
      id: GO:0007224
      label: smoothened signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    qualifier: involved_in
    review:
      summary: SHH is the extracellular ligand that initiates canonical PTCH-SMO Hedgehog signaling.
        This GOA record uses electronic inference (IEA) from GO_REF:0000120.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30139912
          supporting_text: Activation occurs when the lipid-modified HH-N binds to its receptor,
            Patched-1 (PTCH1) protein (15).
        - reference_id: PMID:30139912
          supporting_text: 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).
      additional_reference_ids:
        - PMID:30139912
  - term:
      id: GO:0009949
      label: polarity specification of anterior/posterior axis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: A context-specific anterior-posterior patterning role, prominently in the limb bud.
        This GOA record uses electronic inference (IEA) from GO_REF:0000107.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0010628
      label: positive regulation of gene expression
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0010629
      label: negative regulation of gene expression
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: A context-dependent downstream transcriptional consequence of SHH signaling. This GOA
        record uses electronic inference (IEA) from GO_REF:0000107.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0021904
      label: dorsal/ventral neural tube patterning
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: SHH is a canonical ventralizing signal in dorsal-ventral neural-tube patterning. This
        GOA record uses electronic inference (IEA) from GO_REF:0000107.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0021930
      label: cerebellar granule cell precursor proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:10226030
          supporting_text: treatment of dissociated granule neuron cultures with recombinant Shh
            stimulated
      additional_reference_ids:
        - PMID:10226030
  - term:
      id: GO:0033077
      label: T cell differentiation in thymus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0033089
      label: positive regulation of T cell differentiation in thymus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0033092
      label: positive regulation of immature T cell proliferation in thymus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0042481
      label: regulation of odontogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: A context-specific role in tooth development inferred from the mouse ortholog. This
        GOA record uses electronic inference (IEA) from GO_REF:0000107.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0042733
      label: embryonic digit morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: A well-established context-specific role of SHH signaling in digit patterning. This
        GOA record uses electronic inference (IEA) from GO_REF:0000107.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: SHH binding can suppress PTCH-dependent pro-apoptotic signaling in specific contexts.
        This GOA record uses electronic inference (IEA) from GO_REF:0000107.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0043369
      label: CD4-positive or CD8-positive, alpha-beta T cell lineage commitment
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0045059
      label: positive thymic T cell selection
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0045060
      label: negative thymic T cell selection
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: A downstream GLI-mediated transcriptional consequence of SHH pathway activation. This
        GOA record uses electronic inference (IEA) from GO_REF:0000107.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0046638
      label: positive regulation of alpha-beta T cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: A context-specific immune-development outcome supported by mouse genetics. This GOA
        record uses electronic inference (IEA) from GO_REF:0000107.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0048538
      label: thymus development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: Mouse genetic evidence supports a context-specific role in thymus development. This
        GOA record uses electronic inference (IEA) from GO_REF:0000107.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0048864
      label: stem cell development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0061053
      label: somite development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: SHH is a conserved ventralizing signal during somite development. This GOA record
        uses electronic inference (IEA) from GO_REF:0000107.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0072136
      label: metanephric mesenchymal cell proliferation involved in metanephros development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: A context-specific metanephric proliferation outcome inferred from the mouse
        ortholog. This GOA record uses electronic inference (IEA) from GO_REF:0000107.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0090370
      label: negative regulation of cholesterol efflux
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0097190
      label: apoptotic signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0140853
      label: cholesterol-protein transferase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: enables
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:24342078
          supporting_text: 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.
      additional_reference_ids:
        - PMID:24342078
  - term:
      id: GO:1904339
      label: negative regulation of dopaminergic neuron differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:2000062
      label: negative regulation of ureter smooth muscle cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:2000063
      label: positive regulation of ureter smooth muscle cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:2000357
      label: negative regulation of kidney smooth muscle cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:2000358
      label: positive regulation of kidney smooth muscle cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:2000729
      label: positive regulation of mesenchymal cell proliferation involved in ureter development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: A context-specific ureteric mesenchymal proliferation outcome inferred from the mouse
        ortholog. This GOA record uses electronic inference (IEA) from GO_REF:0000107.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0004175
      label: endopeptidase activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: enables
    review:
      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.
      action: MODIFY
      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_replacement_terms:
        - *id001
      supported_by:
        - reference_id: PMID:24342078
          supporting_text: 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.
      additional_reference_ids:
        - PMID:24342078
  - term:
      id: GO:0016540
      label: protein autoprocessing
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:24342078
          supporting_text: 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.
      additional_reference_ids:
        - PMID:24342078
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: EXP
    original_reference_id: PMID:24342078
    qualifier: located_in
    review:
      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.
      action: ACCEPT
      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.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0140853
      label: cholesterol-protein transferase activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: enables
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:24342078
          supporting_text: 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.
      additional_reference_ids:
        - PMID:24342078
  - term:
      id: GO:1900107
      label: regulation of nodal signaling pathway
    evidence_type: NAS
    original_reference_id: PMID:17507406
    qualifier: involved_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:0007224
      label: smoothened signaling pathway
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30139912
          supporting_text: Activation occurs when the lipid-modified HH-N binds to its receptor,
            Patched-1 (PTCH1) protein (15).
        - reference_id: PMID:30139912
          supporting_text: 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).
      additional_reference_ids:
        - PMID:30139912
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: acts_upstream_of
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0003140
      label: determination of left/right asymmetry in lateral mesoderm
    evidence_type: NAS
    original_reference_id: PMID:17507406
    qualifier: involved_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:0060684
      label: epithelial-mesenchymal cell signaling
    evidence_type: IDA
    original_reference_id: PMID:12221011
    qualifier: acts_upstream_of_or_within
    review:
      summary: Prostate explant experiments support epithelial SHH signaling to adjacent mesenchyme.
        This GOA record uses direct assay (IDA) from PMID:12221011.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0045880
      label: positive regulation of smoothened signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:24342078
    qualifier: involved_in
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30139912
          supporting_text: Activation occurs when the lipid-modified HH-N binds to its receptor,
            Patched-1 (PTCH1) protein (15).
        - reference_id: PMID:30139912
          supporting_text: 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).
      additional_reference_ids:
        - PMID:30139912
  - term:
      id: GO:0005113
      label: patched binding
    evidence_type: IDA
    original_reference_id: PMID:11472839
    qualifier: enables
    review:
      summary: Processed SHH-N directly binds PTCH1/PTCH2, relieving PTCH-mediated inhibition of
        SMO. This GOA record uses direct assay (IDA) from PMID:11472839.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30139912
          supporting_text: Activation occurs when the lipid-modified HH-N binds to its receptor,
            Patched-1 (PTCH1) protein (15).
        - reference_id: PMID:30139912
          supporting_text: 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).
      additional_reference_ids:
        - PMID:30139912
  - term:
      id: GO:0005783
      label: endoplasmic reticulum
    evidence_type: IDA
    original_reference_id: PMID:18534984
    qualifier: located_in
    review:
      summary: The SHH precursor enters the endoplasmic reticulum for autocatalytic processing and
        lipid modification. This GOA record uses direct assay (IDA) from PMID:18534984.
      action: ACCEPT
      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.
  - term:
      id: GO:0005794
      label: Golgi apparatus
    evidence_type: IDA
    original_reference_id: PMID:18534984
    qualifier: located_in
    review:
      summary: SHH traverses the Golgi/secretory pathway during maturation and palmitoylation. This
        GOA record uses direct assay (IDA) from PMID:18534984.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0007224
      label: smoothened signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:31279575
    qualifier: involved_in
    review:
      summary: SHH is the extracellular ligand that initiates canonical PTCH-SMO Hedgehog signaling.
        This GOA record uses direct assay (IDA) from PMID:31279575.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30139912
          supporting_text: Activation occurs when the lipid-modified HH-N binds to its receptor,
            Patched-1 (PTCH1) protein (15).
        - reference_id: PMID:30139912
          supporting_text: 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).
      additional_reference_ids:
        - PMID:30139912
  - term:
      id: GO:0004175
      label: endopeptidase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5358460
    qualifier: enables
    review:
      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.
      action: MODIFY
      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_replacement_terms:
        - *id001
      supported_by:
        - reference_id: PMID:24342078
          supporting_text: 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.
      additional_reference_ids:
        - PMID:24342078
  - term:
      id: GO:0048745
      label: smooth muscle tissue development
    evidence_type: IEP
    original_reference_id: PMID:17850284
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0072205
      label: metanephric collecting duct development
    evidence_type: IEP
    original_reference_id: PMID:17850284
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0031012
      label: extracellular matrix
    evidence_type: HDA
    original_reference_id: PMID:28344315
    qualifier: located_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:0016015
      label: morphogen activity
    evidence_type: TAS
    original_reference_id: PMID:24431302
    qualifier: enables
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30139912
          supporting_text: Activation occurs when the lipid-modified HH-N binds to its receptor,
            Patched-1 (PTCH1) protein (15).
        - reference_id: PMID:30139912
          supporting_text: 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).
      additional_reference_ids:
        - PMID:30139912
  - term:
      id: GO:0071542
      label: dopaminergic neuron differentiation
    evidence_type: TAS
    original_reference_id: PMID:24431302
    qualifier: involved_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5387389
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5483238
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5387389
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5387392
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0045880
      label: positive regulation of smoothened signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:19561609
    qualifier: involved_in
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30139912
          supporting_text: Activation occurs when the lipid-modified HH-N binds to its receptor,
            Patched-1 (PTCH1) protein (15).
        - reference_id: PMID:30139912
          supporting_text: 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).
      additional_reference_ids:
        - PMID:30139912
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-445448
    qualifier: located_in
    review:
      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.
      action: ACCEPT
      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.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5632649
    qualifier: located_in
    review:
      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.
      action: ACCEPT
      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.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5632652
    qualifier: located_in
    review:
      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.
      action: ACCEPT
      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.
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5358336
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5358340
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5358343
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5362386
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5362412
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5362437
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5362441
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5362459
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5362549
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5362448
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5362459
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5362427
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5362549
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5362551
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5362553
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-5362406
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0009949
      label: polarity specification of anterior/posterior axis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0097190
      label: apoptotic signaling pathway
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5358460
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5362450
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5387386
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5483229
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0021930
      label: cerebellar granule cell precursor proliferation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:10226030
          supporting_text: treatment of dissociated granule neuron cultures with recombinant Shh
            stimulated
      additional_reference_ids:
        - PMID:10226030
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5362551
    qualifier: located_in
    review:
      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.
      action: ACCEPT
      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.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5362553
    qualifier: located_in
    review:
      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.
      action: ACCEPT
      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.
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0042481
      label: regulation of odontogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:1900180
      label: regulation of protein localization to nucleus
    evidence_type: IDA
    original_reference_id: PMID:11331587
    qualifier: involved_in
    review:
      summary: SHH relieves PTCH1-mediated cyclin-B1 sequestration, permitting nuclear localization
        in cultured cells. This GOA record uses direct assay (IDA) from PMID:11331587.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0061189
      label: positive regulation of sclerotome development
    evidence_type: IDA
    original_reference_id: PMID:10654605
    qualifier: involved_in
    review:
      summary: Somite explant experiments support positive regulation of sclerotome development by
        SHH-N. This GOA record uses direct assay (IDA) from PMID:10654605.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0090370
      label: negative regulation of cholesterol efflux
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0007418
      label: ventral midline development
    evidence_type: TAS
    original_reference_id: PMID:11001584
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
    evidence_type: IDA
    original_reference_id: PMID:11331587
    qualifier: involved_in
    review:
      summary: SHH promotes proliferation in multiple developmental contexts, including neural
        precursors. This GOA record uses direct assay (IDA) from PMID:11331587.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0009880
      label: embryonic pattern specification
    evidence_type: TAS
    original_reference_id: PMID:11001584
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0016015
      label: morphogen activity
    evidence_type: NAS
    original_reference_id: PMID:8647801
    qualifier: enables
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30139912
          supporting_text: Activation occurs when the lipid-modified HH-N binds to its receptor,
            Patched-1 (PTCH1) protein (15).
        - reference_id: PMID:30139912
          supporting_text: 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).
      additional_reference_ids:
        - PMID:30139912
  - term:
      id: GO:0051781
      label: positive regulation of cell division
    evidence_type: IDA
    original_reference_id: PMID:11331587
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0001947
      label: heart looping
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0003140
      label: determination of left/right asymmetry in lateral mesoderm
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:0007224
      label: smoothened signaling pathway
    evidence_type: IEP
    original_reference_id: PMID:17850284
    qualifier: involved_in
    review:
      summary: SHH is the extracellular ligand that initiates canonical PTCH-SMO Hedgehog signaling.
        This GOA record uses expression-pattern evidence (IEP) from PMID:17850284.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30139912
          supporting_text: Activation occurs when the lipid-modified HH-N binds to its receptor,
            Patched-1 (PTCH1) protein (15).
        - reference_id: PMID:30139912
          supporting_text: 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).
      additional_reference_ids:
        - PMID:30139912
  - term:
      id: GO:0061053
      label: somite development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      summary: SHH is a conserved ventralizing signal during somite development. This GOA record
        uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005113
      label: patched binding
    evidence_type: IDA
    original_reference_id: PMID:8906787
    qualifier: enables
    review:
      summary: Processed SHH-N directly binds PTCH1/PTCH2, relieving PTCH-mediated inhibition of
        SMO. This GOA record uses direct assay (IDA) from PMID:8906787.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30139912
          supporting_text: Activation occurs when the lipid-modified HH-N binds to its receptor,
            Patched-1 (PTCH1) protein (15).
        - reference_id: PMID:30139912
          supporting_text: 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).
      additional_reference_ids:
        - PMID:30139912
  - term:
      id: GO:2000729
      label: positive regulation of mesenchymal cell proliferation involved in ureter development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0033089
      label: positive regulation of T cell differentiation in thymus
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0045059
      label: positive thymic T cell selection
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0045060
      label: negative thymic T cell selection
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0046638
      label: positive regulation of alpha-beta T cell differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0048538
      label: thymus development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0048864
      label: stem cell development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0072136
      label: metanephric mesenchymal cell proliferation involved in metanephros development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:2000062
      label: negative regulation of ureter smooth muscle cell differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:2000063
      label: positive regulation of ureter smooth muscle cell differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:2000357
      label: negative regulation of kidney smooth muscle cell differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:2000358
      label: positive regulation of kidney smooth muscle cell differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:0033077
      label: T cell differentiation in thymus
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0033092
      label: positive regulation of immature T cell proliferation in thymus
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0002320
      label: lymphoid progenitor cell differentiation
    evidence_type: IMP
    original_reference_id: PMID:14764698
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0043369
      label: CD4-positive or CD8-positive, alpha-beta T cell lineage commitment
    evidence_type: IDA
    original_reference_id: PMID:17227833
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:10654605
    qualifier: involved_in
    review:
      summary: A downstream transcriptional consequence of SHH signaling rather than direct
        DNA-binding activity. This GOA record uses direct assay (IDA) from PMID:10654605.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005509
      label: calcium ion binding
    evidence_type: IDA
    original_reference_id: PMID:19561609
    qualifier: enables
    review:
      summary: Calcium stabilizes the SHH signaling domain and participates in one PTCH-binding
        interface. This GOA record uses direct assay (IDA) from PMID:19561609.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IDA
    original_reference_id: PMID:19561609
    qualifier: located_in
    review:
      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.
      action: ACCEPT
      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.
  - term:
      id: GO:0008270
      label: zinc ion binding
    evidence_type: IDA
    original_reference_id: PMID:19561609
    qualifier: enables
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:19561609
          supporting_text: groove of SHH and directly coordinates its Zn2+ cation.
  - term:
      id: GO:0001569
      label: branching involved in blood vessel morphogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0001570
      label: vasculogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0001656
      label: metanephros development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0001658
      label: branching involved in ureteric bud morphogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0001708
      label: cell fate specification
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0001755
      label: neural crest cell migration
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: located_in
    review:
      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.
      action: ACCEPT
      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.
  - term:
      id: GO:0007267
      label: cell-cell signaling
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: ACCEPT
      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.
  - term:
      id: GO:0007389
      label: pattern specification process
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0007405
      label: neuroblast proliferation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0007411
      label: axon guidance
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0007417
      label: central nervous system development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0007507
      label: heart development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0008209
      label: androgen metabolic process
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0009953
      label: dorsal/ventral pattern formation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0030162
      label: regulation of proteolysis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:0030324
      label: lung development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0030326
      label: embryonic limb morphogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0030336
      label: negative regulation of cell migration
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0030539
      label: male genitalia development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0030850
      label: prostate gland development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      summary: Epithelial SHH signals to adjacent mesenchyme during prostate development. This GOA
        record uses curator-reviewed sequence/orthology transfer (ISS) from GO_REF:0000024.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0030900
      label: forebrain development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0030901
      label: midbrain development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0030902
      label: hindbrain development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0042127
      label: regulation of cell population proliferation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0042733
      label: embryonic digit morphogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0043237
      label: laminin-1 binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: enables
    review:
      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.
      action: UNDECIDED
      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.
  - term:
      id: GO:0045121
      label: membrane raft
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: located_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0045596
      label: negative regulation of cell differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0048468
      label: cell development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
  - term:
      id: GO:0048663
      label: neuron fate commitment
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0048754
      label: branching morphogenesis of an epithelial tube
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0007418
      label: ventral midline development
    evidence_type: TAS
    original_reference_id: PMID:8896572
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by
      curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary
      mapping, accompanied by conservative changes to GO terms applied by UniProt
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation data to orthologs
      using Ensembl Compara
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10654605
    title: SHH-N upregulates Sfrp2 to mediate its competitive interaction with WNT1 and WNT4 in the
      somitic mesoderm.
    findings: []
    full_text_unavailable: true
  - id: PMID:11001584
    title: The sonic hedgehog-patched-gli pathway in human development and disease.
    findings: []
    full_text_unavailable: true
  - id: PMID:11331587
    title: Patched1 interacts with cyclin B1 to regulate cell cycle progression.
    findings: []
    full_text_unavailable: true
  - id: PMID:11472839
    title: Comparative biological responses to human Sonic, Indian, and Desert hedgehog.
    findings: []
    full_text_unavailable: true
    reference_review:
      relevance: HIGH
      correctness: VERIFIED
      review_notes: Abstract directly compares recombinant human Hedgehog ligands and reports
        Patched affinity and developmental bioactivity.
  - id: PMID:12221011
    title: Sonic hedgehog activates mesenchymal Gli1 expression during prostate ductal bud
      formation.
    findings: []
    full_text_unavailable: true
  - id: PMID:14764698
    title: Reduced thymocyte development in sonic hedgehog knockout embryos.
    findings: []
    full_text_unavailable: true
  - id: PMID:17227833
    title: Activation of the Hedgehog signaling pathway in T-lineage cells inhibits TCR repertoire
      selection in the thymus and peripheral T-cell activation.
    findings: []
  - id: PMID:17507406
    title: Cerberus is a feedback inhibitor of Nodal asymmetric signaling in the chick embryo.
    findings: []
    full_text_unavailable: true
    reference_review:
      relevance: LOW
      correctness: UNVERIFIED
      review_notes: The cached abstract concerns chick Cerberus feedback on Nodal and does not show
        the basis for the SHH annotation; full text is unavailable.
  - id: PMID:17850284
    title: Immunohistochemical analysis of Sonic hedgehog signalling in normal human urinary tract
      development.
    findings: []
  - id: PMID:18534984
    title: Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation of Sonic
      Hedgehog.
    findings: []
    full_text_unavailable: true
    reference_review:
      relevance: MEDIUM
      correctness: VERIFIED
      review_notes: Abstract directly establishes HHAT-mediated SHH N-palmitoylation during
        secretory-pathway transit.
  - id: PMID:19561609
    title: The structure of SHH in complex with HHIP reveals a recognition role for the Shh pseudo
      active site in signaling.
    findings: []
    full_text_unavailable: true
    reference_review:
      relevance: HIGH
      correctness: VERIFIED
      review_notes: Abstract and structure directly establish the human SHH-HHIP complex and
        zinc-coordinating interface.
  - id: PMID:24342078
    title: 'A new role for Hedgehogs in juxtacrine signaling.'
    findings: []
    reference_review:
      relevance: HIGH
      correctness: VERIFIED
      review_notes: Full text directly analyzes human SHH precursor processing, secretion, and
        signaling and describes its autoprocessing/cholesterol-transfer domain.
  - id: PMID:24431302
    title: Wnt signaling in midbrain dopaminergic neuron development and regenerative medicine for
      Parkinson's disease.
    findings: []
    full_text_unavailable: true
    reference_review:
      relevance: LOW
      correctness: UNVERIFIED
      review_notes: The cached abstract is a Wnt-focused review and does not expose the basis for
        the SHH-specific dopaminergic annotations; full text is unavailable.
  - id: PMID:28344315
    title: Proteomic characterization of human multiple myeloma bone marrow extracellular matrix.
    findings: []
    full_text_unavailable: true
    reference_review:
      relevance: LOW
      correctness: UNVERIFIED
      review_notes: The cached abstract describes a multiple-myeloma ECM proteome but does not
        enumerate SHH; full text is unavailable, so the SHH ECM localization cannot be checked.
  - id: PMID:29954986
    title: 'Structural basis for the recognition of Sonic Hedgehog by human Patched1.'
    findings: []
    full_text_unavailable: true
    reference_review:
      relevance: HIGH
      correctness: VERIFIED
      review_notes: Abstract directly reports the human PTCH1-SHH-N structure and structure-guided
        interaction assays.
  - id: PMID:29995851
    title: 'Structures of human Patched and its complex with native palmitoylated sonic hedgehog.'
    findings: []
    reference_review:
      relevance: HIGH
      correctness: VERIFIED
      review_notes: Full text directly reports native dually lipidated human SHH-N bound to human
        PTCH1 and associated signaling assays.
  - id: PMID:30139912
    title: 'Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex.'
    findings: []
    reference_review:
      relevance: HIGH
      correctness: VERIFIED
      review_notes: Full text directly resolves two PTCH1 molecules engaging SHH-N and tests the
        signaling contribution of both interfaces.
  - id: PMID:31279575
    title: Phosphorylation of Ci/Gli by Fused Family Kinases Promotes Hedgehog Signaling.
    findings: []
    full_text_unavailable: true
  - id: PMID:8647801
    title: 'A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a
      region associated with developmental abnormalities.'
    findings: []
    full_text_unavailable: true
  - id: PMID:8896572
    title: 'Mutations in the human Sonic Hedgehog gene cause holoprosencephaly.'
    findings: []
    full_text_unavailable: true
  - id: PMID:8906787
    title: 'The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog.'
    findings: []
    full_text_unavailable: true
  - id: Reactome:R-HSA-445448
    title: HHIP binds Hedgehog
    findings: []
  - id: Reactome:R-HSA-5358336
    title: P4HB forms mixed disulphides with Hh precursors
    findings: []
  - id: Reactome:R-HSA-5358340
    title: Autoproteolytic cleavage of Hh precursors
    findings: []
  - id: Reactome:R-HSA-5358343
    title: HHAT palmitoylates Hh N-terminal fragment
    findings: []
  - id: Reactome:R-HSA-5358460
    title: HPE SHH variants don't undergo autoproteolytic cleavage
    findings: []
  - id: Reactome:R-HSA-5362386
    title: Glycosylation of Hh
    findings: []
  - id: Reactome:R-HSA-5362412
    title: SYVN1 ubiquitinates Hh C-terminal fragments
    findings: []
  - id: Reactome:R-HSA-5362427
    title: Hh-Np binds GPC5
    findings: []
  - id: Reactome:R-HSA-5362437
    title: C-terminal Hh fragments are bound by lectins
    findings: []
  - id: Reactome:R-HSA-5362441
    title: C-terminal Hh fragments are recruited to SEL1:SYVN1 at the ER membrane
    findings: []
  - id: Reactome:R-HSA-5362448
    title: Hh C-terminal fragments are degraded by the proteasome
    findings: []
  - id: Reactome:R-HSA-5362450
    title: Hh processing variants bind lectins
    findings: []
  - id: Reactome:R-HSA-5362459
    title: VCP-catalyzed ATP hydrolysis promotes the translocation of Hh-C into the cytosol
    findings: []
  - id: Reactome:R-HSA-5362549
    title: Hh-Np traffics to the plasma membrane
    findings: []
  - id: Reactome:R-HSA-5362551
    title: Hh-Np binds SCUBE2 in the extracellular region to promote long-range signalling
    findings: []
  - id: Reactome:R-HSA-5362553
    title: NOTUM releases Hh-Np:GPC5 from the plasma membrane
    findings: []
  - id: Reactome:R-HSA-5387386
    title: Hh processing variants are recruited to SEL1:SYVN at the ER membrane
    findings: []
  - id: Reactome:R-HSA-5387389
    title: Hh processing variants are translocated to the cytosol in a VCP-dependent manner
    findings: []
  - id: Reactome:R-HSA-5387392
    title: processing defective Hh variants are degraded by the proteasome
    findings: []
  - id: Reactome:R-HSA-5483229
    title: HHAT G287V doesn't palmitoylate Hh-Np
    findings: []
  - id: Reactome:R-HSA-5483238
    title: Hh processing variants are ubiquitinated
    findings: []
  - id: Reactome:R-HSA-5632649
    title: Hh-Npp binds GAS1 and PTCH
    findings: []
  - id: Reactome:R-HSA-5632652
    title: Hh-Npp binds CDON and PTCH
    findings: []
  - id: Reactome:R-NUL-5362406
    title: mouse Disp2 binds SHH N-terminal fragment
    findings: []
  - id: PMID:10226030
    title: Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell
      proliferation in the developing mouse cerebellum.
    findings: []
    full_text_unavailable: true
    reference_review:
      relevance: HIGH
      correctness: VERIFIED
      review_notes: Abstract directly demonstrates Purkinje-cell Shh expression and
        antibody/recombinant-protein effects on mouse granule-neuron-precursor proliferation.
core_functions:
  - description: The mature dually lipidated SHH-N morphogen binds Patched receptors on responding
      cells. This removes PTCH-mediated repression of Smoothened and changes GLI-dependent
      transcription, converting spatial SHH availability into concentration- and duration-dependent
      cell-fate and proliferative responses.
    molecular_function:
      id: GO:0005113
      label: patched binding
    directly_involved_in:
      - id: GO:0045880
        label: positive regulation of smoothened signaling pathway
    locations:
      - id: GO:0005576
        label: extracellular region
    supported_by:
      - reference_id: PMID:30139912
        supporting_text: Activation occurs when the lipid-modified HH-N binds to its receptor,
          Patched-1 (PTCH1) protein (15).
      - reference_id: PMID:30139912
        supporting_text: 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).
  - description: 'The C-terminal HINT domain of the SHH precursor catalyzes an intramolecular cholesterolysis
      reaction: precursor cleavage is coupled to transfer of cholesterol onto the newly generated C terminus
      of SHH-N. This self-processing reaction produces the cholesterylated signaling product required
      for its normal trafficking and range.'
    molecular_function:
      id: GO:0140853
      label: cholesterol-protein transferase activity
    directly_involved_in:
      - id: GO:0016540
        label: protein autoprocessing
    locations:
      - id: GO:0005783
        label: endoplasmic reticulum
    supported_by:
      - reference_id: PMID:24342078
        supporting_text: 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.
proposed_new_terms: []
suggested_questions:
  - question: 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?
  - question: 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?
  - question: 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?
  - question: Which developmental phenotypes of human SHH variants arise primarily from defective
      precursor cholesterolysis, impaired secretion/range, or altered PTCH/co-receptor engagement?
suggested_experiments:
  - description: 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.
  - description: 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.
  - description: 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.

Gene Description

Existing Annotations Review

Core Functions

The mature dually lipidated SHH-N morphogen binds Patched receptors on responding cells. This removes PTCH-mediated repression of Smoothened and changes GLI-dependent transcription, converting spatial SHH availability into concentration- and duration-dependent cell-fate and proliferative responses.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

SHH review notes

2026-07-14 — source acquisition and review scope

Protein architecture, maturation, and defining molecular activities

Localization and signaling range

Developmental contexts and the cerebellar decomposition

Annotation decisions and unresolved evidence

Core-function synthesis

📄 View Raw YAML