Pan-metazoan Hedgehog/Smoothened signaling pathway module

A taxon-neutral decomposition of Hedgehog (Hh) signaling, the metazoan cell-cell communication system in which a dually lipidated Hedgehog ligand released by a signal-sending cell controls the activator/repressor balance of Ci/GLI zinc-finger transcription factors in a receiving cell. The module is written around the segments that are shared from cnidarians and insects to vertebrates: autocatalytic cholesterol-coupled processing and N-terminal palmitoylation of the ligand; reception by the twelve-pass Patched receptor and its Ig/fibronectin-domain co-receptors; relief of Patched-mediated restriction of sterol access to the class-F receptor Smoothened; kinase-driven proteolytic processing of Ci/GLI into a transcriptional repressor when the pathway is off; and Smoothened-dependent conversion of Ci/GLI into an activator through Suppressor of fused, Fused-family kinases, and a kinesin-4 scaffold. Where lineages differ they are modeled as variants on an explicit axis rather than as separate pathways: the vertebrate implementation runs the activation step in the primary cilium with GPR161, intraflagellar transport, and KIF7, while the Drosophila implementation runs the equivalent step on a cytoplasmic Hedgehog signaling complex nucleated by the Costal-2 kinesin at the plasma membrane. Sonic hedgehog (SHH) is the vertebrate exemplar ligand, but it is one of three vertebrate paralogs of the single ancestral Hedgehog ligand and is used here only as a representative member.

Boundary decisions. This document replaces an earlier, explicitly vertebrate sketch of the same module id; the pan-metazoan scope is the requested change, so the ciliary machinery that was previously stated as module-level context now sits inside the vertebrate variant, where it belongs. Ligand biogenesis is kept inside the module because Hedgehog performs its own autoproteolysis and cholesterol transfer, so those are activities of a core participant rather than upstream biology. Transcriptional targets, tissue-level patterning outcomes, and pathway-level crosstalk (Wnt, BMP, primary-cilium assembly) are deliberately outside the boundary. HHIP, SCUBE2, and GAS1 are vertebrate accessories and are modeled as an optional reception-tier variant rather than as core steps; glypicans are modeled alongside them because the same heparan-sulfate proteoglycan role is documented in both flies (dally) and vertebrates. Taxon scope. "Pan-metazoan" here means the module is written for the animal clade in which ligand, receptor, transducer, and Ci/GLI effector co-occur, which includes cnidarians, most protostomes, and vertebrates. It is not a claim of universality: nematodes have lost recognizable Hedgehog and Smoothened while expanding Patched-related and Hedgehog-related families (PMID:16204193), and any realization in that lineage would be a different module, not a variant of this one. Grounding provenance. Every UniProt exemplar was taken from a local artifact rather than recalled: the PANTHER family entry tables under interpro/panther/ and the cached GO-CAM activity index gocams/index.tsv. PANTHER family and subfamily labels are copied verbatim from interpro/panther/panther.obo, and the four PTN ancestral nodes are resolved from the committed PAINT IBD slices. Where a genuine component could not be grounded, no identifier was invented (see knowledge_gaps). The Drosophila Patched, Dispatched and Fused exemplars and human DISP1 were left unasserted while UniProt was unreachable and were added once it was; Suppressor of fused, Slimb and Brother of Ihog are still named only in prose, because each has only unreviewed entries under more than one accession. The KIF7/Costal-2 grounding sits on a genuine disagreement between sources rather than on a settled id. PANTHER's own per-organism classification for release 19.0 places both in PTHR24115 (KIF7 at SF445, Costal-2 at SF949), while UniProt's PANTHER cross-reference, which is also what the cached per-family entry tables under interpro/panther/ record, places them in PTHR47969 (SF8 and SF15). The rebuilt member index carries both and treats either as acceptable. This module declares the PTHR24115 subfamilies, following PANTHER's classification as the more direct source for a PANTHER id, but the alternative is a real reading and not an error to be corrected away. Deep research. A module deep-research run was attempted with `just module-deep-research-openscientist hedgehog_signaling` and failed because the provider host is blocked by this environment's network egress policy (403). No deep-research file is therefore present, and none was hand-written in place of one. An ontology gap on the acyltransferase, recorded here rather than as a knowledge gap because a curator rather than an experiment would close it. No molecular-function term describes what the Hedgehog acyltransferase actually does. GO:0019706, which this module and the curated GO-CAM both give it, is defined as transfer of palmitate to a sulfur atom on a cysteine, producing an S-palmitoyl thioester; the enzyme instead forms an amide bond to the alpha-amino group of the ligand's N-terminal cysteine. The chemistry is not in doubt and the process side is already covered, since GO:0018009 names N-terminal peptidyl-L-cysteine N-palmitoylation explicitly and the HHAT gene review uses it. What is missing is the matching activity term: the N-palmitoyltransferase activities GO does have are all peptidyl-lysine, and the only chemically safe existing choice is the linkage-agnostic parent GO:0016409. The term this needs is protein-cysteine N-palmitoyltransferase activity under GO:0016409, the name UniProt and PANTHER already use for this enzyme, and the HHAT gene review carries that proposal as a proposed_new_terms entry. GO:0019706 is kept here because it is what GOA and the GO-CAM use, so the inaccuracy is inherited rather than introduced; a reader should know the term names the wrong bond. Gene-level grounding, which was an open curation gap when this module was written and is now largely closed. The module's leaf claims originally rested on PANTHER family membership, PAINT nodes and GO-CAM activities, with only SHH, SMO and GSK3B reviewed among the human exemplars and nothing on the Drosophila side, which mattered because the pan-metazoan claim is carried by the invertebrate members. Since then PTCH1, SUFU, GLI3, GLI2, KIF7, GPR161, HHAT and STK36 have been curated on the human side, and hh, ptc, smo and ci on the Drosophila side, so the protostome half of the pathway now has gene-level adjudication rather than family evidence alone. Several of those curations fed corrections back into this module and into the family reviews. Remaining participants are unreviewed but peripheral to the core segments. Three Drosophila participants are still named in prose without an accession: Suppressor of fused, Slimb and Brother of Ihog. Each exists only as unreviewed UniProt entries, and more than one accession carries the same gene symbol, so picking one would assert a canonical form UniProt has not designated. Every other participant is grounded: Drosophila ptc (P18502), disp (Q9VNJ5) and fu (P23647), and human DISP1 (Q96F81), are recorded as representative members. The Drosophila Su(fu) gene also appears as a PAINT seed (FB:FBgn0005355) for the SUFU ancestral node cited here, so that clade-level claim holds without a protein accession. Cite the three once UniProt designates reviewed entries, or record a chosen unreviewed accession together with the reason it was preferred over its siblings. This is a data-representation question, not a biological one.