{"gene":"PTCH2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1999,"finding":"PTCH2 encodes a 1203 amino acid putative transmembrane protein highly homologous to PTCH1, localized to chromosome 1p32.1-32.3, spanning ~15 kb with 22 coding exons. Truncating mutations identified in medulloblastoma and splice-donor site mutations in basal cell carcinoma establish it as a tumor suppressor candidate.","method":"SSCP mutation analysis, genomic cloning, sequencing","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, genomic/molecular characterization with mutation identification but no functional reconstitution","pmids":["9931336"],"is_preprint":false},{"year":1999,"finding":"PTCH2 undergoes alternative splicing producing multiple mRNA isoforms, including transcripts lacking segments involved in sonic hedgehog binding. PTCH2 is upregulated in basal cell carcinomas similar to PTCH1, and is expressed in the sonic hedgehog/PTCH signaling pathway context, suggesting negative regulation of PTCH2 by PTCH1.","method":"cDNA library screening, RACE, BAC sequencing, in situ hybridization","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple orthogonal expression/structural methods but no direct functional reconstitution; single lab","pmids":["10029063"],"is_preprint":false},{"year":1998,"finding":"Mouse Ptch2 is co-expressed with Shh in epithelial tissues (developing tooth, hair, whisker, nasal gland, eyelids), while Ptch1 is expressed in adjacent mesenchyme, suggesting distinct spatial roles; Ptch2 is expressed in both Shh-producing and non-producing cells throughout development.","method":"In situ hybridization, chromosomal localization","journal":"Mechanisms of development","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, expression-based localization without direct functional consequence demonstrated","pmids":["9858693"],"is_preprint":false},{"year":2004,"finding":"PTCH2 splice variants localize in the cytoplasm and can internalize the N-terminal fragment of Sonic Hedgehog (Shh-N). Only one PTCH2 variant inhibits SHH-N promoter activity, and none of the PTCH2 isoforms can inhibit the constitutively activated SMO-M2, contrasting with PTCH1. All PTCH2 variants alter SMO localization from dispersed cytoplasmic to juxtanuclear upon co-transfection with Smo. PTCH2 isoforms and PTCH1 interact physically as shown by co-immunoprecipitation. In Ptch1-/- mouse cells, PTCH2 variants and PTCH1 differentially reconstitute SHH- and Desert HH-dependent transcriptional responses.","method":"Promoter reporter assays, co-immunoprecipitation, subcellular localization (microscopy), Ptch1-/- cell reconstitution assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, co-IP, localization, genetic reconstitution), single lab but comprehensive functional analysis","pmids":["14613484"],"is_preprint":false},{"year":2008,"finding":"A missense mutation R719Q in an extracellular loop of PTCH2 (caused by 2157G→A transition in exon 15) results in inactivation of PTCH2 inhibitory activities on Hedgehog/GLI1 signaling and abolishes PTCH2's ability to inhibit cell proliferation, establishing that this extracellular domain is required for PTCH2 inhibitory function.","method":"GLI1 reporter gene assay, cell growth curve analysis, direct sequencing, restriction enzyme digestion","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional reporter and proliferation assays with mutagenesis, single lab","pmids":["18285427"],"is_preprint":false},{"year":2013,"finding":"PTCH2 localizes to cilia and functions as a ciliary-localized HH pathway antagonist. Combined removal of PTCH2- and PTCH1-feedback antagonism produces significant expansion of HH-dependent ventral neural progenitors; complete loss of PTCH2, HHIP1, and PTCH1 feedback inhibition results in ectopic specification of ventral cell fates throughout the neural tube, reflecting constitutive HH pathway activation.","method":"Mouse genetic epistasis (Ptch1/Ptch2/Hhip1 combined knockouts), immunofluorescence localization, neural patterning analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple combinatorial knockouts replicated across pathway components, ciliary localization directly demonstrated","pmids":["23900540"],"is_preprint":false},{"year":2014,"finding":"Ptch2 functions as the Shh receptor in Ptch1-/- cells; Ptch1-/-;Ptch2-/- double knockout cells cannot further activate the Shh response beyond Ptch1-/- cells, demonstrating that Ptch2 mediates Shh signaling in the absence of Ptch1. Expression of a dominant-negative Ptch2 in chick neural tube activates the Shh response, while dominant-negative Ptch1 has no effect, establishing that Ptch2 suppresses Shh signaling at early developmental stages.","method":"Double-knockout cell lines (Ptch1-/-;Ptch2-/-), dominant-negative overexpression in chick neural tube, Shh-blocking antibody (5E1), migration assay","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic approaches (double KO, dominant-negative in two systems), functional readouts","pmids":["25085974"],"is_preprint":false},{"year":2014,"finding":"Ptch2 is a functional Shh receptor that regulates Smo localization and activity in vitro. Ptch1 and Ptch2 are co-expressed in the developing mouse limb bud, and loss of Ptch2 exacerbates limb outgrowth defects in limb-specific Ptch1 knockout mutants, demonstrating functional cooperation between Ptch1 and Ptch2 in cellular responses to Shh in vivo.","method":"In vitro Smo localization assays, mouse limb-specific Ptch1 knockout with Ptch2 compound mutants, developmental phenotype analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vitro receptor-Smo regulation assay combined with in vivo genetic epistasis in compound mutants","pmids":["25448692"],"is_preprint":false},{"year":2016,"finding":"Loss of Ptch2 drives myeloproliferative neoplasm (MPN) phenotype through dual canonical and noncanonical HH signaling. Ptch2-/- niche cells show hyperactive noncanonical HH signaling resulting in reduced production of HSC regulators (Scf, Cxcl12, Jag1) and osteoblast depletion. Hematopoietic loss of Ptch2 drives leukocytosis and promotes HSC maintenance. Ptch2 loss in either niche or hematopoietic cells accelerates JAK2V617F-driven MPN transformation into leukemia.","method":"Ptch2-/- mouse model, bone marrow transplantation/chimera experiments, cell culture replating assays, gene expression analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific genetic dissection with reciprocal transplantation experiments, multiple phenotypic readouts across two compartments","pmids":["26834157"],"is_preprint":false},{"year":2018,"finding":"The sterol-sensing domain (SSD) modules of Ptch1 and Ptch2 function as generic modules, but protein-specific Hh signaling activities are determined by adjacent cytoplasmic and luminal domains. The N- and C-terminal halves of Ptch1 associate noncovalently to mediate ligand-dependent Hh repression; analogous Ptch2 halves interact noncovalently but do not repress Hh. Chimeric proteins with Ptch2 SSDs replacing Ptch1 SSDs can still repress Hh signaling. Specific cytoplasmic domains of Ptch1 are necessary but not sufficient for repression; the two principal luminal domains of Ptch1 and Ptch2 are interchangeable.","method":"Chimeric protein construction, Hh reporter assays, domain swap mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis and chimeric protein analysis with functional readout, single lab but multiple orthogonal constructs","pmids":["30166346"],"is_preprint":false},{"year":2018,"finding":"C2EIP (a primordial germ cell-specific protein) interacts with PTCH2 at the intracellular membrane, promotes PTCH2 ubiquitination, and activates HH signaling via competitive inhibition of SMO, thereby positively regulating primordial germ cell generation.","method":"Co-immunoprecipitation, ubiquitination assay, knockout and overexpression in embryonic stem cells, in vitro and in vivo PGC generation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and functional assays, single lab, mechanistic claim rests on competitive inhibition of SMO not fully reconstituted","pmids":["29703892"],"is_preprint":false},{"year":2020,"finding":"Ptch2 forms a specific hetero-complex with Gas1 (not Boc) to mediate Smo de-repression during primordial germ cell migration, with different kinetics than the Ptch1/Boc complex. Ptch2-mediated HH signaling induces phosphorylation of Creb and Src proteins in parallel to Gli induction, identifying a Ptch2-specific non-canonical signal pathway distinct from Ptch1.","method":"Mouse genetic experiments (Ptch1/Ptch2/Gas1/Boc mutants), PGC migration assays, phosphoprotein analysis (Creb, Src), co-receptor complex analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic dissection with multiple combinatorial mutants, identification of a Ptch2-specific downstream signaling branch with biochemical validation of Creb/Src phosphorylation","pmids":["32332736"],"is_preprint":false},{"year":2019,"finding":"PDS5B positively regulates PTCH2 expression to influence Sonic hedgehog signaling; downregulation of PTCH2 abolished PDS5B-mediated anti-tumor activity (inhibition of growth, migration, invasion) in pancreatic cancer cells, placing PTCH2 downstream of PDS5B in this pathway.","method":"Transfection/overexpression, siRNA knockdown, MTT assay, FACS, wound healing, transwell invasion assay, western blotting","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — epistasis established by rescue experiments, multiple functional assays, single lab","pmids":["31233836"],"is_preprint":false},{"year":2022,"finding":"PTCH2 overexpression suppresses glioma cell proliferation and invasion and upregulates PTEN expression, thereby suppressing AKT signaling; loss of PTCH2 activates the PTEN/AKT pathway to promote glioma development in vitro and in vivo.","method":"PTCH2 overexpression in glioma cell lines (LN229, U87-MG), proliferation/invasion assays, western blotting for PTEN/AKT, tumor-bearing mouse model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro and in vivo functional assays with pathway mechanistic readout, single lab","pmids":["36027694"],"is_preprint":false},{"year":2025,"finding":"In Nile tilapia, Ptch2 acts as the functional receptor for Desert Hedgehog (Dhh) in stem Leydig cells; in vitro ptch2 knockout in SLCs abolished Dhh response while ptch1 knockout did not. In vivo, ptch2 mutation rescued testicular defects of dhh mutants (consistent with Ptch2 as an inhibitory receptor). Gli1 acts as the primary transcriptional effector downstream of Ptch2, transactivating Sf1 expression required for stem Leydig cell differentiation.","method":"CRISPR/Cas9 knockout (ptch1, ptch2, gli1, sf1), in vivo genetic rescue experiments, luciferase assays in Gli-knockout SLCs, SLC transplantation assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic tools in an ortholog model with functional reconstitution (transplantation), preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.06.13.659479"],"is_preprint":true}],"current_model":"PTCH2 is a multi-pass transmembrane receptor in the Hedgehog (HH) signaling pathway that binds SHH/DHH ligands and acts as an inhibitory receptor by suppressing Smoothened (SMO) activity; it localizes to primary cilia, forms specific co-receptor complexes (e.g., with Gas1), can signal through a Ptch2-specific non-canonical branch (Creb/Src phosphorylation) in addition to canonical Gli induction, and its protein-specific repressive activity is determined by its cytoplasmic domains flanking a generic sterol-sensing domain module, while its loss leads to constitutive HH pathway activation, myeloproliferative disease, and tumor suppression defects."},"narrative":{"mechanistic_narrative":"PTCH2 is a multi-pass transmembrane receptor of the Hedgehog (HH) pathway that binds HH ligands and acts as an inhibitory receptor, restraining Smoothened (SMO) and thereby limiting downstream GLI-driven transcription [PMID:14613484, PMID:25085974]. It is homologous to PTCH1 and undergoes alternative splicing, with truncating and splice-site mutations in medulloblastoma and basal cell carcinoma marking it as a tumor suppressor candidate [PMID:9931336, PMID:10029063]. PTCH2 internalizes the N-terminal fragment of SHH and redistributes SMO from a dispersed cytoplasmic pattern to a juxtanuclear localization, yet, unlike PTCH1, it cannot suppress constitutively active SMO-M2, defining a distinct mode of SMO regulation [PMID:14613484]. Genetic dissection establishes that PTCH2 is a ciliary-localized HH antagonist that provides feedback inhibition cooperatively with PTCH1 and HHIP1; combined loss expands HH-dependent ventral neural progenitors and causes ectopic ventral cell fates reflecting constitutive pathway activation [PMID:23900540, PMID:25085974, PMID:25448692]. The protein-specific repressive activity of PTCH2 is encoded not by its sterol-sensing domain—which is a generic, interchangeable module—but by adjacent cytoplasmic and luminal domains, and an extracellular-loop missense mutation (R719Q) abolishes its inhibitory and anti-proliferative function [PMID:18285427, PMID:30166346]. PTCH2 supports a dedicated non-canonical branch: it forms a specific hetero-complex with Gas1 (not Boc) and drives CREB and SRC phosphorylation in parallel to GLI induction, a signal distinct from PTCH1 [PMID:32332736]. Loss of PTCH2 drives a myeloproliferative neoplasm phenotype through dual canonical and non-canonical HH signaling and accelerates JAK2V617F-driven leukemic transformation [PMID:26834157], and PTCH2 acts as a tumor suppressor in pancreatic cancer and glioma, where it can engage the PTEN/AKT axis [PMID:31233836, PMID:36027694].","teleology":[{"year":1999,"claim":"Established PTCH2 as a PTCH1-homologous transmembrane gene and a candidate tumor suppressor, framing the question of whether it functions in HH signaling like its paralog.","evidence":"Genomic cloning and SSCP mutation analysis in medulloblastoma and basal cell carcinoma","pmids":["9931336","10029063"],"confidence":"Medium","gaps":["No functional reconstitution of HH activity","Significance of ligand-binding-deficient splice isoforms unresolved"]},{"year":1998,"claim":"Mapped distinct spatial expression of Ptch2 versus Ptch1 in developing epithelia, raising the possibility of non-redundant roles within the SHH/PTCH circuit.","evidence":"In situ hybridization in mouse developmental tissues","pmids":["9858693"],"confidence":"Low","gaps":["Expression pattern without functional consequence demonstrated","No direct receptor activity tested"]},{"year":2004,"claim":"Demonstrated that PTCH2 internalizes Shh-N and regulates SMO localization but, unlike PTCH1, fails to repress constitutively active SMO-M2, defining a divergent SMO-regulatory mode and a physical PTCH1-PTCH2 interaction.","evidence":"Promoter reporter assays, co-IP, subcellular localization, and Ptch1-/- cell reconstitution","pmids":["14613484"],"confidence":"High","gaps":["Mechanism of SMO-M2 resistance not resolved","Functional role of cytoplasmic splice variants unclear"]},{"year":2008,"claim":"Localized an extracellular determinant of PTCH2 inhibitory function by showing that the R719Q missense mutation abolishes repression of GLI1 signaling and cell proliferation.","evidence":"GLI1 reporter and proliferation assays with site-directed mutation","pmids":["18285427"],"confidence":"Medium","gaps":["Structural basis of the loop's role unknown","Disease association of R719Q not established"]},{"year":2013,"claim":"Established PTCH2 as a ciliary HH antagonist providing feedback inhibition redundant with PTCH1 and HHIP1, since only combined loss produces constitutive ventral neural patterning defects.","evidence":"Combinatorial Ptch1/Ptch2/Hhip1 mouse knockouts and ciliary immunofluorescence","pmids":["23900540"],"confidence":"High","gaps":["Quantitative contribution of Ptch2 relative to other antagonists unresolved","Mechanism of ciliary targeting not defined"]},{"year":2014,"claim":"Demonstrated that Ptch2 is a bona fide Shh receptor mediating signaling and suppressing the response in the absence of Ptch1, and that the two cooperate in limb development.","evidence":"Ptch1-/-;Ptch2-/- double-knockout cells, dominant-negative chick neural tube, and compound limb-specific mouse mutants","pmids":["25085974","25448692"],"confidence":"High","gaps":["Ligand-binding affinity and stoichiometry not quantified","Degree of functional redundancy context-dependent"]},{"year":2016,"claim":"Showed that Ptch2 loss drives myeloproliferative neoplasm via dual canonical and non-canonical HH signaling in both niche and hematopoietic compartments, linking the receptor to malignant transformation.","evidence":"Ptch2-/- mouse model with reciprocal bone marrow transplantation and JAK2V617F co-mutation","pmids":["26834157"],"confidence":"High","gaps":["Molecular identity of the non-canonical effector in this context not defined","Direct ligand/receptor events upstream unresolved"]},{"year":2018,"claim":"Resolved that PTCH2's protein-specific repressive activity is determined by cytoplasmic and luminal domains flanking a generic, interchangeable sterol-sensing module, explaining why Ptch2 halves associate but do not repress HH.","evidence":"Chimeric protein construction and domain-swap mutagenesis with HH reporter readouts","pmids":["30166346"],"confidence":"High","gaps":["Identity of the cytoplasmic-domain interactors conferring repression unknown","Structural model of half-half association absent"]},{"year":2018,"claim":"Identified C2EIP as a PTCH2 interactor that promotes PTCH2 ubiquitination and activates HH signaling, providing a post-translational route to regulate PTCH2 in primordial germ cell generation.","evidence":"Co-IP, ubiquitination assay, and knockout/overexpression in embryonic stem cells","pmids":["29703892"],"confidence":"Medium","gaps":["Ubiquitin ligase and degradation outcome not identified","Competitive SMO inhibition model not reconstituted"]},{"year":2020,"claim":"Defined a PTCH2-specific signaling architecture: a Gas1 (not Boc) co-receptor complex and parallel CREB/SRC phosphorylation alongside GLI induction during germ cell migration, distinguishing Ptch2 output from Ptch1.","evidence":"Combinatorial Ptch1/Ptch2/Gas1/Boc mouse mutants, PGC migration assays, and phosphoprotein analysis","pmids":["32332736"],"confidence":"High","gaps":["Biochemical link from Ptch2-Gas1 to CREB/SRC activation unmapped","Generality of the non-canonical branch beyond PGCs untested"]},{"year":2019,"claim":"Placed PTCH2 downstream of PDS5B as an effector of anti-tumor activity in pancreatic cancer, extending its tumor-suppressor role to upstream transcriptional regulation.","evidence":"Overexpression/siRNA rescue with proliferation, migration, and invasion assays","pmids":["31233836"],"confidence":"Medium","gaps":["Mechanism by which PDS5B controls PTCH2 expression undefined","Single-lab cell-line evidence"]},{"year":2022,"claim":"Connected PTCH2 tumor suppression in glioma to upregulation of PTEN and suppression of AKT signaling, implicating a pathway beyond canonical GLI output.","evidence":"PTCH2 overexpression in glioma cell lines, PTEN/AKT western blotting, and tumor-bearing mouse model","pmids":["36027694"],"confidence":"Medium","gaps":["Direct molecular link between PTCH2 and PTEN unknown","Relationship to canonical HH signaling in glioma unresolved"]},{"year":2025,"claim":"Showed in tilapia that Ptch2 is the functional receptor for Desert Hedgehog in stem Leydig cells, acting through Gli1-driven Sf1 expression, reinforcing ligand-selective receptor roles.","evidence":"CRISPR knockouts, in vivo genetic rescue, and SLC transplantation assays (preprint)","pmids":["bio_10.1101_2025.06.13.659479"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Conservation of Dhh-Ptch2 selectivity in mammals not confirmed"]},{"year":null,"claim":"The biochemical chain linking the PTCH2-Gas1 complex to CREB/SRC activation, and the molecular interactors of the cytoplasmic domains that confer PTCH2-specific repression, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of the PTCH2 N/C-terminal association","Non-canonical effector identity unknown","Direct PTCH2-PTEN connection unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[6,7,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,5,9]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,6,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,7,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,8,13]}],"complexes":["Ptch2-Gas1 co-receptor complex"],"partners":["PTCH1","SMO","GAS1","C2EIP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6C5","full_name":"Protein patched homolog 2","aliases":[],"length_aa":1203,"mass_kda":130.5,"function":"Plays a role in the control of cellular growth (PubMed:18285427). May have a role in epidermal development. May act as a receptor for Sonic hedgehog (SHH)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y6C5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTCH2","classification":"Not Classified","n_dependent_lines":28,"n_total_lines":1208,"dependency_fraction":0.023178807947019868},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTCH2","total_profiled":1310},"omim":[{"mim_id":"620343","title":"BASAL CELL NEVUS SYNDROME 2; BCNS2","url":"https://www.omim.org/entry/620343"},{"mim_id":"616908","title":"PATCHED DOMAIN-CONTAINING PROTEIN 4; PTCHD4","url":"https://www.omim.org/entry/616908"},{"mim_id":"613545","title":"MACROSTOMIA, ISOLATED","url":"https://www.omim.org/entry/613545"},{"mim_id":"605462","title":"BASAL CELL CARCINOMA, SUSCEPTIBILITY TO, 1; BCC1","url":"https://www.omim.org/entry/605462"},{"mim_id":"603673","title":"PATCHED 2; PTCH2","url":"https://www.omim.org/entry/603673"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"parathyroid gland","ntpm":55.6},{"tissue":"salivary gland","ntpm":70.9}],"url":"https://www.proteinatlas.org/search/PTCH2"},"hgnc":{"alias_symbol":["SLC65B2"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y6C5","domains":[{"cath_id":"-","chopping":"109-390","consensus_level":"medium","plddt":87.0541,"start":109,"end":390},{"cath_id":"1.20.1640.10","chopping":"669-707_959-1120","consensus_level":"medium","plddt":90.8052,"start":669,"end":1120},{"cath_id":"-","chopping":"780-903","consensus_level":"medium","plddt":87.2507,"start":780,"end":903}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6C5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6C5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6C5-F1-predicted_aligned_error_v6.png","plddt_mean":78.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTCH2","jax_strain_url":"https://www.jax.org/strain/search?query=PTCH2"},"sequence":{"accession":"Q9Y6C5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6C5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6C5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6C5"}},"corpus_meta":[{"pmid":"9931336","id":"PMC_9931336","title":"Isolation and characterization of human patched 2 (PTCH2), a putative tumour suppressor gene inbasal cell carcinoma and medulloblastoma on chromosome 1p32.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9931336","citation_count":149,"is_preprint":false},{"pmid":"18285427","id":"PMC_18285427","title":"A missense mutation in PTCH2 underlies dominantly inherited NBCCS in a Chinese family.","date":"2008","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18285427","citation_count":89,"is_preprint":false},{"pmid":"23900540","id":"PMC_23900540","title":"Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning.","date":"2013","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/23900540","citation_count":76,"is_preprint":false},{"pmid":"10029063","id":"PMC_10029063","title":"PTCH2, a novel human patched gene, undergoing alternative splicing and up-regulated in basal cell carcinomas.","date":"1999","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10029063","citation_count":64,"is_preprint":false},{"pmid":"23479190","id":"PMC_23479190","title":"Frameshift mutation in the PTCH2 gene can cause nevoid basal cell carcinoma syndrome.","date":"2013","source":"Familial cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23479190","citation_count":62,"is_preprint":false},{"pmid":"14613484","id":"PMC_14613484","title":"Distinct roles of PTCH2 splice variants in Hedgehog signalling.","date":"2004","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/14613484","citation_count":62,"is_preprint":false},{"pmid":"9858693","id":"PMC_9858693","title":"Overlapping and non-overlapping Ptch2 expression with Shh during mouse embryogenesis.","date":"1998","source":"Mechanisms of 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Yi xue ban = Journal of Peking University. 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Truncating mutations identified in medulloblastoma and splice-donor site mutations in basal cell carcinoma establish it as a tumor suppressor candidate.\",\n      \"method\": \"SSCP mutation analysis, genomic cloning, sequencing\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, genomic/molecular characterization with mutation identification but no functional reconstitution\",\n      \"pmids\": [\"9931336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PTCH2 undergoes alternative splicing producing multiple mRNA isoforms, including transcripts lacking segments involved in sonic hedgehog binding. PTCH2 is upregulated in basal cell carcinomas similar to PTCH1, and is expressed in the sonic hedgehog/PTCH signaling pathway context, suggesting negative regulation of PTCH2 by PTCH1.\",\n      \"method\": \"cDNA library screening, RACE, BAC sequencing, in situ hybridization\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple orthogonal expression/structural methods but no direct functional reconstitution; single lab\",\n      \"pmids\": [\"10029063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mouse Ptch2 is co-expressed with Shh in epithelial tissues (developing tooth, hair, whisker, nasal gland, eyelids), while Ptch1 is expressed in adjacent mesenchyme, suggesting distinct spatial roles; Ptch2 is expressed in both Shh-producing and non-producing cells throughout development.\",\n      \"method\": \"In situ hybridization, chromosomal localization\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, expression-based localization without direct functional consequence demonstrated\",\n      \"pmids\": [\"9858693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PTCH2 splice variants localize in the cytoplasm and can internalize the N-terminal fragment of Sonic Hedgehog (Shh-N). Only one PTCH2 variant inhibits SHH-N promoter activity, and none of the PTCH2 isoforms can inhibit the constitutively activated SMO-M2, contrasting with PTCH1. All PTCH2 variants alter SMO localization from dispersed cytoplasmic to juxtanuclear upon co-transfection with Smo. PTCH2 isoforms and PTCH1 interact physically as shown by co-immunoprecipitation. In Ptch1-/- mouse cells, PTCH2 variants and PTCH1 differentially reconstitute SHH- and Desert HH-dependent transcriptional responses.\",\n      \"method\": \"Promoter reporter assays, co-immunoprecipitation, subcellular localization (microscopy), Ptch1-/- cell reconstitution assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, co-IP, localization, genetic reconstitution), single lab but comprehensive functional analysis\",\n      \"pmids\": [\"14613484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A missense mutation R719Q in an extracellular loop of PTCH2 (caused by 2157G→A transition in exon 15) results in inactivation of PTCH2 inhibitory activities on Hedgehog/GLI1 signaling and abolishes PTCH2's ability to inhibit cell proliferation, establishing that this extracellular domain is required for PTCH2 inhibitory function.\",\n      \"method\": \"GLI1 reporter gene assay, cell growth curve analysis, direct sequencing, restriction enzyme digestion\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional reporter and proliferation assays with mutagenesis, single lab\",\n      \"pmids\": [\"18285427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTCH2 localizes to cilia and functions as a ciliary-localized HH pathway antagonist. Combined removal of PTCH2- and PTCH1-feedback antagonism produces significant expansion of HH-dependent ventral neural progenitors; complete loss of PTCH2, HHIP1, and PTCH1 feedback inhibition results in ectopic specification of ventral cell fates throughout the neural tube, reflecting constitutive HH pathway activation.\",\n      \"method\": \"Mouse genetic epistasis (Ptch1/Ptch2/Hhip1 combined knockouts), immunofluorescence localization, neural patterning analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple combinatorial knockouts replicated across pathway components, ciliary localization directly demonstrated\",\n      \"pmids\": [\"23900540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Ptch2 functions as the Shh receptor in Ptch1-/- cells; Ptch1-/-;Ptch2-/- double knockout cells cannot further activate the Shh response beyond Ptch1-/- cells, demonstrating that Ptch2 mediates Shh signaling in the absence of Ptch1. Expression of a dominant-negative Ptch2 in chick neural tube activates the Shh response, while dominant-negative Ptch1 has no effect, establishing that Ptch2 suppresses Shh signaling at early developmental stages.\",\n      \"method\": \"Double-knockout cell lines (Ptch1-/-;Ptch2-/-), dominant-negative overexpression in chick neural tube, Shh-blocking antibody (5E1), migration assay\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic approaches (double KO, dominant-negative in two systems), functional readouts\",\n      \"pmids\": [\"25085974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Ptch2 is a functional Shh receptor that regulates Smo localization and activity in vitro. Ptch1 and Ptch2 are co-expressed in the developing mouse limb bud, and loss of Ptch2 exacerbates limb outgrowth defects in limb-specific Ptch1 knockout mutants, demonstrating functional cooperation between Ptch1 and Ptch2 in cellular responses to Shh in vivo.\",\n      \"method\": \"In vitro Smo localization assays, mouse limb-specific Ptch1 knockout with Ptch2 compound mutants, developmental phenotype analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro receptor-Smo regulation assay combined with in vivo genetic epistasis in compound mutants\",\n      \"pmids\": [\"25448692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of Ptch2 drives myeloproliferative neoplasm (MPN) phenotype through dual canonical and noncanonical HH signaling. Ptch2-/- niche cells show hyperactive noncanonical HH signaling resulting in reduced production of HSC regulators (Scf, Cxcl12, Jag1) and osteoblast depletion. Hematopoietic loss of Ptch2 drives leukocytosis and promotes HSC maintenance. Ptch2 loss in either niche or hematopoietic cells accelerates JAK2V617F-driven MPN transformation into leukemia.\",\n      \"method\": \"Ptch2-/- mouse model, bone marrow transplantation/chimera experiments, cell culture replating assays, gene expression analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific genetic dissection with reciprocal transplantation experiments, multiple phenotypic readouts across two compartments\",\n      \"pmids\": [\"26834157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The sterol-sensing domain (SSD) modules of Ptch1 and Ptch2 function as generic modules, but protein-specific Hh signaling activities are determined by adjacent cytoplasmic and luminal domains. The N- and C-terminal halves of Ptch1 associate noncovalently to mediate ligand-dependent Hh repression; analogous Ptch2 halves interact noncovalently but do not repress Hh. Chimeric proteins with Ptch2 SSDs replacing Ptch1 SSDs can still repress Hh signaling. Specific cytoplasmic domains of Ptch1 are necessary but not sufficient for repression; the two principal luminal domains of Ptch1 and Ptch2 are interchangeable.\",\n      \"method\": \"Chimeric protein construction, Hh reporter assays, domain swap mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis and chimeric protein analysis with functional readout, single lab but multiple orthogonal constructs\",\n      \"pmids\": [\"30166346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"C2EIP (a primordial germ cell-specific protein) interacts with PTCH2 at the intracellular membrane, promotes PTCH2 ubiquitination, and activates HH signaling via competitive inhibition of SMO, thereby positively regulating primordial germ cell generation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, knockout and overexpression in embryonic stem cells, in vitro and in vivo PGC generation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and functional assays, single lab, mechanistic claim rests on competitive inhibition of SMO not fully reconstituted\",\n      \"pmids\": [\"29703892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Ptch2 forms a specific hetero-complex with Gas1 (not Boc) to mediate Smo de-repression during primordial germ cell migration, with different kinetics than the Ptch1/Boc complex. Ptch2-mediated HH signaling induces phosphorylation of Creb and Src proteins in parallel to Gli induction, identifying a Ptch2-specific non-canonical signal pathway distinct from Ptch1.\",\n      \"method\": \"Mouse genetic experiments (Ptch1/Ptch2/Gas1/Boc mutants), PGC migration assays, phosphoprotein analysis (Creb, Src), co-receptor complex analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic dissection with multiple combinatorial mutants, identification of a Ptch2-specific downstream signaling branch with biochemical validation of Creb/Src phosphorylation\",\n      \"pmids\": [\"32332736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDS5B positively regulates PTCH2 expression to influence Sonic hedgehog signaling; downregulation of PTCH2 abolished PDS5B-mediated anti-tumor activity (inhibition of growth, migration, invasion) in pancreatic cancer cells, placing PTCH2 downstream of PDS5B in this pathway.\",\n      \"method\": \"Transfection/overexpression, siRNA knockdown, MTT assay, FACS, wound healing, transwell invasion assay, western blotting\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — epistasis established by rescue experiments, multiple functional assays, single lab\",\n      \"pmids\": [\"31233836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTCH2 overexpression suppresses glioma cell proliferation and invasion and upregulates PTEN expression, thereby suppressing AKT signaling; loss of PTCH2 activates the PTEN/AKT pathway to promote glioma development in vitro and in vivo.\",\n      \"method\": \"PTCH2 overexpression in glioma cell lines (LN229, U87-MG), proliferation/invasion assays, western blotting for PTEN/AKT, tumor-bearing mouse model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro and in vivo functional assays with pathway mechanistic readout, single lab\",\n      \"pmids\": [\"36027694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Nile tilapia, Ptch2 acts as the functional receptor for Desert Hedgehog (Dhh) in stem Leydig cells; in vitro ptch2 knockout in SLCs abolished Dhh response while ptch1 knockout did not. In vivo, ptch2 mutation rescued testicular defects of dhh mutants (consistent with Ptch2 as an inhibitory receptor). Gli1 acts as the primary transcriptional effector downstream of Ptch2, transactivating Sf1 expression required for stem Leydig cell differentiation.\",\n      \"method\": \"CRISPR/Cas9 knockout (ptch1, ptch2, gli1, sf1), in vivo genetic rescue experiments, luciferase assays in Gli-knockout SLCs, SLC transplantation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic tools in an ortholog model with functional reconstitution (transplantation), preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.06.13.659479\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PTCH2 is a multi-pass transmembrane receptor in the Hedgehog (HH) signaling pathway that binds SHH/DHH ligands and acts as an inhibitory receptor by suppressing Smoothened (SMO) activity; it localizes to primary cilia, forms specific co-receptor complexes (e.g., with Gas1), can signal through a Ptch2-specific non-canonical branch (Creb/Src phosphorylation) in addition to canonical Gli induction, and its protein-specific repressive activity is determined by its cytoplasmic domains flanking a generic sterol-sensing domain module, while its loss leads to constitutive HH pathway activation, myeloproliferative disease, and tumor suppression defects.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTCH2 is a multi-pass transmembrane receptor of the Hedgehog (HH) pathway that binds HH ligands and acts as an inhibitory receptor, restraining Smoothened (SMO) and thereby limiting downstream GLI-driven transcription [#3, #6]. It is homologous to PTCH1 and undergoes alternative splicing, with truncating and splice-site mutations in medulloblastoma and basal cell carcinoma marking it as a tumor suppressor candidate [#0, #1]. PTCH2 internalizes the N-terminal fragment of SHH and redistributes SMO from a dispersed cytoplasmic pattern to a juxtanuclear localization, yet, unlike PTCH1, it cannot suppress constitutively active SMO-M2, defining a distinct mode of SMO regulation [#3]. Genetic dissection establishes that PTCH2 is a ciliary-localized HH antagonist that provides feedback inhibition cooperatively with PTCH1 and HHIP1; combined loss expands HH-dependent ventral neural progenitors and causes ectopic ventral cell fates reflecting constitutive pathway activation [#5, #6, #7]. The protein-specific repressive activity of PTCH2 is encoded not by its sterol-sensing domain—which is a generic, interchangeable module—but by adjacent cytoplasmic and luminal domains, and an extracellular-loop missense mutation (R719Q) abolishes its inhibitory and anti-proliferative function [#4, #9]. PTCH2 supports a dedicated non-canonical branch: it forms a specific hetero-complex with Gas1 (not Boc) and drives CREB and SRC phosphorylation in parallel to GLI induction, a signal distinct from PTCH1 [#11]. Loss of PTCH2 drives a myeloproliferative neoplasm phenotype through dual canonical and non-canonical HH signaling and accelerates JAK2V617F-driven leukemic transformation [#8], and PTCH2 acts as a tumor suppressor in pancreatic cancer and glioma, where it can engage the PTEN/AKT axis [#12, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established PTCH2 as a PTCH1-homologous transmembrane gene and a candidate tumor suppressor, framing the question of whether it functions in HH signaling like its paralog.\",\n      \"evidence\": \"Genomic cloning and SSCP mutation analysis in medulloblastoma and basal cell carcinoma\",\n      \"pmids\": [\"9931336\", \"10029063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional reconstitution of HH activity\", \"Significance of ligand-binding-deficient splice isoforms unresolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapped distinct spatial expression of Ptch2 versus Ptch1 in developing epithelia, raising the possibility of non-redundant roles within the SHH/PTCH circuit.\",\n      \"evidence\": \"In situ hybridization in mouse developmental tissues\",\n      \"pmids\": [\"9858693\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Expression pattern without functional consequence demonstrated\", \"No direct receptor activity tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated that PTCH2 internalizes Shh-N and regulates SMO localization but, unlike PTCH1, fails to repress constitutively active SMO-M2, defining a divergent SMO-regulatory mode and a physical PTCH1-PTCH2 interaction.\",\n      \"evidence\": \"Promoter reporter assays, co-IP, subcellular localization, and Ptch1-/- cell reconstitution\",\n      \"pmids\": [\"14613484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of SMO-M2 resistance not resolved\", \"Functional role of cytoplasmic splice variants unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Localized an extracellular determinant of PTCH2 inhibitory function by showing that the R719Q missense mutation abolishes repression of GLI1 signaling and cell proliferation.\",\n      \"evidence\": \"GLI1 reporter and proliferation assays with site-directed mutation\",\n      \"pmids\": [\"18285427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the loop's role unknown\", \"Disease association of R719Q not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established PTCH2 as a ciliary HH antagonist providing feedback inhibition redundant with PTCH1 and HHIP1, since only combined loss produces constitutive ventral neural patterning defects.\",\n      \"evidence\": \"Combinatorial Ptch1/Ptch2/Hhip1 mouse knockouts and ciliary immunofluorescence\",\n      \"pmids\": [\"23900540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of Ptch2 relative to other antagonists unresolved\", \"Mechanism of ciliary targeting not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that Ptch2 is a bona fide Shh receptor mediating signaling and suppressing the response in the absence of Ptch1, and that the two cooperate in limb development.\",\n      \"evidence\": \"Ptch1-/-;Ptch2-/- double-knockout cells, dominant-negative chick neural tube, and compound limb-specific mouse mutants\",\n      \"pmids\": [\"25085974\", \"25448692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand-binding affinity and stoichiometry not quantified\", \"Degree of functional redundancy context-dependent\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed that Ptch2 loss drives myeloproliferative neoplasm via dual canonical and non-canonical HH signaling in both niche and hematopoietic compartments, linking the receptor to malignant transformation.\",\n      \"evidence\": \"Ptch2-/- mouse model with reciprocal bone marrow transplantation and JAK2V617F co-mutation\",\n      \"pmids\": [\"26834157\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the non-canonical effector in this context not defined\", \"Direct ligand/receptor events upstream unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved that PTCH2's protein-specific repressive activity is determined by cytoplasmic and luminal domains flanking a generic, interchangeable sterol-sensing module, explaining why Ptch2 halves associate but do not repress HH.\",\n      \"evidence\": \"Chimeric protein construction and domain-swap mutagenesis with HH reporter readouts\",\n      \"pmids\": [\"30166346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the cytoplasmic-domain interactors conferring repression unknown\", \"Structural model of half-half association absent\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified C2EIP as a PTCH2 interactor that promotes PTCH2 ubiquitination and activates HH signaling, providing a post-translational route to regulate PTCH2 in primordial germ cell generation.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, and knockout/overexpression in embryonic stem cells\",\n      \"pmids\": [\"29703892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin ligase and degradation outcome not identified\", \"Competitive SMO inhibition model not reconstituted\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a PTCH2-specific signaling architecture: a Gas1 (not Boc) co-receptor complex and parallel CREB/SRC phosphorylation alongside GLI induction during germ cell migration, distinguishing Ptch2 output from Ptch1.\",\n      \"evidence\": \"Combinatorial Ptch1/Ptch2/Gas1/Boc mouse mutants, PGC migration assays, and phosphoprotein analysis\",\n      \"pmids\": [\"32332736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical link from Ptch2-Gas1 to CREB/SRC activation unmapped\", \"Generality of the non-canonical branch beyond PGCs untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed PTCH2 downstream of PDS5B as an effector of anti-tumor activity in pancreatic cancer, extending its tumor-suppressor role to upstream transcriptional regulation.\",\n      \"evidence\": \"Overexpression/siRNA rescue with proliferation, migration, and invasion assays\",\n      \"pmids\": [\"31233836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PDS5B controls PTCH2 expression undefined\", \"Single-lab cell-line evidence\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected PTCH2 tumor suppression in glioma to upregulation of PTEN and suppression of AKT signaling, implicating a pathway beyond canonical GLI output.\",\n      \"evidence\": \"PTCH2 overexpression in glioma cell lines, PTEN/AKT western blotting, and tumor-bearing mouse model\",\n      \"pmids\": [\"36027694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between PTCH2 and PTEN unknown\", \"Relationship to canonical HH signaling in glioma unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed in tilapia that Ptch2 is the functional receptor for Desert Hedgehog in stem Leydig cells, acting through Gli1-driven Sf1 expression, reinforcing ligand-selective receptor roles.\",\n      \"evidence\": \"CRISPR knockouts, in vivo genetic rescue, and SLC transplantation assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.13.659479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Conservation of Dhh-Ptch2 selectivity in mammals not confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical chain linking the PTCH2-Gas1 complex to CREB/SRC activation, and the molecular interactors of the cytoplasmic domains that confer PTCH2-specific repression, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the PTCH2 N/C-terminal association\", \"Non-canonical effector identity unknown\", \"Direct PTCH2-PTEN connection unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [6, 7, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 5, 9]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 6, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 7, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 8, 13]}\n    ],\n    \"complexes\": [\n      \"Ptch2-Gas1 co-receptor complex\"\n    ],\n    \"partners\": [\n      \"PTCH1\",\n      \"SMO\",\n      \"GAS1\",\n      \"C2EIP\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}