Affinage

PTCH2

Protein patched homolog 2 · UniProt Q9Y6C5

Length
1203 aa
Mass
130.5 kDa
Annotated
2026-04-28
33 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTCH2 is a twelve-pass transmembrane receptor in the Hedgehog (HH) signaling pathway that functions as a ligand-dependent feedback antagonist by binding Sonic and Desert Hedgehog ligands, regulating Smoothened (SMO) subcellular localization and activity, and repressing HH target gene transcription through its sterol-sensing domains and cytoplasmic regions (PMID:14613484, PMID:30166346, PMID:25085974). PTCH2 localizes to primary cilia and cooperates with PTCH1 to attenuate HH signaling during vertebrate neural patterning, limb development, and hematopoiesis, where its loss drives myeloproliferative disease through dysregulation of HSC niche factors including Scf, Cxcl12, and Jag1 (PMID:23900540, PMID:25448692, PMID:26834157). PTCH2 forms a specific hetero-complex with the co-receptor Gas1 (distinct from the Ptch1–Boc complex) and activates a non-canonical signaling branch involving Creb and Src phosphorylation during primordial germ cell migration (PMID:32332736). Truncating mutations in PTCH2 have been identified in medulloblastoma and basal cell carcinoma, and the extracellular loop residue R719 is functionally required for its tumor-suppressive inhibition of HH pathway activity (PMID:9931336, PMID:18285427).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1998 Low

    Identification of mouse Ptch2 with an expression pattern overlapping yet distinct from Ptch1 in HH-producing and adjacent tissues raised the question of whether a second Patched receptor has non-redundant roles in HH signaling.

    Evidence In situ hybridization and chromosomal mapping in mouse embryonic tissues

    PMID:9858693

    Open questions at the time
    • Expression pattern alone; no functional data demonstrating distinct signaling role
    • No loss-of-function or gain-of-function experiments performed
  2. 1999 Medium

    Cloning of human PTCH2, mapping to 1p32, and identification of truncating mutations in medulloblastoma and splice-site mutations in BCC established PTCH2 as a candidate tumor suppressor in the HH pathway, while discovery of alternative splicing affecting SHH-binding regions and transcriptional upregulation by HH signaling placed it as a pathway feedback component.

    Evidence Genomic cloning, SSCP mutation analysis, cDNA library screening, RACE, in situ hybridization

    PMID:10029063 PMID:9931336

    Open questions at the time
    • No direct demonstration of tumor suppressor function in cell-based or animal models
    • Functional consequences of individual splice isoforms not determined
  3. 2004 High

    Functional dissection revealed that PTCH2 internalizes SHH-N, physically interacts with PTCH1, and redirects SMO from the cytoplasm to a juxtanuclear compartment, but unlike PTCH1 cannot inhibit constitutively active SMO-M2, establishing that PTCH2 regulates SMO through a mechanism partially distinct from PTCH1.

    Evidence Co-immunoprecipitation, immunofluorescence, SHH-N internalization assay, promoter reporter assays, Ptch1−/− cell reconstitution

    PMID:14613484

    Open questions at the time
    • Mechanism by which PTCH2 alters SMO localization not resolved
    • Whether PTCH2–PTCH1 interaction is required for SMO regulation unclear
  4. 2008 Medium

    The missense mutation R719Q in an extracellular loop abolished PTCH2 inhibitory activity on HH signaling and cell proliferation, pinpointing a critical functional residue for tumor suppressor activity.

    Evidence GLI1 reporter assay and cell growth curve analysis with R719Q mutant

    PMID:18285427

    Open questions at the time
    • No structural basis for why R719Q disrupts function
    • Single mutant study; other extracellular loop residues not systematically tested
  5. 2013 High

    Mouse genetic epistasis with PTCH1 and HHIP1 demonstrated that PTCH2 is a ciliary-localized feedback antagonist that is dispensable alone but essential in combination for restraining HH-dependent ventral neural progenitor expansion, resolving why single Ptch2 knockouts have mild phenotypes.

    Evidence Compound knockout mice (Ptch1/Ptch2/Hhip1), neural tube patterning analysis, ciliary localization imaging

    PMID:23900540

    Open questions at the time
    • Mechanism of PTCH2 ciliary localization not defined
    • Whether PTCH2 feedback antagonism operates identically across all HH-responsive tissues unknown
  6. 2014 High

    Two independent studies established that PTCH2 is a bona fide SHH receptor that mediates residual HH signaling in Ptch1-null cells and cooperates with PTCH1 in vivo for limb outgrowth, resolving the question of whether PTCH2 functions as a true receptor or merely a modulator.

    Evidence Dominant-negative Ptch2 in chick neural tube, Ptch1−/−;Ptch2−/− double-KO cells, limb-specific Ptch1-KO combined with Ptch2-KO, SMO localization assays

    PMID:25085974 PMID:25448692

    Open questions at the time
    • Relative affinities of PTCH2 vs PTCH1 for different HH ligands not quantified
    • Whether PTCH2 mediates cholesterol transport like PTCH1 not addressed
  7. 2016 High

    Ptch2 knockout mice revealed that PTCH2 regulates the hematopoietic niche through both canonical and noncanonical HH signaling, with loss causing osteoblast depletion, reduced Scf/Cxcl12/Jag1 production, leukocytosis, and myeloproliferative disease, establishing a physiological role beyond development.

    Evidence Ptch2−/− mouse model, bone marrow transplantation, flow cytometry, gene expression analysis, HSC functional assays

    PMID:26834157

    Open questions at the time
    • Molecular identity of the noncanonical HH signaling mechanism downstream of PTCH2 in hematopoietic niche not defined
    • Whether myeloproliferative phenotype is cell-autonomous or niche-dependent not fully resolved
  8. 2018 High

    Domain-swap chimeras showed that the sterol-sensing domains of PTCH2 are interchangeable with those of PTCH1 for HH repression, but PTCH1 cytoplasmic domains are uniquely required, explaining the functional divergence between the paralogs at a structural level; separately, C2EIP was identified as a PTCH2-interacting protein that promotes its ubiquitination to activate HH signaling during primordial germ cell differentiation.

    Evidence Chimeric PTCH1/2 proteins with HH reporter assays, co-IP of N/C-terminal halves; C2EIP–PTCH2 co-IP, ubiquitination assay, PGC differentiation in ESCs

    PMID:29703892 PMID:30166346

    Open questions at the time
    • Identity of the E3 ubiquitin ligase for PTCH2 not determined
    • Structural basis for why PTCH2 cytoplasmic domains cannot substitute for PTCH1 unknown
    • C2EIP–PTCH2 interaction validated by co-IP only; reciprocal and endogenous confirmation limited
  9. 2020 High

    Discovery that Ptch2 forms a specific complex with Gas1 (not Boc) and activates Creb/Src phosphorylation alongside canonical Gli signaling during primordial germ cell migration defined a non-canonical Ptch2-specific signaling branch, distinguishing it mechanistically from Ptch1.

    Evidence Mouse genetic analysis of PGC migration with Ptch1/2 and Gas1/Boc knockouts, phosphorylation analysis of Creb and Src, Gli induction assays

    PMID:32332736

    Open questions at the time
    • Whether Creb/Src phosphorylation is direct or requires intermediary kinases unknown
    • Generalizability of Ptch2–Gas1 complex beyond PGC migration not established
  10. 2022 Medium

    Ptch2 loss increased mesenchymal stem cells and bone volume, and PTCH2 overexpression upregulated PTEN to suppress AKT signaling in glioma, expanding the functional scope of PTCH2 to stem cell homeostasis and a PTEN/AKT regulatory axis.

    Evidence Ptch2−/− mouse (incisor, bone, wound healing phenotypes); PTCH2 overexpression in glioma lines with PTEN/AKT western blots and xenograft survival

    PMID:35574464 PMID:36027694

    Open questions at the time
    • Mechanism by which PTCH2 regulates PTEN expression not identified
    • Whether MSC expansion phenotype is cell-autonomous or niche-mediated not resolved
    • PTEN regulation could be indirect via canonical HH pathway modulation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Critical open questions include: the structural basis for PTCH2 function (no cryo-EM or crystal structure), whether PTCH2 transports cholesterol like PTCH1, the identity of kinases mediating Ptch2-specific Creb/Src phosphorylation, and the molecular mechanism by which PTCH2 cytoplasmic domains fail to repress HH signaling when substituted for those of PTCH1.
  • No structural model of PTCH2 available
  • Cholesterol transport function not tested
  • Downstream mediators of Ptch2-specific non-canonical signaling uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 2 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3
Partners
C2EIPDHHGAS1PTCH1SHHSMO
Complex memberships
Ptch2-Gas1 co-receptor complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 PTCH2 encodes a 1203 amino acid putative transmembrane protein highly homologous to PTCH1, localized to chromosome 1p32.1-32.3, comprising 22 coding exons spanning ~15 kb of genomic DNA; truncating mutations identified in medulloblastoma and splice donor site mutations in basal cell carcinoma implicate it as a tumor suppressor. SSCP mutation analysis, genomic cloning, direct sequencing Human molecular genetics Medium 9931336
1999 PTCH2 undergoes alternative splicing producing multiple mRNA isoforms, including transcripts lacking segments involved in Sonic Hedgehog binding; PTCH2 is a transcriptional target upregulated by HH signaling (negative regulation by PTCH1), linking it to the SHH/PTCH signaling pathway. cDNA library screening, RACE, BAC sequencing, in situ hybridization, radiation hybrid mapping Cancer research Medium 10029063
1998 Mouse Ptch2 is expressed both in Shh-producing epithelial cells (tooth, hair, whisker) and in adjacent non-producing cells, overlapping but distinct from Ptch1 expression pattern, suggesting distinct roles in Shh signaling during development. In situ hybridization, chromosomal localization Mechanisms of development Low 9858693
2004 PTCH2 splice variants localized in the cytoplasm can internalize the N-terminal fragment of Sonic HH (Shh-N); only one PTCH2 variant inhibits SHH-N promoter activity whereas none can inhibit activated SMO-M2 (unlike PTCH1); all PTCH2 isoforms alter SMO localization from cytoplasm to juxtanuclear region upon co-transfection; PTCH2 isoforms physically interact with PTCH1 (confirmed by co-immunoprecipitation); PTCH2 variants and PTCH1 differentially reconstitute SHH- and Desert HH-dependent transcriptional responses in Ptch1-/- cells. Promoter reporter assays, immunofluorescence localization, co-immunoprecipitation, Ptch1-/- cell reconstitution, Shh-N internalization assay The Biochemical journal High 14613484
2008 The PTCH2 missense mutation R719Q (in an extracellular loop) results in loss of PTCH2 inhibitory activity on the SHH signaling pathway and loss of ability to inhibit cell proliferation, demonstrating that this extracellular domain is functionally required for PTCH2 tumor suppressor activity. GLI1 reporter gene assay, cell growth curve analysis, direct sequencing, restriction enzyme digestion Journal of medical genetics Medium 18285427
2013 PTCH2 functions as a ciliary-localized HH pathway antagonist in vertebrate neural patterning; while dispensable alone, combined loss of PTCH2 and PTCH1 feedback antagonism produces significant expansion of HH-dependent ventral neural progenitors; triple loss of PTCH2, HHIP1, and PTCH1 feedback results in ectopic specification of ventral cell fates throughout the neural tube reflecting constitutive HH pathway activation. Mouse genetic epistasis (Ptch1, Ptch2, Hhip1 knockout combinations), neural tube patterning analysis, ciliary localization imaging Development (Cambridge, England) High 23900540
2014 Ptch2 mediates Shh signaling in the absence of Ptch1: expression of dominant-negative Ptch2 in chick neural tube activates the Shh response; Ptch1-/-;Ptch2-/- cells cannot further activate the Shh response, demonstrating Ptch2 is required for the residual Shh sensitivity in Ptch1-/- cells. Dominant-negative expression in chick neural tube, Ptch1-/-;Ptch2-/- double-knockout cell analysis, Shh-blocking antibody (5E1) inhibition, fibroblast migration assay Development (Cambridge, England) High 25085974
2014 Ptch2 is a functional Shh receptor that regulates SMO localization and activity in vitro; Ptch1 and Ptch2 co-operate in regulating cellular responses to Shh in vivo, as loss of Ptch2 exacerbates limb outgrowth defects in limb-specific Ptch1 knockout mutants. In vitro SMO localization assay, limb-specific Ptch1 knockout combined with Ptch2 knockout, limb bud co-expression analysis Developmental biology High 25448692
2016 Ptch2 loss in hematopoietic niche cells drives 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-/- mice develop a myeloproliferative neoplasm phenotype demonstrating that Ptch2 regulates both canonical and noncanonical HH signaling in hematopoiesis. Ptch2-/- mouse model, bone marrow transplantation, flow cytometry, gene expression analysis, HSC functional assays (5-FU treatment, replating) The Journal of experimental medicine High 26834157
2018 The sterol-sensing domains (SSDs) of PTCH2 can substitute for those of PTCH1 in chimeric proteins to repress HH signaling, demonstrating SSDs act as generic modules; however, the cytoplasmic domains of PTCH1 are necessary but not sufficient for HH repression, and the two principal luminal domains of PTCH1 and PTCH2 are interchangeable; the N-terminal and C-terminal halves of PTCH1 associate noncovalently to mediate ligand-dependent Hh regulation, whereas analogous PTCH2 regions interact but do not repress the pathway. Chimeric protein construction, HH pathway reporter assays, co-immunoprecipitation of PTCH1 N- and C-terminal halves, domain-swap mutagenesis The Journal of biological chemistry High 30166346
2018 C2EIP interacts with PTCH2 at the intracellular membrane, promotes PTCH2 ubiquitination, and thereby activates HH signaling via competitive inhibition of SMO to regulate primordial germ cell generation from embryonic stem cells. Co-immunoprecipitation (C2EIP-PTCH2 interaction), ubiquitination assay, C2EIP knockout/overexpression, PGC differentiation assay Cell death & disease Medium 29703892
2020 Ptch2 forms a specific hetero-complex with Gas1 (while Ptch1 partners with Boc) to mediate Smo de-repression with distinct kinetics in primordial germ cell migration; Ptch2-mediated HH signaling induces phosphorylation of Creb and Src proteins in parallel to Gli induction, defining a Ptch2-specific non-canonical signal pathway distinct from Ptch1. Genetic analysis of primordial germ cell migration in mouse, co-receptor complex characterization, phosphorylation analysis (Creb, Src), Gli induction assays, Ptch1/2 and Gas1/Boc knockout combinations Nature communications High 32332736
2022 PTCH2 overexpression upregulates tumor suppressor PTEN expression, leading to suppression of pro-survival AKT signals in glioma cells, suppressing proliferation and invasion. PTCH2 overexpression in glioma cell lines (LN229, U87-MG), western blotting for PTEN/AKT, in vitro proliferation/invasion assays, in vivo tumor-bearing mouse survival Biochemical and biophysical research communications Medium 36027694
2022 Loss of Ptch2 increases number of putative mesenchymal stem cells in continuously growing incisor, causes increased bone length/volume linked to augmented MSC differentiation potential in bone marrow, and alters skin wound closure, establishing Ptch2 as a regulator of HH signaling in MSC biology and organ regeneration. Ptch2-/- mouse model, histology, immunostaining, microCT, CFU assay, in vitro differentiation assay, in vivo wound healing assay Frontiers in physiology Medium 35574464

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Isolation and characterization of human patched 2 (PTCH2), a putative tumour suppressor gene inbasal cell carcinoma and medulloblastoma on chromosome 1p32. Human molecular genetics 149 9931336
2008 A missense mutation in PTCH2 underlies dominantly inherited NBCCS in a Chinese family. Journal of medical genetics 89 18285427
2013 Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning. Development (Cambridge, England) 76 23900540
1999 PTCH2, a novel human patched gene, undergoing alternative splicing and up-regulated in basal cell carcinomas. Cancer research 64 10029063
2004 Distinct roles of PTCH2 splice variants in Hedgehog signalling. The Biochemical journal 62 14613484
1998 Overlapping and non-overlapping Ptch2 expression with Shh during mouse embryogenesis. Mechanisms of development 61 9858693
2013 Frameshift mutation in the PTCH2 gene can cause nevoid basal cell carcinoma syndrome. Familial cancer 60 23479190
2014 Ptch2 mediates the Shh response in Ptch1-/- cells. Development (Cambridge, England) 40 25085974
2014 Ptch2 shares overlapping functions with Ptch1 in Smo regulation and limb development. Developmental biology 39 25448692
2006 Lack of Rb and p53 delays cerebellar development and predisposes to large cell anaplastic medulloblastoma through amplification of N-Myc and Ptch2. Cancer research 37 16707443
2016 Ptch2 loss drives myeloproliferation and myeloproliferative neoplasm progression. The Journal of experimental medicine 35 26834157
2019 Hotspot DAXX, PTCH2 and CYFIP2 mutations in pancreatic neuroendocrine neoplasms. Endocrine-related cancer 24 30021865
2020 Ptch2/Gas1 and Ptch1/Boc differentially regulate Hedgehog signalling in murine primordial germ cell migration. Nature communications 22 32332736
2019 PDS5B regulates cell proliferation and motility via upregulation of Ptch2 in pancreatic cancer cells. Cancer letters 17 31233836
2018 Immunohistochemical evaluation of Sonic Hedgehog signaling pathway proteins (Shh, Ptch1, Ptch2, Smo, Gli1, Gli2, and Gli3) in sporadic and syndromic odontogenic keratocysts. Clinical oral investigations 17 29564556
2019 A healthy individual with a homozygous PTCH2 frameshift variant: Are variants of PTCH2 associated with nevoid basal cell carcinoma syndrome? Human genome variation 15 30820324
2017 Congenital embryonal rhabdomyosarcoma caused by heterozygous concomitant PTCH1 and PTCH2 germline mutations. European journal of human genetics : EJHG 15 29230040
2021 PTCH2 is not a strong candidate gene for gorlin syndrome predisposition. Familial cancer 14 34170463
2020 Gorlin-like phenotype in a patient with a PTCH2 variant of uncertain significance. European journal of medical genetics 14 31945512
2018 The protein-specific activities of the transmembrane modules of Ptch1 and Ptch2 are determined by their adjacent protein domains. The Journal of biological chemistry 12 30166346
2018 Interaction of the primordial germ cell-specific protein C2EIP with PTCH2 directs differentiation of embryonic stem cells via HH signaling activation. Cell death & disease 11 29703892
2022 Inherited rare and common variants in PTCH1 and PTCH2 contributing to the predisposition to reproductive cancers. Gene 8 34990798
2008 [PTCH2 gene alterations in keratocystic odontogenic tumors associated with nevoid basal cell carcinoma syndrome]. Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 6 18278130
2021 Expression pattern of Ptch2 in mouse embryonic maxillofacial development. Acta histochemica 4 34979374
2022 Ptch2 is a Potential Regulator of Mesenchymal Stem Cells. Frontiers in physiology 3 35574464
2002 Genomic structure and refined chromosomal localization of the mouse Ptch2 gene. Cytogenetic and genome research 3 12438747
2024 Identification of rare variants in PTCH2 associated with non-syndromic orofacial clefts. Gene 2 38360123
2020 Author Correction: Ptch2/Gas1 and Ptch1/Boc differentially regulate Hedgehog signalling in murine primordial germ cell migration. Nature communications 2 32371876
2024 Gorlin-Like Phenotype in a Young Girl With a De Novo PTCH2 Variant Mutation of Uncertain Significance. The American Journal of dermatopathology 1 38354379
2022 Reduced PTCH2 expression is associated with glioma development through its regulation of the PTEN/AKT signaling pathway. Biochemical and biophysical research communications 1 36027694
2026 Ptch2 Deficiency Triggers Lipoma Formation and Adipogenic Transcriptome Reprogramming in Nile tilapia (Oreochromis niloticus). Animals : an open access journal from MDPI 0 41681386
2025 Dual PTCH2 mutation [Ser391*, Leu104Pro]: unveiling a potential new genetic susceptibility factor for glioma development. Investigational new drugs 0 39800815
2020 [Exploring parent-of-origin effects for non-syndromic cleft lip with or without cleft palate on PTCH1, PTCH2, SHH, SMO genes in Chinese case-parent trios]. Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 0 33047712