Affinage

PTCH2

Protein patched homolog 2 · UniProt Q9Y6C5

Length
1203 aa
Mass
130.5 kDa
Annotated
2026-06-10
33 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 Medium

    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

    PMID:10029063 PMID:9931336

    Open questions at the time
    • No functional reconstitution of HH activity
    • Significance of ligand-binding-deficient splice isoforms unresolved
  2. 1998 Low

    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

    PMID:9858693

    Open questions at the time
    • Expression pattern without functional consequence demonstrated
    • No direct receptor activity tested
  3. 2004 High

    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

    PMID:14613484

    Open questions at the time
    • Mechanism of SMO-M2 resistance not resolved
    • Functional role of cytoplasmic splice variants unclear
  4. 2008 Medium

    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

    PMID:18285427

    Open questions at the time
    • Structural basis of the loop's role unknown
    • Disease association of R719Q not established
  5. 2013 High

    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

    PMID:23900540

    Open questions at the time
    • Quantitative contribution of Ptch2 relative to other antagonists unresolved
    • Mechanism of ciliary targeting not defined
  6. 2014 High

    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

    PMID:25085974 PMID:25448692

    Open questions at the time
    • Ligand-binding affinity and stoichiometry not quantified
    • Degree of functional redundancy context-dependent
  7. 2016 High

    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

    PMID:26834157

    Open questions at the time
    • Molecular identity of the non-canonical effector in this context not defined
    • Direct ligand/receptor events upstream unresolved
  8. 2018 High

    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

    PMID:30166346

    Open questions at the time
    • Identity of the cytoplasmic-domain interactors conferring repression unknown
    • Structural model of half-half association absent
  9. 2018 Medium

    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

    PMID:29703892

    Open questions at the time
    • Ubiquitin ligase and degradation outcome not identified
    • Competitive SMO inhibition model not reconstituted
  10. 2020 High

    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

    PMID:32332736

    Open questions at the time
    • Biochemical link from Ptch2-Gas1 to CREB/SRC activation unmapped
    • Generality of the non-canonical branch beyond PGCs untested
  11. 2019 Medium

    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

    PMID:31233836

    Open questions at the time
    • Mechanism by which PDS5B controls PTCH2 expression undefined
    • Single-lab cell-line evidence
  12. 2022 Medium

    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

    PMID:36027694

    Open questions at the time
    • Direct molecular link between PTCH2 and PTEN unknown
    • Relationship to canonical HH signaling in glioma unresolved
  13. 2025 Medium

    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)

    PMID:bio_10.1101_2025.06.13.659479

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Conservation of Dhh-Ptch2 selectivity in mammals not confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No structural model of the PTCH2 N/C-terminal association
  • Non-canonical effector identity unknown
  • Direct PTCH2-PTEN connection unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0060089 molecular transducer activity 1
Localization
GO:0005886 plasma membrane 2 GO:0005829 cytosol 1 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3
Partners
C2EIPGAS1PTCH1SMO
Complex memberships
Ptch2-Gas1 co-receptor complex

Evidence

Reading pass · 15 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, 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. SSCP mutation analysis, genomic cloning, 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 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. cDNA library screening, RACE, BAC sequencing, in situ hybridization Cancer research Medium 10029063
1998 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. In situ hybridization, chromosomal localization Mechanisms of development Low 9858693
2004 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. Promoter reporter assays, co-immunoprecipitation, subcellular localization (microscopy), Ptch1-/- cell reconstitution assays The Biochemical journal High 14613484
2008 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. GLI1 reporter gene assay, cell growth curve analysis, direct sequencing, restriction enzyme digestion Journal of medical genetics Medium 18285427
2013 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. Mouse genetic epistasis (Ptch1/Ptch2/Hhip1 combined knockouts), immunofluorescence localization, neural patterning analysis Development (Cambridge, England) High 23900540
2014 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. Double-knockout cell lines (Ptch1-/-;Ptch2-/-), dominant-negative overexpression in chick neural tube, Shh-blocking antibody (5E1), 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 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. In vitro Smo localization assays, mouse limb-specific Ptch1 knockout with Ptch2 compound mutants, developmental phenotype analysis Developmental biology High 25448692
2016 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. Ptch2-/- mouse model, bone marrow transplantation/chimera experiments, cell culture replating assays, gene expression analysis The Journal of experimental medicine High 26834157
2018 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. Chimeric protein construction, Hh reporter assays, domain swap mutagenesis The Journal of biological chemistry High 30166346
2018 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. Co-immunoprecipitation, ubiquitination assay, knockout and overexpression in embryonic stem cells, in vitro and in vivo PGC generation assays Cell death & disease Medium 29703892
2020 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. Mouse genetic experiments (Ptch1/Ptch2/Gas1/Boc mutants), PGC migration assays, phosphoprotein analysis (Creb, Src), co-receptor complex analysis Nature communications High 32332736
2019 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. Transfection/overexpression, siRNA knockdown, MTT assay, FACS, wound healing, transwell invasion assay, western blotting Cancer letters Medium 31233836
2022 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. PTCH2 overexpression in glioma cell lines (LN229, U87-MG), proliferation/invasion assays, western blotting for PTEN/AKT, tumor-bearing mouse model Biochemical and biophysical research communications Medium 36027694
2025 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. CRISPR/Cas9 knockout (ptch1, ptch2, gli1, sf1), in vivo genetic rescue experiments, luciferase assays in Gli-knockout SLCs, SLC transplantation assays bioRxivpreprint Medium bio_10.1101_2025.06.13.659479

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
2013 Frameshift mutation in the PTCH2 gene can cause nevoid basal cell carcinoma syndrome. Familial cancer 62 23479190
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
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 16 30820324
2021 PTCH2 is not a strong candidate gene for gorlin syndrome predisposition. Familial cancer 15 34170463
2017 Congenital embryonal rhabdomyosarcoma caused by heterozygous concomitant PTCH1 and PTCH2 germline mutations. European journal of human genetics : EJHG 15 29230040
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
2024 Identification of rare variants in PTCH2 associated with non-syndromic orofacial clefts. Gene 3 38360123
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
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

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