Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOQ0K9V)

• DOT Name: Protein patched homolog 2 (PTCH2)
• Synonyms: PTC2
• Gene Name: PTCH2
• Related Disease:
  Advanced cancer
  Gastrointestinal stromal tumour
  Oculodentodigital dysplasia
  Pulmonary hypertension, primary, 3
  Skin cancer
  T-cell leukaemia
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid gland papillary carcinoma
  Thyroid tumor
  Basal cell nevus syndrome
  Medulloblastoma
  Pancreatic cancer
  Rhabdomyosarcoma
  Commissural facial cleft
  Hereditary hemochromatosis
  Myeloproliferative neoplasm
• UniProt ID: PTC2_HUMAN
• Pfam ID: PF02460 ; PF12349
• Sequence:
  MTRSPPLRELPPSYTPPARTAAPQILAGSLKAPLWLRAYFQGLLFSLGCGIQRHCGKVLF
  LGLLAFGALALGLRMAIIETNLEQLWVEVGSRVSQELHYTKEKLGEEAAYTSQMLIQTAR
  QEGENILTPEALGLHLQAALTASKVQVSLYGKSWDLNKICYKSGVPLIENGMIERMIEKL
  FPCVILTPLDCFWEGAKLQGGSAYLPGRPDIQWTNLDPEQLLEELGPFASLEGFRELLDK
  AQVGQAYVGRPCLHPDDLHCPPSAPNHHSRQAPNVAHELSGGCHGFSHKFMHWQEELLLG
  GMARDPQGELLRAEALQSTFLLMSPRQLYEHFRGDYQTHDIGWSEEQASTVLQAWQRRFV
  QLAQEALPENASQQIHAFSSTTLDDILHAFSEVSAARVVGGYLLMLAYACVTMLRWDCAQ
  SQGSVGLAGVLLVALAVASGLGLCALLGITFNAATTQVLPFLALGIGVDDVFLLAHAFTE
  ALPGTPLQERMGECLQRTGTSVVLTSINNMAAFLMAALVPIPALRAFSLQAAIVVGCTFV
  AVMLVFPAILSLDLRRRHCQRLDVLCCFSSPCSAQVIQILPQELGDGTVPVGIAHLTATV
  QAFTHCEASSQHVVTILPPQAHLVPPPSDPLGSELFSPGGSTRDLLGQEEETRQKAACKS
  LPCARWNLAHFARYQFAPLLLQSHAKAIVLVLFGALLGLSLYGATLVQDGLALTDVVPRG
  TKEHAFLSAQLRYFSLYEVALVTQGGFDYAHSQRALFDLHQRFSSLKAVLPPPATQAPRT
  WLHYYRNWLQGIQAAFDQDWASGRITRHSYRNGSEDGALAYKLLIQTGDAQEPLDFSQLT
  TRKLVDREGLIPPELFYMGLTVWVSSDPLGLAASQANFYPPPPEWLHDKYDTTGENLRIP
  PAQPLEFAQFPFLLRGLQKTADFVEAIEGARAACAEAGQAGVHAYPSGSPFLFWEQYLGL
  RRCFLLAVCILLVCTFLVCALLLLNPWTAGLIVLVLAMMTVELFGIMGFLGIKLSAIPVV
  ILVASVGIGVEFTVHVALGFLTTQGSRNLRAAHALEHTFAPVTDGAISTLLGLLMLAGSH
  FDFIVRYFFAALTVLTLLGLLHGLVLLPVLLSILGPPPEVIQMYKESPEILSPPAPQGGG
  LRWGASSSLPQSFARVTTSMTVAIHPPPLPGAYIHPAPDEPPWSPAATSSGNLSSRGPGP
  ATG
• Function: Plays a role in the control of cellular growth. May have a role in epidermal development. May act as a receptor for Sonic hedgehog (SHH).
• KEGG Pathway:
  Hedgehog sig.ling pathway (hsa04340)
  Pathways in cancer (hsa05200)
  Basal cell carcinoma (hsa05217)
• Reactome Pathway: Class B/2 (Secretin family receptors) (R-HSA-373080)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[2]
Oculodentodigital dysplasia	DISSWR9C	Strong	GermlineCausalMutation	[3]
Pulmonary hypertension, primary, 3	DIS1J9D4	Strong	Genetic Variation	[4]
Skin cancer	DISTM18U	Strong	Biomarker	[5]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[6]
Thyroid cancer	DIS3VLDH	Strong	Biomarker	[7]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[7]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Biomarker	[8]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[9]
Basal cell nevus syndrome	DIST8BC2	Moderate	Autosomal dominant	[10]
Medulloblastoma	DISZD2ZL	moderate	Genetic Variation	[11]
Pancreatic cancer	DISJC981	moderate	Biomarker	[12]
Rhabdomyosarcoma	DISNR7MS	moderate	Genetic Variation	[13]
Commissural facial cleft	DISYV18K	Supportive	Autosomal dominant	[14]
Hereditary hemochromatosis	DISVG5MT	Limited	Altered Expression	[15]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Biomarker	[16]

2 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Protein patched homolog 2 (PTCH2).	[17]
Vismodegib	DM5IXKQ	Approved	Vismodegib decreases the expression of Protein patched homolog 2 (PTCH2).	[18]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein patched homolog 2 (PTCH2).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Protein patched homolog 2 (PTCH2).	[20]

References

• [1] Molecular changes in endometriosis-associated ovarian clear cell carcinoma.Eur J Cancer. 2015 Sep;51(13):1831-42. doi: 10.1016/j.ejca.2015.05.011. Epub 2015 Jun 6.
• [2] Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression. Oncotarget. 2016 Nov 29;7(48):78226-78241. doi: 10.18632/oncotarget.12909.
• [3] Frameshift mutation in the PTCH2 gene can cause nevoid basal cell carcinoma syndrome.Fam Cancer. 2013 Dec;12(4):611-4. doi: 10.1007/s10689-013-9623-1.
• [4] Genetic interaction between Ptc2 and protein phosphatase 4 (PP4) in the regulation of DNA damage response and virulence in Candida albicans.FEMS Yeast Res. 2019 Dec 1;19(8):foz075. doi: 10.1093/femsyr/foz075.
• [5] Patched-2 functions to limit Patched-1 deficient skin cancer growth.Cell Oncol (Dordr). 2018 Aug;41(4):427-437. doi: 10.1007/s13402-018-0381-9. Epub 2018 Jun 4.
• [6] Gene expression profile of empirically delineated classes of unexplained chronic fatigue.Pharmacogenomics. 2006 Apr;7(3):375-86. doi: 10.2217/14622416.7.3.375.
• [7] RET oncoproteins induce tyrosine phosphorylation changes of proteins involved in RNA metabolism.Cell Signal. 2006 Dec;18(12):2272-82. doi: 10.1016/j.cellsig.2006.05.016. Epub 2006 May 24.
• [8] Clinical, genetic, and immunohistochemical characterization of 70 Ukrainian adult cases with post-Chornobyl papillary thyroid carcinoma.Eur J Endocrinol. 2012 Jun;166(6):1049-60. doi: 10.1530/EJE-12-0144. Epub 2012 Mar 28.
• [9] Familial adenomatous polyposis-associated thyroid cancer: a clinical, pathological, and molecular genetics study.Am J Pathol. 1999 Jan;154(1):127-35. doi: 10.1016/S0002-9440(10)65259-5.
• [10] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [11] Isolation and characterization of human patched 2 (PTCH2), a putative tumour suppressor gene inbasal cell carcinoma and medulloblastoma on chromosome 1p32.Hum Mol Genet. 1999 Feb;8(2):291-7. doi: 10.1093/hmg/8.2.291.
• [12] PDS5B regulates cell proliferation and motility via upregulation of Ptch2 in pancreatic cancer cells.Cancer Lett. 2019 Sep 28;460:65-74. doi: 10.1016/j.canlet.2019.06.014. Epub 2019 Jun 22.
• [13] Congenital embryonal rhabdomyosarcoma caused by heterozygous concomitant PTCH1 and PTCH2 germline mutations.Eur J Hum Genet. 2018 Jan;26(1):137-142. doi: 10.1038/s41431-017-0048-4. Epub 2017 Dec 11.
• [14] A susceptibility locus on 1p32-1p34 for congenital macrostomia in a Chinese family and identification of a novel PTCH2 mutation. Am J Med Genet A. 2009 Mar;149A(3):521-4. doi: 10.1002/ajmg.a.32647.
• [15] Interaction of the primordial germ cell-specific protein C2EIP with PTCH2 directs differentiation of embryonic stem cells via HH signaling activation.Cell Death Dis. 2018 May 1;9(5):497. doi: 10.1038/s41419-018-0557-2.
• [16] Ptch2 loss drives myeloproliferation and myeloproliferative neoplasm progression.J Exp Med. 2016 Feb 8;213(2):273-90. doi: 10.1084/jem.20150556. Epub 2016 Feb 1.
• [17] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [18] Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms. PLoS One. 2011;6(11):e27306. doi: 10.1371/journal.pone.0027306. Epub 2011 Nov 8.
• [19] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [20] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.