Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4PGEAB)

• DOT Name: Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)
• Synonyms: PEST phosphatase-interacting protein 1; CD2-binding protein 1; H-PIP
• Gene Name: PSTPIP1
• Related Disease:
  Abscess
  Acne vulgaris
  Autoimmune disease
  Bacterial arthritis
  Camptodactyly-arthropathy-coxa vara-pericarditis syndrome
  Crohn disease
  Cryopyrin-associated periodic syndrome
  Dermatitis
  Familial Mediterranean fever
  Hepatocellular carcinoma
  Hereditary periodic fever syndrome
  Hidradenitis suppurativa
  Infective arthritis
  Inflammatory bowel disease
  Juvenile idiopathic arthritis
  Leukopenia
  Mevalonate kinase deficiency
  Neoplasm
  Postaxial polydactyly type A
  Pyogenic arthritis-pyoderma gangrenosum-acne syndrome
  Rheumatoid arthritis
  Ulcerative colitis
  Recurrent infections-inflammatory syndrome due to zinc metabolism disorder syndrome
  Behcet disease
  Squamous cell carcinoma
• UniProt ID: PPIP1_HUMAN
• PDB ID: 2DIL; 7AAL; 7AAM; 7AAN
• Pfam ID: PF00611 ; PF00018
• Sequence:
  MMPQLQFKDAFWCRDFTAHTGYEVLLQRLLDGRKMCKDMEELLRQRAQAEERYGKELVQI
  ARKAGGQTEINSLRASFDSLKQQMENVGSSHIQLALTLREELRSLEEFRERQKEQRKKYE
  AVMDRVQKSKLSLYKKAMESKKTYEQKCRDADDAEQAFERISANGHQKQVEKSQNKARQC
  KDSATEAERVYRQSIAQLEKVRAEWEQEHRTTCEAFQLQEFDRLTILRNALWVHSNQLSM
  QCVKDDELYEEVRLTLEGCSIDADIDSFIQAKSTGTEPPAPVPYQNYYDREVTPLTSSPG
  IQPSCGMIKRFSGLLHGSPKTTSLAASAASTETLTPTPERNEGVYTAIAVQEIQGNPASP
  AQEYRALYDYTAQNPDELDLSAGDILEVILEGEDGWWTVERNGQRGFVPGSYLEKL
• Function: Involved in regulation of the actin cytoskeleton. May regulate WAS actin-bundling activity. Bridges the interaction between ABL1 and PTPN18 leading to ABL1 dephosphorylation. May play a role as a scaffold protein between PTPN12 and WAS and allow PTPN12 to dephosphorylate WAS. Has the potential to physically couple CD2 and CD2AP to WAS. Acts downstream of CD2 and CD2AP to recruit WAS to the T-cell:APC contact site so as to promote the actin polymerization required for synapse induction during T-cell activation. Down-regulates CD2-stimulated adhesion through the coupling of PTPN12 to CD2. Also has a role in innate immunity and the inflammatory response. Recruited to inflammasomes by MEFV. Induces formation of pyroptosomes, large supramolecular structures composed of oligomerized PYCARD dimers which form prior to inflammatory apoptosis. Binding to MEFV allows MEFV to bind to PYCARD and facilitates pyroptosome formation. Regulates endocytosis and cell migration in neutrophils.
• Tissue Specificity: Highly expressed in the peripheral blood leukocytes, granulocytes and monocytes, namely in T-cells and natural killer cells, and in spleen. Weakly expressed in the thymus, small intestine, lung and placenta.
• KEGG Pathway: NOD-like receptor sig.ling pathway (hsa04621)
• Reactome Pathway:
  Purinergic signaling in leishmaniasis infection (R-HSA-9660826)
  The NLRP3 inflammasome (R-HSA-844456)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Abscess	DISAP982	Definitive	Biomarker	[1]
Acne vulgaris	DISKW8PI	Strong	Biomarker	[2]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[3]
Bacterial arthritis	DIS8R241	Strong	Genetic Variation	[4]
Camptodactyly-arthropathy-coxa vara-pericarditis syndrome	DISZB072	Strong	Biomarker	[5]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[1]
Cryopyrin-associated periodic syndrome	DISPXXOZ	Strong	Biomarker	[6]
Dermatitis	DISY5SZC	Strong	Altered Expression	[7]
Familial Mediterranean fever	DISVP5WP	Strong	Genetic Variation	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[8]
Hereditary periodic fever syndrome	DISS9RWQ	Strong	Biomarker	[9]
Hidradenitis suppurativa	DIS3ZNAK	Strong	Biomarker	[2]
Infective arthritis	DIS8YJPR	Strong	Genetic Variation	[4]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[10]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[9]
Leukopenia	DISJMBMM	Strong	Genetic Variation	[11]
Mevalonate kinase deficiency	DISSTRVK	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Postaxial polydactyly type A	DIS4IIPW	Strong	Genetic Variation	[12]
Pyogenic arthritis-pyoderma gangrenosum-acne syndrome	DIS7E15X	Strong	Autosomal dominant	[13]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[14]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[5]
Recurrent infections-inflammatory syndrome due to zinc metabolism disorder syndrome	DISFE4YQ	Supportive	Unknown	[15]
Behcet disease	DISSYMBS	Limited	Genetic Variation	[16]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1).	[20]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1).	[21]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1).	[22]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1).	[26]

References

• [1] Longest form of CCTG microsatellite repeat in the promoter of the CD2BP1/PSTPIP1 gene is associated with aseptic abscesses and with Crohn disease in French patients.Dig Dis Sci. 2010 Jun;55(6):1681-8. doi: 10.1007/s10620-009-0929-7.
• [2] Pyoderma gangrenosum and its syndromic forms: evidence for a link with autoinflammation.Br J Dermatol. 2016 Nov;175(5):882-891. doi: 10.1111/bjd.14691. Epub 2016 Aug 23.
• [3] Proline-serine-threonine phosphatase interacting protein1 inhibition of T-cell receptor signaling depends on its SH3 domain.FEBS J. 2014 Sep;281(17):3844-54. doi: 10.1111/febs.12912. Epub 2014 Aug 5.
• [4] A novel de novo PSTPIP1 mutation in a boy with pyogenic arthritis, pyoderma gangrenosum, acne (PAPA) syndrome.Clin Exp Rheumatol. 2014 Nov-Dec;32(6):956-8. Epub 2014 Jun 24.
• [5] Pyoderma gangrenosum, acne and ulcerative colitis in a patient with a novel mutation in the PSTPIP1 gene.Clin Exp Dermatol. 2015 Jun;40(4):367-72. doi: 10.1111/ced.12585. Epub 2015 Feb 16.
• [6] Autoinflammatory gene mutations in Behet's disease.Ann Rheum Dis. 2007 Jun;66(6):832-4. doi: 10.1136/ard.2006.068841. Epub 2007 Jan 9.
• [7] Inflammation in mice ectopically expressing human Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne (PAPA) Syndrome-associated PSTPIP1 A230T mutant proteins.J Biol Chem. 2013 Feb 15;288(7):4594-601. doi: 10.1074/jbc.M112.443077. Epub 2013 Jan 4.
• [8] LncRNA PAPAS promotes hepatocellular carcinoma by interacting with miR-188-5p.J Cell Biochem. 2019 Aug;120(8):13494-13500. doi: 10.1002/jcb.28623. Epub 2019 Mar 28.
• [9] Autoinflammatory genes and susceptibility to psoriatic juvenile idiopathic arthritis.Arthritis Rheum. 2008 Jul;58(7):2142-6. doi: 10.1002/art.23604.
• [10] Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder.Hum Mol Genet. 2002 Apr 15;11(8):961-9. doi: 10.1093/hmg/11.8.961.
• [11] PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome: A rare cause of childhood neutropenia associated with systemic inflammation and hyperzincemia.Pediatr Blood Cancer. 2019 Jan;66(1):e27439. doi: 10.1002/pbc.27439. Epub 2018 Sep 10.
• [12] Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway.Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13501-6. doi: 10.1073/pnas.2135380100. Epub 2003 Oct 31.
• [13] Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome maps to chromosome 15q. Am J Hum Genet. 2000 Apr;66(4):1443-8. doi: 10.1086/302866. Epub 2000 Mar 21.
• [14] Identification of novel mutations in CD2BP1 gene in clinically proven rheumatoid arthritis patients of south India.Eur J Med Genet. 2016 Aug;59(8):404-12. doi: 10.1016/j.ejmg.2016.05.009. Epub 2016 May 13.
• [15] Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases. J Allergy Clin Immunol. 2015 Nov;136(5):1337-45. doi: 10.1016/j.jaci.2015.04.016. Epub 2015 May 27.
• [16] Mutational profile of rare variants in inflammasome-related genes in Behet disease: A Next Generation Sequencing approach.Sci Rep. 2017 Aug 16;7(1):8453. doi: 10.1038/s41598-017-09164-7.
• [17] LncRNA PAPAS promotes oral squamous cell carcinoma by upregulating transforming growth factor-1.J Cell Biochem. 2019 Sep;120(9):16120-16127. doi: 10.1002/jcb.28893. Epub 2019 May 17.
• [18] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [19] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [22] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [23] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [24] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [25] 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.
• [26] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [27] 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.