Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4BE2M4)

• DOT Name: Protein phosphatase Slingshot homolog 1 (SSH1)
• Synonyms: EC 3.1.3.16; EC 3.1.3.48; SSH-like protein 1; SSH-1L; hSSH-1L
• Gene Name: SSH1
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Neoplasm
  Porokeratosis
  Disseminated superficial actinic porokeratosis
  Gastric cancer
  High blood pressure
  Stomach cancer
• UniProt ID: SSH1_HUMAN
• EC Number: 3.1.3.16; 3.1.3.48
• Pfam ID: PF08766 ; PF00782
• Sequence:
  MALVTLQRSPTPSAASSSASNSELEAGSEEDRKLNLSLSESFFMVKGAALFLQQGSSPQG
  QRSLQHPHKHAGDLPQHLQVMINLLRCEDRIKLAVRLESAWADRVRYMVVVYSSGRQDTE
  ENILLGVDFSSKESKSCTIGMVLRLWSDTKIHLDGDGGFSVSTAGRMHIFKPVSVQAMWS
  ALQVLHKACEVARRHNYFPGGVALIWATYYESCISSEQSCINEWNAMQDLESTRPDSPAL
  FVDKPTEGERTERLIKAKLRSIMMSQDLENVTSKEIRNELEKQMNCNLKELKEFIDNEML
  LILGQMDKPSLIFDHLYLGSEWNASNLEELQGSGVDYILNVTREIDNFFPGLFAYHNIRV
  YDEETTDLLAHWNEAYHFINKAKRNHSKCLVHCKMGVSRSASTVIAYAMKEFGWPLEKAY
  NYVKQKRSITRPNAGFMRQLSEYEGILDASKQRHNKLWRQQTDSSLQQPVDDPAGPGDFL
  PETPDGTPESQLPFLDDAAQPGLGPPLPCCFRRLSDPLLPSPEDETGSLVHLEDPEREAL
  LEEAAPPAEVHRPARQPQQGSGLCEKDVKKKLEFGSPKGRSGSLLQVEETEREEGLGAGR
  WGQLPTQLDQNLLNSENLNNNSKRSCPNGMEDDAIFGILNKVKPSYKSCADCMYPTASGA
  PEASRERCEDPNAPAICTQPAFLPHITSSPVAHLASRSRVPEKPASGPTEPPPFLPPAGS
  RRADTSGPGAGAALEPPASLLEPSRETPKVLPKSLLLKNSHCDKNPPSTEVVIKEESSPK
  KDMKPAKDLRLLFSNESEKPTTNSYLMQHQESIIQLQKAGLVRKHTKELERLKSVPADPA
  PPSRDGPASRLEASIPEESQDPAALHELGPLVMPSQAGSDEKSEAAPASLEGGSLKSPPP
  FFYRLDHTSSFSKDFLKTICYTPTSSSMSSNLTRSSSSDSIHSVRGKPGLVKQRTQEIET
  RLRLAGLTVSSPLKRSHSLAKLGSLTFSTEDLSSEADPSTVADSQDTTLSESSFLHEPQG
  TPRDPAATSKPSGKPAPENLKSPSWMSKS
• Function: Protein phosphatase which regulates actin filament dynamics. Dephosphorylates and activates the actin binding/depolymerizing factor cofilin, which subsequently binds to actin filaments and stimulates their disassembly. Inhibitory phosphorylation of cofilin is mediated by LIMK1, which may also be dephosphorylated and inactivated by this protein.
• KEGG Pathway:
  Axon guidance (hsa04360)
  Regulation of actin cytoskeleton (hsa04810)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Porokeratosis	DISJPL2I	Strong	Genetic Variation	[4]
Disseminated superficial actinic porokeratosis	DISELZ77	Limited	Biomarker	[5]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[6]
High blood pressure	DISY2OHH	Limited	Biomarker	[7]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[6]

4 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 Protein phosphatase Slingshot homolog 1 (SSH1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein phosphatase Slingshot homolog 1 (SSH1).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein phosphatase Slingshot homolog 1 (SSH1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein phosphatase Slingshot homolog 1 (SSH1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein phosphatase Slingshot homolog 1 (SSH1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein phosphatase Slingshot homolog 1 (SSH1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein phosphatase Slingshot homolog 1 (SSH1).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Protein phosphatase Slingshot homolog 1 (SSH1).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protein phosphatase Slingshot homolog 1 (SSH1).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein phosphatase Slingshot homolog 1 (SSH1).	[14]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Protein phosphatase Slingshot homolog 1 (SSH1).	[18]

References

• [1] SSH3 facilitates colorectal cancer cell invasion and metastasis by affecting signaling cascades involving LIMK1/Rac1.Am J Cancer Res. 2019 May 1;9(5):1061-1073. eCollection 2019.
• [2] Slingshot-1L, a cofilin phosphatase, induces primary breast cancer metastasis.Oncotarget. 2017 Aug 3;8(39):66195-66203. doi: 10.18632/oncotarget.19855. eCollection 2017 Sep 12.
• [3] LIMK/cofilin pathway and Slingshot are implicated in human colorectal cancer progression and chemoresistance.Virchows Arch. 2018 May;472(5):727-737. doi: 10.1007/s00428-018-2298-0. Epub 2018 Jan 19.
• [4] Fine mapping and identification of a candidate gene SSH1 in disseminated superficial actinic porokeratosis.Hum Mutat. 2004 Nov;24(5):438. doi: 10.1002/humu.9283.
• [5] Identification of a genetic locus for autosomal dominant disseminated superficial actinic porokeratosis on chromosome 1p31.3-p31.1.Hum Genet. 2008 Jun;123(5):507-13. doi: 10.1007/s00439-008-0504-x. Epub 2008 Apr 29.
• [6] SSH1 expression is associated with gastric cancer progression and predicts a poor prognosis.BMC Gastroenterol. 2018 Jan 16;18(1):12. doi: 10.1186/s12876-018-0739-5.
• [7] The cofilin phosphatase slingshot homolog 1 restrains angiotensin II-induced vascular hypertrophy and fibrosis in vivo.Lab Invest. 2019 Mar;99(3):399-410. doi: 10.1038/s41374-018-0116-6. Epub 2018 Oct 5.
• [8] 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.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [13] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [14] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [15] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] 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.
• [18] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.