Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5RHUYJ)

• DOT Name: A-kinase anchor protein SPHKAP (SPHKAP)
• Synonyms: SPHK1-interactor and AKAP domain-containing protein; Sphingosine kinase type 1-interacting protein
• Gene Name: SPHKAP
• Related Disease:
  Acute myelogenous leukaemia
  Glioma
  Adult glioblastoma
  Aicardi-Goutieres syndrome
  Alzheimer disease
  Bladder cancer
  Endometriosis
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Neoplasm
  Non-insulin dependent diabetes
  Skin cancer
  Skin carcinoma
  Tauopathy
  Urinary bladder cancer
  Urinary bladder neoplasm
  Cutaneous melanoma
  Melanoma
  Breast carcinoma
  Schizophrenia
• UniProt ID: SPKAP_HUMAN
• Pfam ID: PF05716
• Sequence:
  MDGNSLLSVPSNLESSRMYDVLEPQQGRGCGSSGSGPGNSITACKKVLRSNSLLESTDYW
  LQNQRMPCQIGFVEDKSENCASVCFVNLDVNKDECSTEHLQQKLVNVSPDLPKLISSMNV
  QQPKENEIVVLSGLASGNLQADFEVSQCPWLPDICLVQCARGNRPNSTNCIIFEINKFLI
  GLELVQERQLHLETNILKLEDDTNCSLSSIEEDFLTASEHLEEESEVDESRNDYENINVS
  ANVLESKQLKGATQVEWNCNKEKWLYALEDKYINKYPTPLIKTERSPENLTKNTALQSLD
  PSAKPSQWKREAVGNGRQATHYYHSEAFKGQMEKSQALYIPKDAYFSMMDKDVPSACAVA
  EQRSNLNPGDHEDTRNALPPRQDGEVTTGKYATNLAESVLQDAFIRLSQSQSTLPQESAV
  SVSVGSSLLPSCYSTKDTVVSRSWNELPKIVVVQSPDGSDAAPQPGISSWPEMEVSVETS
  SILSGENSSRQPQSALEVALACAATVIGTISSPQATERLKMEQVVSNFPPGSSGALQTQA
  PQGLKEPSINEYSFPSALCGMTQVASAVAVCGLGEREEVTCSVAPSGSLPPAAEASEAMP
  PLCGLASMELGKEAIAKGLLKEAALVLTRPNTYSSIGDFLDSMNRRIMETASKSQTLCSE
  NVVRNELAHTLSNVILRHSIDEVHHKNMIIDPNDNRHSSEILDTLMESTNQLLLDVICFT
  FKKMSHIVRLGECPAVLSKETIRRRETEPSCQPSDPGASQAWTKATESSSSSPLSNSHNT
  SLVINNLVDGMYSKQDKGGVRPGLFKNPTLQSQLSRSHRVPDSSTATTSSKEIYLKGIAG
  EDTKSPHHSENECRASSEGQRSPTVSQSRSGSQEAEESIHPNTQEKYNCATSRINEVQVN
  LSLLGDDLLLPAQSTLQTKHPDIYCITDFAEELADTVVSMATEIAAICLDNSSGKQPWFC
  AWKRGSEFLMTPNVPCRSLKRKKESQGSGTAVRKHKPPRLSEIKRKTDEHPELKEKLMNR
  VVDESMNLEDVPDSVNLFANEVAAKIMNLTEFSMVDGMWQAQGYPRNRLLSGDRWSRLKA
  SSCESIPEEDSEARAYVNSLGLMSTLSQPVSRASSVSKQSSCESITDEFSRFMVNQMENE
  GRGFELLLDYYAGKNASSILNSAMQQACRKSDHLSVRPSCPSKQSSTESITEEFYRYMLR
  DIERDSRESASSRRSSQDWTAGLLSPSLRSPVCHRQSSMPDSRSPCSRLTVNVPIKANSL
  DGFAQNCPQDFLSVQPVSSASSSGLCKSDSCLYRRGGTDHITNMLIHETWASSIEALMRK
  NKIIVDDAEEADTEPVSGGSPSQAEKCANRLAASRMCSGPTLLVQESLDCPRKDSVTECK
  QPPVSSLSKTASLTNHSPLDSKKETSSCQDPVPINHKRRSLCSREVPLIQIETDQREACA
  GEPEPFLSKSSLLEEAEGHSNDKNIPDVVRGGDTAVSACQIHSDSLDTRDVPEAEASTEA
  RAPDEAPNPPSSSEESTGSWTQLANEEDNPDDTSSFLQLSERSMSNGNSSATSSLGIMDL
  DIYQESMPSSPMINELVEEKKILKGQSESTEAPASGPPTGTASPQRSLLVINFDLEPECP
  DAELRATLQWIAASELGIPTIYFKKSQENRIEKFLDVVQLVHRKSWKVGDIFHAVVQYCK
  MHEEQKDGRLSLFDWLLELG
• Function: Anchoring protein that binds preferentially to the type I regulatory subunit of c-AMP-dependent protein kinase (PKA type I) and targets it to distinct subcellular compartments. May act as a converging factor linking cAMP and sphingosine signaling pathways. Plays a regulatory role in the modulation of SPHK1.
• Tissue Specificity: Highly expressed in heart. Both isoforms abundantly expressed in ventricle. Also expressed in spleen, ovary and brain.

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Altered Expression	[1]
Glioma	DIS5RPEH	Definitive	Altered Expression	[2]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[3]
Aicardi-Goutieres syndrome	DIS1NH4X	Strong	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[5]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[6]
Endometriosis	DISX1AG8	Strong	Altered Expression	[7]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[9]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[10]
Skin cancer	DISTM18U	Strong	Biomarker	[11]
Skin carcinoma	DISUZREN	Strong	Genetic Variation	[12]
Tauopathy	DISY2IPA	Strong	Altered Expression	[5]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[6]
Cutaneous melanoma	DIS3MMH9	moderate	Biomarker	[13]
Melanoma	DIS1RRCY	moderate	Biomarker	[13]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[14]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of A-kinase anchor protein SPHKAP (SPHKAP).	[16]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of A-kinase anchor protein SPHKAP (SPHKAP).	[17]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of A-kinase anchor protein SPHKAP (SPHKAP).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of A-kinase anchor protein SPHKAP (SPHKAP).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of A-kinase anchor protein SPHKAP (SPHKAP).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of A-kinase anchor protein SPHKAP (SPHKAP).	[20]

References

• [1] Genome wide analysis of acute myeloid leukemia reveal leukemia specific methylome and subtype specific hypomethylation of repeats.PLoS One. 2012;7(3):e33213. doi: 10.1371/journal.pone.0033213. Epub 2012 Mar 29.
• [2] Sphingosine kinase 1 is up-regulated during hypoxia in U87MG glioma cells. Role of hypoxia-inducible factors 1 and 2.J Biol Chem. 2008 Feb 8;283(6):3365-3375. doi: 10.1074/jbc.M708241200. Epub 2007 Nov 30.
• [3] Lipid phosphatases SKIP and SHIP2 regulate fibronectin-dependent cell migration in glioblastoma.FEBS J. 2019 Mar;286(6):1120-1135. doi: 10.1111/febs.14769. Epub 2019 Feb 16.
• [4] A precisely regulated gene expression cassette potently modulates metastasis and survival in multiple solid cancers.PLoS Genet. 2008 Jul 18;4(7):e1000129. doi: 10.1371/journal.pgen.1000129.
• [5] A Novel Microtubule-Tau Association Enhancer and Neuroprotective Drug Candidate: Ac-SKIP.Front Cell Neurosci. 2019 Oct 1;13:435. doi: 10.3389/fncel.2019.00435. eCollection 2019.
• [6] SKIP expression is correlated with clinical prognosis in patients with bladder cancer.Int J Clin Exp Pathol. 2014 Mar 15;7(4):1695-701. eCollection 2014.
• [7] Sphingosine pathway deregulation in endometriotic tissues.Fertil Steril. 2012 Apr;97(4):904-11. doi: 10.1016/j.fertnstert.2011.12.051. Epub 2012 Jan 24.
• [8] High SKIP expression is correlated with poor prognosis and cell proliferation of hepatocellular carcinoma.Med Oncol. 2013;30(3):537. doi: 10.1007/s12032-013-0537-4. Epub 2013 May 22.
• [9] Differential SKIP expression in PTEN-deficient glioblastoma regulates cellular proliferation and migration.Oncogene. 2015 Jul;34(28):3711-27. doi: 10.1038/onc.2014.303. Epub 2014 Sep 22.
• [10] Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes.Nat Commun. 2018 Jul 27;9(1):2941. doi: 10.1038/s41467-018-04951-w.
• [11] Melanocortin-1 receptor, skin cancer and phenotypic characteristics (M-SKIP) project: study design and methods for pooling results of genetic epidemiological studies.BMC Med Res Methodol. 2012 Aug 3;12:116. doi: 10.1186/1471-2288-12-116.
• [12] MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project.Br J Cancer. 2015 Jul 14;113(2):354-63. doi: 10.1038/bjc.2015.231. Epub 2015 Jun 23.
• [13] MC1R variants increased the risk of sporadic cutaneous melanoma in darker-pigmented Caucasians: a pooled-analysis from the M-SKIP project.Int J Cancer. 2015 Feb 1;136(3):618-31. doi: 10.1002/ijc.29018. Epub 2014 Jun 18.
• [14] Expression and prognostic role of SKIP in human breast carcinoma.J Mol Histol. 2014 Apr;45(2):169-80. doi: 10.1007/s10735-013-9546-z. Epub 2013 Oct 23.
• [15] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [16] 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.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] 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.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] 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.