Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEYSV5M)

• DOT Name: GSK3B-interacting protein (GSKIP)
• Synonyms: GSKIP; GSK3beta interaction protein
• Gene Name: GSKIP
• Related Disease:
  Alzheimer disease
  Myeloid leukaemia
  Hepatocellular carcinoma
  Advanced cancer
• UniProt ID: GSKIP_HUMAN
• PDB ID: 1SGO
• Pfam ID: PF05303
• Sequence:
  METDCNPMELSSMSGFEEGSELNGFEGTDMKDMRLEAEAVVNDVLFAVNNMFVSKSLRCA
  DDVAYINVETKERNRYCLELTEAGLKVVGYAFDQVDDHLQTPYHETVYSLLDTLSPAYRE
  AFGNALLQRLEALKRDGQS
• Function: A-kinase anchoring protein for GSK3B and PKA that regulates or facilitates their kinase activity towards their targets. The ternary complex enhances Wnt-induced signaling by facilitating the GSK3B- and PKA-induced phosphorylation of beta-catenin leading to beta-catenin degradation and stabilization respectively. Upon cAMP activation, the ternary complex contributes to neuroprotection against oxidative stress-induced apoptosis by facilitating the PKA-induced phosphorylation of DML1 and PKA-induced inactivation of GSK3B. During neurite outgrowth promotes neuron proliferation; while increases beta-catenin-induced transcriptional activity through GSK3B kinase activity inhibition, reduces N-cadherin level to promote cell cycle progression.
• Tissue Specificity: Detected in heart, brain, placenta, liver, skeletal muscle, kidney, testis, lung and pancreas.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	moderate	Posttranslational Modification	[3]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[2]

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 GSK3B-interacting protein (GSKIP).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of GSK3B-interacting protein (GSKIP).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of GSK3B-interacting protein (GSKIP).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of GSK3B-interacting protein (GSKIP).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of GSK3B-interacting protein (GSKIP).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of GSK3B-interacting protein (GSKIP).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of GSK3B-interacting protein (GSKIP).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of GSK3B-interacting protein (GSKIP).	[9]

References

• [1] GSKIP-Mediated Anchoring Increases Phosphorylation of Tau by PKA but Not by GSK3beta via cAMP/PKA/GSKIP/GSK3/Tau Axis Signaling in Cerebrospinal Fluid and iPS Cells in Alzheimer Disease.J Clin Med. 2019 Oct 21;8(10):1751. doi: 10.3390/jcm8101751.
• [2] Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.Nat Genet. 2015 Oct;47(10):1131-40. doi: 10.1038/ng.3380. Epub 2015 Aug 17.
• [3] LncRNA HANR Promotes Tumorigenesis and Increase of Chemoresistance in Hepatocellular Carcinoma.Cell Physiol Biochem. 2017;43(5):1926-1938. doi: 10.1159/000484116. Epub 2017 Oct 20.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells. Environ Toxicol. 2018 Nov;33(11):1168-1181. doi: 10.1002/tox.22623. Epub 2018 Aug 27.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [9] 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.
• [10] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.