Details of Drug Off-Target (DOT)

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

• DOT Name: A-kinase anchor protein 10, mitochondrial (AKAP10)
• Synonyms: AKAP-10; Dual specificity A kinase-anchoring protein 2; D-AKAP-2; Protein kinase A-anchoring protein 10; PRKA10
• Gene Name: AKAP10
• Related Disease:
  Myocardial infarction
  Adenoma
  Bipolar disorder
  Breast cancer
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Hereditary breast carcinoma
  High blood pressure
  Neoplasm
• UniProt ID: AKA10_HUMAN
• PDB ID: 3IM4; 3TMH
• Pfam ID: PF00615
• Sequence:
  MRGAGPSPRQSPRTLRPDPGPAMSFFRRKVKGKEQEKTSDVKSIKASISVHSPQKSTKNH
  ALLEAAGPSHVAINAISANMDSFSSSRTATLKKQPSHMEAAHFGDLGRSCLDYQTQETKS
  SLSKTLEQVLHDTIVLPYFIQFMELRRMEHLVKFWLEAESFHSTTWSRIRAHSLNTVKQS
  SLAEPVSPSKKHETTASFLTDSLDKRLEDSGSAQLFMTHSEGIDLNNRTNSTQNHLLLSQ
  ECDSAHSLRLEMARAGTHQVSMETQESSSTLTVASRNSPASPLKELSGKLMKSIEQDAVN
  TFTKYISPDAAKPIPITEAMRNDIIARICGEDGQVDPNCFVLAQSIVFSAMEQEHFSEFL
  RSHHFCKYQIEVLTSGTVYLADILFCESALFYFSEYMEKEDAVNILQFWLAADNFQSQLA
  AKKGQYDGQEAQNDAMILYDKYFSLQATHPLGFDDVVRLEIESNICREGGPLPNCFTTPL
  RQAWTTMEKVFLPGFLSSNLYYKYLNDLIHSVRGDEFLGGNVSLTAPGSVGPPDESHPGS
  SDSSASQSSVKKASIKILKNFDEAIIVDAASLDPESLYQRTYAGKMTFGRVSDLGQFIRE
  SEPEPDVRKSKGSMFSQAMKKWVQGNTDEAQEELAWKIAKMIVSDIMQQAQYDQPLEKST
  KL
• Function: Differentially targeted protein that binds to type I and II regulatory subunits of protein kinase A and anchors them to the mitochondria or the plasma membrane. Although the physiological relevance between PKA and AKAPS with mitochondria is not fully understood, one idea is that BAD, a proapoptotic member, is phosphorylated and inactivated by mitochondria-anchored PKA. It cannot be excluded too that it may facilitate PKA as well as G protein signal transduction, by acting as an adapter for assembling multiprotein complexes. With its RGS domain, it could lead to the interaction to G-alpha proteins, providing a link between the signaling machinery and the downstream kinase.
• Reactome Pathway: Factors involved in megakaryocyte development and platelet production (R-HSA-983231)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Myocardial infarction	DIS655KI	Definitive	Genetic Variation	[1]
Adenoma	DIS78ZEV	Strong	Altered Expression	[2]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Colon cancer	DISVC52G	Strong	Altered Expression	[5]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[6]
Hereditary breast carcinoma	DISAEZT5	Strong	Genetic Variation	[4]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of A-kinase anchor protein 10, mitochondrial (AKAP10).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of A-kinase anchor protein 10, mitochondrial (AKAP10).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of A-kinase anchor protein 10, mitochondrial (AKAP10).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of A-kinase anchor protein 10, mitochondrial (AKAP10).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of A-kinase anchor protein 10, mitochondrial (AKAP10).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of A-kinase anchor protein 10, mitochondrial (AKAP10).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of A-kinase anchor protein 10, mitochondrial (AKAP10).	[12]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of A-kinase anchor protein 10, mitochondrial (AKAP10).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of A-kinase anchor protein 10, mitochondrial (AKAP10).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of A-kinase anchor protein 10, mitochondrial (AKAP10).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of A-kinase anchor protein 10, mitochondrial (AKAP10).	[18]

References

• [1] Association of gene polymorphisms with myocardial infarction in individuals with different lipid profiles.Int J Mol Med. 2007 Oct;20(4):581-90.
• [2] A-kinase anchoring proteins 10 expression in relation to 2073A/G polymorphism and tumor progression in patients with colorectal cancer.Pathol Oncol Res. 2013 Jul;19(3):521-7. doi: 10.1007/s12253-013-9612-6. Epub 2013 Mar 7.
• [3] Survey of the effect of genetic variations on gene expression in human prefrontal cortex and its application to genetics of psychiatric disorders.Neurosci Res. 2011 Jun;70(2):238-42. doi: 10.1016/j.neures.2011.02.012. Epub 2011 Mar 4.
• [4] The functional genetic variant Ile646Val located in the kinase binding domain of the A-kinase anchoring protein 10 is associated with familial breast cancer.Carcinogenesis. 2007 Feb;28(2):423-6. doi: 10.1093/carcin/bgl164. Epub 2006 Sep 6.
• [5] PKA RI/A-kinase anchoring proteins 10 signaling pathway and the prognosis of colorectal cancer.J Gastroenterol Hepatol. 2015 Mar;30(3):496-503. doi: 10.1111/jgh.12689.
• [6] The Ile646Val (2073A>G) polymorphism in the kinase-binding domain of A-kinase anchoring protein 10 and the risk of colorectal cancer.Oncology. 2009;76(3):199-204. doi: 10.1159/000201572. Epub 2009 Feb 11.
• [7] Polymorphism 1936A > G in the AKAP10 gene (encoding A-kinase-anchoring protein 10) is associated with higher cholesterol cord blood concentration in Polish full-term newsborns.J Perinat Med. 2013 Mar;41(2):205-10. doi: 10.1515/jpm-2012-0048.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [10] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [11] 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.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [14] 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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.