Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQGT916)

• DOT Name: Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3)
• Synonyms: Protein Nezha
• Gene Name: CAMSAP3
• Related Disease: Lung carcinoma
• UniProt ID: CAMP3_HUMAN
• Pfam ID: PF17095 ; PF11971 ; PF08683
• Sequence:
  MVEAAPPGPGPLRRTFLVPEIKSLDQYDFSRAKAAASLAWVLRAAFGGAEHVPPELWEPF
  YTDQYAQEHVKPPVTRLLLSAELYCRAWRQALPQLETPPNPSALLALLARRGTVPALPER
  PVREADLRHQPILMGAHLAVIDALMAAFAFEWTKTLPGPLALTSLEHKLLFWVDTTVRRL
  QEKTEQEAAQRASPAAPADGAAPAQPSIRYRKDRVVARRAPCFPTVTSLQDLASGAALAA
  TIHCYCPQLLRLEEVCLKDPMSVADSLYNLQLVQDFCASRLPRGCPLSLEDLLYVPPPLK
  VNLVVMLAELFMCFEVLKPDFVQVKDLPDGHAASPRGTEASPPQNNSGSSSPVFTFRHPL
  LSSGGPQSPLRGSTGSLKSSPSMSHMEALGKAWNRQLSRPLSQAVSFSTPFGLDSDVDVV
  MGDPVLLRSVSSDSLGPPRPAPARTPTQPPPEPGDLPTIEEALQIIHSAEPRLLPDGAAD
  GSFYLHSPEGPSKPSLASPYLPEGTSKPLSDRPTKAPVYMPHPETPSKPSPCLVGEASKP
  PAPSEGSPKAVASSPAATNSEVKMTSFAERKKQLVKAEAEAGAGSPTSTPAPPEALSSEM
  SELSARLEEKRRAIEAQKRRIEAIFAKHRQRLGKSAFLQVQPREASGEAEAEAEEADSGP
  VPGGERPAGEGQGEPTSRPKAVTFSPDLGPVPHEGLGEYNRAVSKLSAALSSLQRDMQRL
  TDQQQRLLAPPEAPGSAPPPAAWVIPGPTTGPKAASPSPARRVPATRRSPGPGPSQSPRS
  PKHTRPAELRLAPLTRVLTPPHDVDSLPHLRKFSPSQVPVQTRSSILLAEETPPEEPAAR
  PGLIEIPLGSLADPAAEDEGDGSPAGAEDSLEEEASSEGEPRVGLGFFYKDEDKPEDEMA
  QKRASLLERQQRRAEEARRRKQWQEVEKEQRREEAARLAQEEAPGPAPLVSAVPMATPAP
  AARAPAEEEVGPRKGDFTRQEYERRAQLKLMDDLDKVLRPRAAGSGGPGRGGRRATRPRS
  GCCDDSALARSPARGLLGSRLSKIYSQSTLSLSTVANEAHNNLGVKRPTSRAPSPSGLMS
  PSRLPGSRERDWENGSNASSPASVPEYTGPRLYKEPSAKSNKFIIHNALSHCCLAGKVNE
  PQKNRILEEIEKSKANHFLILFRDSSCQFRALYTLSGETEELSRLAGYGPRTVTPAMVEG
  IYKYNSDRKRFTQIPAKTMSMSVDAFTIQGHLWQGKKPTTPKKGGGTPK
• Function: Key microtubule-organizing protein that specifically binds the minus-end of non-centrosomal microtubules and regulates their dynamics and organization. Specifically recognizes growing microtubule minus-ends and autonomously decorates and stabilizes microtubule lattice formed by microtubule minus-end polymerization. Acts on free microtubule minus-ends that are not capped by microtubule-nucleating proteins or other factors and protects microtubule minus-ends from depolymerization. In addition, it also reduces the velocity of microtubule polymerization. Required for the biogenesis and the maintenance of zonula adherens by anchoring the minus-end of microtubules to zonula adherens and by recruiting the kinesin KIFC3 to those junctional sites. Required for orienting the apical-to-basal polarity of microtubules in epithelial cells: acts by tethering non-centrosomal microtubules to the apical cortex, leading to their longitudinal orientation. Plays a key role in early embryos, which lack centrosomes: accumulates at the microtubule bridges that connect pairs of cells and enables the formation of a non-centrosomal microtubule-organizing center that directs intracellular transport in the early embryo. Couples non-centrosomal microtubules with actin: interaction with MACF1 at the minus ends of non-centrosomal microtubules, tethers the microtubules to actin filaments, regulating focal adhesion size and cell migration. Plays a key role in the generation of non-centrosomal microtubules by accumulating in the pericentrosomal region and cooperating with KATNA1 to release non-centrosomal microtubules from the centrosome. Through the microtubule cytoskeleton, also regulates the organization of cellular organelles including the Golgi and the early endosomes. Through interaction with AKAP9, involved in translocation of Golgi vesicles in epithelial cells, where microtubules are mainly non-centrosomal. Plays an important role in motile cilia function by facilitatating proper orientation of basal bodies and formation of central microtubule pairs in motile cilia.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung carcinoma	DISTR26C	Strong	Biomarker	[1]

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 Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3).	[2]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3).	[11]

9 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 Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3).	[6]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3).	[12]

References

• [1] Loss of CAMSAP3 promotes EMT via the modification of microtubule-Akt machinery.J Cell Sci. 2018 Oct 29;131(21):jcs216168. doi: 10.1242/jcs.216168.
• [2] 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.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] 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.
• [6] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [7] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.