Details of Drug Off-Target (DOT)

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

DOT Name Nck-associated protein 1-like (NCKAP1L)
Synonyms Hematopoietic protein 1; Membrane-associated protein HEM-1
Gene Name NCKAP1L
Related Disease
Immunodeficiency 72 with autoinflammation ( )
Small lymphocytic lymphoma ( )
Wiskott-Aldrich syndrome ( )
Neoplasm ( )
UniProt ID
NCKPL_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Pfam ID
PF09735
Sequence
MSLTSAYQHKLAEKLTILNDRGQGVLIRMYNIKKTCSDPKSKPPFLLEKSMEPSLKYINK
KFPNIDVRNSTQHLGPVHREKAEIIRFLTNYYQSFVDVMEFRDHVYELLNTIDACQCHFD
INLNFDFTRSYLDLIVTYTSVILLLSRIEDRRILIGMYNCAHEMLHGHGDPSFARLGQMV
LEYDHPLKKLTEEFGPHTKAVSGALLSLHFLFVRRNQGAEQWRSAQLLSLISNPPAMINP
ANSDTMACEYLSVEVMERWIIIGFLLCHGCLNSNSQCQKLWKLCLQGSLYITLIREDVLQ
VHKVTEDLFSSLKGYGKRVADIKESKEHVIANSGQFHCQRRQFLRMAVKELETVLADEPG
LLGPKALFAFMALSFIRDEVTWLVRHTENVTKTKTPEDYADSSIAELLFLLEGIRSLVRR
HIKVIQQYHLQYLARFDALVLSDIIQNLSVCPEEESIIMSSFVSILSSLNLKQVDNGEKF
EFSGLRLDWFRLQAYTSVAKAPLHLHENPDLAKVMNLIVFHSRMLDSVEKLLVETSDLST
FCFHLRIFEKMFAMTLEESAMLRYAIAFPLICAHFVHCTHEMCPEEYPHLKNHGLHHCNS
FLEELAKQTSNCVLEICAEQRNLSEQLLPKHCATTISKAKNKKTRKQRQTPRKGEPERDK
PGAESHRKNRSIVTNMDKLHLNLTELALTMNHVYSFSVFEHTIFPSEYLSSHLEARLNRA
IVWLAGYNATTQEIVRPSELLAGVKAYIGFIQSLAQFLGADASRVIRNALLQQTQPLDSC
GEQTITTLYTNWYLESLLRQASSGTIILSPAMQAFVSLPREGEQNFSAEEFSDISEMRAL
AELLGPYGMKFLSENLMWHVTSQIVELKKLVVENMDILVQIRSNFSKPDLMASLLPQLTG
AENVLKRMTIIGVILSFRAMAQEGLREVFSSHCPFLMGPIECLKEFVTPDTDIKVTLSIF
ELASAAGVGCDIDPALVAAIANLKADTSSPEEEYKVACLLLIFLAVSLPLLATDPSSFYS
IEKDGYNNNIHCLTKAIIQVSAALFTLYNKNIETHLKEFLVVASVSLLQLGQETDKLKTR
NRESISLLMRLVVEESSFLTLDMLESCFPYVLLRNAYREVSRAFHLN
Function
Essential hematopoietic-specific regulator of the actin cytoskeleton (Probable). Controls lymphocyte development, activation, proliferation and homeostasis, erythrocyte membrane stability, as well as phagocytosis and migration by neutrophils and macrophages. Component of the WAVE2 complex which signals downstream of RAC to stimulate F-actin polymerization. Required for stabilization and/or translation of the WAVE2 complex proteins in hematopoietic cells. Within the WAVE2 complex, enables the cortical actin network to restrain excessive degranulation and granule release by T-cells. Required for efficient T-lymphocyte and neutrophil migration. Exhibits complex cycles of activation and inhibition to generate waves of propagating the assembly with actin. Also involved in mechanisms WAVE-independent to regulate myosin and actin polymerization during neutrophil chemotaxis. In T-cells, required for proper mechanistic target of rapamycin complex 2 (mTORC2)-dependent AKT phosphorylation, cell proliferation and cytokine secretion, including that of IL2 and TNF.
Tissue Specificity Expressed only in cells of hematopoietic origin . Expressed in neutrophils (at protein level) . Expressed in T-cells (at protein level) .
KEGG Pathway
Regulation of actin cytoskeleton (hsa04810 )
Pathogenic Escherichia coli infection (hsa05130 )
Salmonella infection (hsa05132 )
Reactome Pathway
VEGFA-VEGFR2 Pathway (R-HSA-4420097 )
RHO GTPases Activate WASPs and WAVEs (R-HSA-5663213 )
Neutrophil degranulation (R-HSA-6798695 )
RAC1 GTPase cycle (R-HSA-9013149 )
RAC2 GTPase cycle (R-HSA-9013404 )
RAC3 GTPase cycle (R-HSA-9013423 )
FCGR3A-mediated phagocytosis (R-HSA-9664422 )
Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482 )

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Immunodeficiency 72 with autoinflammation DIS5LJLP Strong Autosomal recessive [1]
Small lymphocytic lymphoma DIS30POX Strong Biomarker [2]
Wiskott-Aldrich syndrome DISATMDB Strong Biomarker [3]
Neoplasm DISZKGEW Limited Biomarker [4]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
5 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate affects the expression of Nck-associated protein 1-like (NCKAP1L). [5]
Tretinoin DM49DUI Approved Tretinoin increases the expression of Nck-associated protein 1-like (NCKAP1L). [6]
Testosterone DM7HUNW Approved Testosterone decreases the expression of Nck-associated protein 1-like (NCKAP1L). [7]
Triclosan DMZUR4N Approved Triclosan increases the expression of Nck-associated protein 1-like (NCKAP1L). [8]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Nck-associated protein 1-like (NCKAP1L). [10]
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1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of Nck-associated protein 1-like (NCKAP1L). [9]
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References

1 A point mutation in the murine Hem1 gene reveals an essential role for Hematopoietic protein 1 in lymphopoiesis and innate immunity. J Exp Med. 2008 Nov 24;205(12):2899-913. doi: 10.1084/jem.20080340. Epub 2008 Nov 17.
2 ATM, CTLA4, MNDA, and HEM1 in high versus low CD38 expressing B-cell chronic lymphocytic leukemia.Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5295-304. doi: 10.1158/1078-0432.CCR-07-0283.
3 The Wave2 scaffold Hem-1 is required for transition of fetal liver hematopoiesis to bone marrow.Nat Commun. 2018 Jun 18;9(1):2377. doi: 10.1038/s41467-018-04716-5.
4 Tumor expression studies indicate that HEM-1 is unlikely to be the active factor in oncogenic osteomalacia.Bone. 1998 Dec;23(6):549-53. doi: 10.1016/s8756-3282(98)00136-7.
5 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.
6 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.
7 The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
8 Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
9 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.
10 Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.