Target Information
Target General Infomation | |||||
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Target ID |
T89747
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Former ID |
TTDI02385
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Target Name |
mRNA of Abl
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Gene Name |
ABL1
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Synonyms |
Abelson murine leukemia viral oncogene homolog 1 (mRNA); Abelson tyrosine-protein kinase 1 (mRNA); Proto-oncogene c-Abl (mRNA); Tyrosine-protein kinase ABL1 (mRNA); p150 (mRNA); ABL1
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Target Type |
Discontinued
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Disease | Chronic myelogenous leukaemia [ICD9: 205.1; ICD10: C92.1] | ||||
Function |
Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulatingpositively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage- induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin- associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1.
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BioChemical Class |
Kinase
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UniProt ID | |||||
EC Number |
EC 2.7.10.2
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Sequence |
MLEICLKLVGCKSKKGLSSSSSCYLEEALQRPVASDFEPQGLSEAARWNSKENLLAGPSE
NDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPSNYITPVN SLEKHSWYHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRSISLRYEGRVYHYRINTAS DGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNYDKWEMERT DITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAAVMKEIKHPNLVQ LLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQISSAMEYLEKKNFI HRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWTAPESLAYNKFSIKS DVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCPEKVYELMRACWQWNP SDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLLQAPELPTKTRTSRRAAE HRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEGGLNEDERLLPKDKKTNLF SALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDISNGALAFTPLDTADPAKSP KPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATGEEEGGGSSSKRFLRSCSAS CVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKPALPRKRAGENRSDQVTRGTV TPPPRLVKKNEEAADEVFKDIMESSPGSSPPNLTPKPLRRQVTVAPASGLPHKEEAGKGS ALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHKHSSESPGRDKGKLSRLKPAPP PPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLVDAVNSDAAKPSQPGEGLKKPVL PATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSSTAFIPLISTRVSLRKTRQPPE RIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAGKNLYTFCVSYVDSIQQMRNK FAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSSVKEISDIVQR |
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Drugs and Mode of Action | |||||
Pathways | |||||
KEGG Pathway | ErbB signaling pathway | ||||
Ras signaling pathway | |||||
Cell cycle | |||||
Axon guidance | |||||
Neurotrophin signaling pathway | |||||
Pathogenic Escherichia coli infection | |||||
Shigellosis | |||||
Pathways in cancer | |||||
MicroRNAs in cancer | |||||
Chronic myeloid leukemia | |||||
Viral myocarditis | |||||
PANTHER Pathway | Axon guidance mediated by Slit/Robo | ||||
Pathway Interaction Database | p73 transcription factor network | ||||
ATM pathway | |||||
Regulation of Telomerase | |||||
Posttranslational regulation of adherens junction stability and dissassembly | |||||
Lissencephaly gene (LIS1) in neuronal migration and development | |||||
PDGFR-beta signaling pathway | |||||
Neurotrophic factor-mediated Trk receptor signaling | |||||
Validated transcriptional targets of TAp63 isoforms | |||||
p53 pathway | |||||
Regulation of retinoblastoma protein | |||||
Reactome | Regulation of actin dynamics for phagocytic cup formation | ||||
CDO in myogenesis | |||||
RHO GTPases Activate WASPs and WAVEs | |||||
HDR through Single Strand Annealing (SSA) | |||||
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks | |||||
Factors involved in megakaryocyte development and platelet production | |||||
WikiPathways | DNA Damage Response (only ATM dependent) | ||||
DNA Damage Response | |||||
ErbB Signaling Pathway | |||||
EGF/EGFR Signaling Pathway | |||||
Apoptosis-related network due to altered Notch3 in ovarian cancer | |||||
Fcgamma receptor (FCGR) dependent phagocytosis | |||||
ATM Signaling Pathway | |||||
Retinoblastoma (RB) in Cancer | |||||
Integrated Pancreatic Cancer Pathway | |||||
Pathogenic Escherichia coli infection | |||||
Regulation of Microtubule Cytoskeleton | |||||
Integrated Breast Cancer Pathway | |||||
Signaling by Robo receptor | |||||
Myogenesis | |||||
Factors involved in megakaryocyte development and platelet production | |||||
TP53 Network | |||||
miRNAs involved in DNA damage response | |||||
miRNA Regulation of DNA Damage Response | |||||
References | |||||
Ref 529744 | Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol. 2008 Nov;4(11):691-9. | ||||
Ref 530633 | Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature. 2010 Jan 28;463(7280):501-6. | ||||
Ref 531471 | Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant. Bioorg Med Chem Lett. 2011 Jun 15;21(12):3743-8. | ||||
Ref 532248 | Rapid discovery of a novel series of Abl kinase inhibitors by application of an integrated microfluidic synthesis and screening platform. J Med Chem. 2013 Apr 11;56(7):3033-47. |
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