Target Information
Target General Infomation | |||||
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Target ID |
T92144
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Former ID |
TTDC00161
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Target Name |
Angiopoietin 1 receptor
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Gene Name |
TEK
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Synonyms |
CD202b antigen; Endothelial Cell-Specific Receptor TIE-2; P140 TEK; Tunica interna endothelial cell kinase; Tyrosine-protein kinase receptor TEK; Tyrosine-protein kinase receptor TIE-2; TEK
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Target Type |
Clinical Trial
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Disease | Arthritis; Myelodysplastic syndrome [ICD9:710-719, 238.7; ICD10: M00-M25, D46] | ||||
Cancer [ICD9: 140-229; ICD10: C00-C96] | |||||
Ischemia [ICD9: 459.89; ICD10: I99.8] | |||||
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48] | |||||
Function |
Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post- natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoiningcells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1.
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BioChemical Class |
Kinase
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Target Validation |
T92144
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UniProt ID | |||||
EC Number |
EC 2.7.10.1
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Sequence |
MDSLASLVLCGVSLLLSGTVEGAMDLILINSLPLVSDAETSLTCIASGWRPHEPITIGRD
FEALMNQHQDPLEVTQDVTREWAKKVVWKREKASKINGAYFCEGRVRGEAIRIRTMKMRQ QASFLPATLTMTVDKGDNVNISFKKVLIKEEDAVIYKNGSFIHSVPRHEVPDILEVHLPH AQPQDAGVYSARYIGGNLFTSAFTRLIVRRCEAQKWGPECNHLCTACMNNGVCHEDTGEC ICPPGFMGRTCEKACELHTFGRTCKERCSGQEGCKSYVFCLPDPYGCSCATGWKGLQCNE ACHPGFYGPDCKLRCSCNNGEMCDRFQGCLCSPGWQGLQCEREGIQRMTPKIVDLPDHIE VNSGKFNPICKASGWPLPTNEEMTLVKPDGTVLHPKDFNHTDHFSVAIFTIHRILPPDSG VWVCSVNTVAGMVEKPFNISVKVLPKPLNAPNVIDTGHNFAVINISSEPYFGDGPIKSKK LLYKPVNHYEAWQHIQVTNEIVTLNYLEPRTEYELCVQLVRRGEGGEGHPGPVRRFTTAS IGLPPPRGLNLLPKSQTTLNLTWQPIFPSSEDDFYVEVERRSVQKSDQQNIKVPGNLTSV LLNNLHPREQYVVRARVNTKAQGEWSEDLTAWTLSDILPPQPENIKISNITHSSAVISWT ILDGYSISSITIRYKVQGKNEDQHVDVKIKNATITQYQLKGLEPETAYQVDIFAENNIGS SNPAFSHELVTLPESQAPADLGGGKMLLIAILGSAGMTCLTVLLAFLIILQLKRANVQRR MAQAFQNVREEPAVQFNSGTLALNRKVKNNPDPTIYPVLDWNDIKFQDVIGEGNFGQVLK ARIKKDGLRMDAAIKRMKEYASKDDHRDFAGELEVLCKLGHHPNIINLLGACEHRGYLYL AIEYAPHGNLLDFLRKSRVLETDPAFAIANSTASTLSSQQLLHFAADVARGMDYLSQKQF IHRDLAARNILVGENYVAKIADFGLSRGQEVYVKKTMGRLPVRWMAIESLNYSVYTTNSD VWSYGVLLWEIVSLGGTPYCGMTCAELYEKLPQGYRLEKPLNCDDEVYDLMRQCWREKPY ERPSFAQILVSLNRMLEERKTYVNTTLYEKFTYAGIDCSAEEAA |
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Structure |
1FVR; 2GY5; 2GY7; 2OO8; 2OSC; 2P4I; 2WQB; 3BEA; 3L8P; 4K0V; 4X3J
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Drugs and Mode of Action | |||||
Inhibitor | (4-Phenoxy-phenyl)-quinazolin-4-yl-amine | Drug Info | [525876] | ||
3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione | Drug Info | [528032] | |||
3,4-diphenyl-1H-pyrrole-2,5-dione | Drug Info | [528032] | |||
3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione | Drug Info | [528032] | |||
3-(indole-3-yl)-4-phenyl-1H-pyrrole-2,5-dione | Drug Info | [528032] | |||
A-420983 | Drug Info | [527057] | |||
Altiratinib | Drug Info | [550598] | |||
compound 8h | Drug Info | [531471] | |||
Tie-2 inhibitors | Drug Info | [543511] | |||
Modulator | AP-101 | Drug Info | [543511] | ||
ARRY-614 | Drug Info | ||||
CEP-11981 | Drug Info | [543511] | |||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
KEGG Pathway | Ras signaling pathway | ||||
Rap1 signaling pathway | |||||
HIF-1 signaling pathway | |||||
PI3K-Akt signaling pathway | |||||
Rheumatoid arthritis | |||||
NetPath Pathway | Wnt Signaling Pathway | ||||
PANTHER Pathway | Angiogenesis | ||||
Pathway Interaction Database | Angiopoietin receptor Tie2-mediated signaling | ||||
SHP2 signaling | |||||
Reactome | Tie2 Signaling | ||||
RAF/MAP kinase cascade | |||||
WikiPathways | Wnt Signaling Pathway Netpath | ||||
Cell surface interactions at the vascular wall | |||||
Angiogenesis | |||||
References | |||||
Ref 522626 | ClinicalTrials.gov (NCT00875264) Open-Label Study to Determine the Maximum Tolerated Oral Dose of the Kinase Inhibitor CEP-11981 in Patients With Advanced Cancer. U.S. National Institutes of Health. | ||||
Ref 542989 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8189). | ||||
Ref 525876 | Bioorg Med Chem Lett. 2000 Oct 2;10(19):2167-70.Pyrrolo[2,3-d]pyrimidines containing an extended 5-substituent as potent and selective inhibitors of lck I. | ||||
Ref 527057 | Bioorg Med Chem Lett. 2004 May 17;14(10):2613-6.A-420983: a potent, orally active inhibitor of lck with efficacy in a model of transplant rejection. | ||||
Ref 528032 | J Med Chem. 2006 Feb 23;49(4):1271-81.Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors. | ||||
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. |
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