View source for 6mwe


==CRYSTAL STRUCTURE OF TIE2 IN COMPLEX WITH DECIPERA COMPOUND DP1919==
<StructureSection load='6mwe' size='340' side='right'caption='[[6mwe]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6mwe]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MWE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MWE FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.05&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=919:4-[4-({[3-TERT-BUTYL-1-(QUINOLIN-6-YL)-1H-PYRAZOL-5-YL]CARBAMOYL}AMINO)-3-FLUOROPHENOXY]-N-METHYLPYRIDINE-2-CARBOXAMIDE'>919</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6mwe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mwe OCA], [https://pdbe.org/6mwe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mwe RCSB], [https://www.ebi.ac.uk/pdbsum/6mwe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mwe ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/TIE2_HUMAN TIE2_HUMAN] Defects in TEK are a cause of dominantly inherited venous malformations (VMCM) [MIM:[https://omim.org/entry/600195 600195]; an error of vascular morphogenesis characterized by dilated, serpiginous channels.<ref>PMID:18366015</ref> <ref>PMID:20651738</ref> <ref>PMID:8980225</ref> <ref>PMID:10369874</ref> <ref>PMID:19888299</ref>   Note=May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation.<ref>PMID:18366015</ref> <ref>PMID:20651738</ref> 
== Function ==
[https://www.uniprot.org/uniprot/TIE2_HUMAN TIE2_HUMAN] 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 adjoining cells, 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.<ref>PMID:9204896</ref> <ref>PMID:12816861</ref> <ref>PMID:15284220</ref> <ref>PMID:14665640</ref> <ref>PMID:15851516</ref> <ref>PMID:18425120</ref> <ref>PMID:18425119</ref> <ref>PMID:19223473</ref> <ref>PMID:18366015</ref> <ref>PMID:20651738</ref> 
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== Publication Abstract from PubMed ==
Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation, and metastasis, which can offset the effects of chemotherapy, radiation, and antiangiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and protumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2(+) myeloid cell infiltration, antiangiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2(Hi)/Vegf-A(Hi) macrophages in the tumor microenvironment of metastasis (TMEM). The antitumor effects of rebastinib enhance the efficacy of microtubule inhibiting chemotherapeutic agents, either eribulin or paclitaxel, by reducing tumor volume, metastasis, and improving overall survival. Rebastinib inhibition of angiopoietin/Tie2 signaling impairs multiple pathways in tumor progression mediated by protumoral Tie2(+) macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in cancer patients. Mol Cancer Ther; 16(11); 2486-501. (c)2017 AACR.

The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2(Hi) Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors.,Harney AS, Karagiannis GS, Pignatelli J, Smith BD, Kadioglu E, Wise SC, Hood MM, Kaufman MD, Leary CB, Lu WP, Al-Ani G, Chen X, Entenberg D, Oktay MH, Wang Y, Chun L, De Palma M, Jones JG, Flynn DL, Condeelis JS Mol Cancer Ther. 2017 Nov;16(11):2486-2501. doi: 10.1158/1535-7163.MCT-17-0241. , Epub 2017 Aug 24. PMID:28838996<ref>PMID:28838996</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6mwe" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Abendroth J]]
[[Category: Chun L]]
[[Category: Edwards TE]]