| Structural highlights
Disease
TIE2_HUMAN Defects in TEK are a cause of dominantly inherited venous malformations (VMCM) [MIM:600195; an error of vascular morphogenesis characterized by dilated, serpiginous channels.[1] [2] [3] [4] [5] Note=May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation.[6] [7]
Function
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.[8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
Publication Abstract from PubMed
Angiopoietin (Angpt)-Tie receptor 2 (Tie2) plays key roles in vascular development and homeostasis as well as pathological vascular remodeling. Therefore, Tie2-agonistic antibody and engineered Angpt1 variants have been developed as potential therapeutics for ischemic and inflammatory vascular diseases. However, their underlying mechanisms for Tie2 clustering and activation remain elusive and the poor manufacturability and stability of Angpt1 variants limit their clinical application. Here, we develop a human Tie2-agonistic antibody (hTAAB), which targets the membrane proximal fibronectin type III domain of Tie2 distinct from the Angpt-binding site. Our Tie2/hTAAB complex structures reveal that hTAAB tethers the preformed Tie2 homodimers into polygonal assemblies through specific binding to Tie2 Fn3 domain. Notably, the polygonal Tie2 clustering induced by hTAAB is critical for Tie2 activation and are resistant to antagonism by Angpt2. Our results provide insight into the molecular mechanism of Tie2 clustering and activation mediated by hTAAB, and the structure-based humanization of hTAAB creates a potential clinical application.
Structural insights into the clustering and activation of Tie2 receptor mediated by Tie2 agonistic antibody.,Jo G, Bae J, Hong HJ, Han AR, Kim DK, Hong SP, Kim JA, Lee S, Koh GY, Kim HM Nat Commun. 2021 Nov 1;12(1):6287. doi: 10.1038/s41467-021-26620-1. PMID:34725372[18]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Martin V, Liu D, Fueyo J, Gomez-Manzano C. Tie2: a journey from normal angiogenesis to cancer and beyond. Histol Histopathol. 2008 Jun;23(6):773-80. PMID:18366015
- ↑ Huang H, Bhat A, Woodnutt G, Lappe R. Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer. 2010 Aug;10(8):575-85. doi: 10.1038/nrc2894. PMID:20651738 doi:10.1038/nrc2894
- ↑ Vikkula M, Boon LM, Carraway KL 3rd, Calvert JT, Diamonti AJ, Goumnerov B, Pasyk KA, Marchuk DA, Warman ML, Cantley LC, Mulliken JB, Olsen BR. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell. 1996 Dec 27;87(7):1181-90. PMID:8980225
- ↑ Calvert JT, Riney TJ, Kontos CD, Cha EH, Prieto VG, Shea CR, Berg JN, Nevin NC, Simpson SA, Pasyk KA, Speer MC, Peters KG, Marchuk DA. Allelic and locus heterogeneity in inherited venous malformations. Hum Mol Genet. 1999 Jul;8(7):1279-89. PMID:10369874
- ↑ Wouters V, Limaye N, Uebelhoer M, Irrthum A, Boon LM, Mulliken JB, Enjolras O, Baselga E, Berg J, Dompmartin A, Ivarsson SA, Kangesu L, Lacassie Y, Murphy J, Teebi AS, Penington A, Rieu P, Vikkula M. Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects. Eur J Hum Genet. 2010 Apr;18(4):414-20. doi: 10.1038/ejhg.2009.193. Epub 2009 Nov, 4. PMID:19888299 doi:10.1038/ejhg.2009.193
- ↑ Martin V, Liu D, Fueyo J, Gomez-Manzano C. Tie2: a journey from normal angiogenesis to cancer and beyond. Histol Histopathol. 2008 Jun;23(6):773-80. PMID:18366015
- ↑ Huang H, Bhat A, Woodnutt G, Lappe R. Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer. 2010 Aug;10(8):575-85. doi: 10.1038/nrc2894. PMID:20651738 doi:10.1038/nrc2894
- ↑ Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997 Jul 4;277(5322):55-60. PMID:9204896
- ↑ Cascone I, Audero E, Giraudo E, Napione L, Maniero F, Philips MR, Collard JG, Serini G, Bussolino F. Tie-2-dependent activation of RhoA and Rac1 participates in endothelial cell motility triggered by angiopoietin-1. Blood. 2003 Oct 1;102(7):2482-90. Epub 2003 Jun 19. PMID:12816861 doi:10.1182/blood-2003-03-0670
- ↑ Lee HJ, Cho CH, Hwang SJ, Choi HH, Kim KT, Ahn SY, Kim JH, Oh JL, Lee GM, Koh GY. Biological characterization of angiopoietin-3 and angiopoietin-4. FASEB J. 2004 Aug;18(11):1200-8. PMID:15284220 doi:10.1096/fj.03-1466com
- ↑ Audero E, Cascone I, Maniero F, Napione L, Arese M, Lanfrancone L, Bussolino F. Adaptor ShcA protein binds tyrosine kinase Tie2 receptor and regulates migration and sprouting but not survival of endothelial cells. J Biol Chem. 2004 Mar 26;279(13):13224-33. Epub 2003 Dec 9. PMID:14665640 doi:10.1074/jbc.M307456200
- ↑ Saharinen P, Kerkela K, Ekman N, Marron M, Brindle N, Lee GM, Augustin H, Koh GY, Alitalo K. Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J Cell Biol. 2005 Apr 25;169(2):239-43. PMID:15851516 doi:10.1083/jcb.200411105
- ↑ Fukuhara S, Sako K, Minami T, Noda K, Kim HZ, Kodama T, Shibuya M, Takakura N, Koh GY, Mochizuki N. Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. Nat Cell Biol. 2008 May;10(5):513-26. doi: 10.1038/ncb1714. Epub 2008 Apr 20. PMID:18425120 doi:10.1038/ncb1714
- ↑ Saharinen P, Eklund L, Miettinen J, Wirkkala R, Anisimov A, Winderlich M, Nottebaum A, Vestweber D, Deutsch U, Koh GY, Olsen BR, Alitalo K. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat Cell Biol. 2008 May;10(5):527-37. doi: 10.1038/ncb1715. Epub 2008 Apr 20. PMID:18425119 doi:10.1038/ncb1715
- ↑ Yuan HT, Khankin EV, Karumanchi SA, Parikh SM. Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium. Mol Cell Biol. 2009 Apr;29(8):2011-22. doi: 10.1128/MCB.01472-08. Epub 2009 Feb, 17. PMID:19223473 doi:10.1128/MCB.01472-08
- ↑ Martin V, Liu D, Fueyo J, Gomez-Manzano C. Tie2: a journey from normal angiogenesis to cancer and beyond. Histol Histopathol. 2008 Jun;23(6):773-80. PMID:18366015
- ↑ Huang H, Bhat A, Woodnutt G, Lappe R. Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer. 2010 Aug;10(8):575-85. doi: 10.1038/nrc2894. PMID:20651738 doi:10.1038/nrc2894
- ↑ Jo G, Bae J, Hong HJ, Han AR, Kim DK, Hong SP, Kim JA, Lee S, Koh GY, Kim HM. Structural insights into the clustering and activation of Tie2 receptor mediated by Tie2 agonistic antibody. Nat Commun. 2021 Nov 1;12(1):6287. PMID:34725372 doi:10.1038/s41467-021-26620-1
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