4jyo

Structural highlights

Function

ANGP1_HUMAN Binds and activates TEK/TIE2 receptor by inducing its dimerization and tyrosine phosphorylation. Plays an important role in the regulation of angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Required for normal angiogenesis and heart development during embryogenesis. 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. Mediates blood vessel maturation/stability. Implicated in endothelial developmental processes later and distinct from that of VEGF. Appears to play a crucial role in mediating reciprocal interactions between the endothelium and surrounding matrix and mesenchyme.^{[1] [2] [3] [4]}

References

1. ↑ 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
2. ↑ 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
3. ↑ 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
4. ↑ 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
5. ↑ Yu X, Seegar TC, Dalton AC, Tzvetkova-Robev D, Goldgur Y, Rajashankar KR, Nikolov DB, Barton WA. Structural basis for angiopoietin-1-mediated signaling initiation. Proc Natl Acad Sci U S A. 2013 Apr 30;110(18):7205-10. doi:, 10.1073/pnas.1216890110. Epub 2013 Apr 16. PMID:23592718 doi:http://dx.doi.org/10.1073/pnas.1216890110