Abstract

Angiogenesis is a complex cellular process involving the branching, expansion, and maturation of primordial blood vessels into a complex microvasculature. The Angiopoietin/Tie receptor-ligand system plays a central role in these events. The Angiopoietins are secreted molecules that signal through the endothelial specific Tie2 receptor. This is a unique receptor tyrosine kinase signaling system in that distinct Angiopoietin ligands, although highly homologous, may function as agonist or antagonist in a context dependent manner. A detailed understanding of the mechanisms of Angiopoietin-Tie signaling and their function during angiogenesis requires comprehensive structural and biophysical analysis of both the Angiopoietins and the Tie receptors as well as of their interactions. The specific goals of this proposal include: i) structural analysis of the ligand binding domain of at least two Angiopoietin family members, ii) structural analysis of the ligand-binding domain of Tie2 as well as of the equivalent region of the related orphan receptor Tie1, iii) structural analysis of receptor recognition and formation of an Angiopoietin-Tie2 complex and iv) biochemical characterization of Angiopoietin-Tie interactions and receptor activation. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077249-02
Application #
6899838
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Goldman, Stephen
Project Start
2004-08-01
Project End
2009-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
2
Fiscal Year
2005
Total Cost
$342,600
Indirect Cost

  Institution

Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Barton, William A; Dalton, Annamarie C; Seegar, Tom C M et al. (2014) Tie2 and Eph receptor tyrosine kinase activation and signaling. Cold Spring Harb Perspect Biol 6:
Yu, Xuehong; Seegar, Tom C M; Dalton, Annamarie C et al. (2013) Structural basis for angiopoietin-1-mediated signaling initiation. Proc Natl Acad Sci U S A 110:7205-10
Seegar, Tom C M; Eller, Becca; Tzvetkova-Robev, Dorothea et al. (2010) Tie1-Tie2 interactions mediate functional differences between angiopoietin ligands. Mol Cell 37:643-55
Barton, William A; Tzvetkova-Robev, Dorothea; Miranda, Edward P et al. (2006) Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex. Nat Struct Mol Biol 13:524-32
Barton, William A; Tzvetkova-Robev, Dorothea; Erdjument-Bromage, Hediye et al. (2006) Highly efficient selenomethionine labeling of recombinant proteins produced in mammalian cells. Protein Sci 15:2008-13