Constitutive association of Tie1 and Tie2 with endothelial integrins is functionally modulated by angiopoietin-1 and fibronectin

Annamarie C. Dalton, Tomer Shlamkovitch, Niv Papo, William A. Barton

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Functional cross-talk between Tie2 and Integrin signaling pathways is essential to coordinate endothelial cell adhesion and migration in response to the extracellular matrix, yet the mechanisms behind this phenomenon are unclear. Here, we examine the possibility that receptor cross-talk is driven through uncharacterized Tie-integrin interactions on the endothelial surface. Using a live cell FRET-based proximity assay, we monitor Tie-integrin receptor recognition and demonstrate that both Tie1 and Tie2 readily associate with integrins α5β1 and αVβ3 through their respective ectodomains. Although not required, Tie2-integrin association is significantly enhanced in the presence of the extracellular component and integrin ligand fibronectin. In vitro binding assays with purified components reveal that Tieintegrin recognition is direct, and further demonstrate that the receptor binding domain of the Tie2 ligand Ang-1, but not the receptor binding domain of Ang-2, can independently associate with α5β1 or αVβ3. Finally, we reveal that cooperative Tie/integrin interactions selectively stimulate ERK/MAPK signaling in the presence of both Ang-1 and fibronectin, suggesting a molecular mechanism to sensitize Tie2 to extracellular matrix. We provide a mechanistic model highlighting the role of receptor localization and association in regulating distinct signaling cascades and in turn, the angiogenic switch.

Original languageEnglish
Article numbere0163732
JournalPLoS ONE
Volume11
Issue number10
DOIs
StatePublished - 1 Oct 2016

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