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Targeting the Tie2–αvβ3 integrin axis with bi-specific reagents for the inhibition of angiogenesis

Overview of attention for article published in BMC Biology, August 2018
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Title
Targeting the Tie2–αvβ3 integrin axis with bi-specific reagents for the inhibition of angiogenesis
Published in
BMC Biology, August 2018
DOI 10.1186/s12915-018-0557-9
Pubmed ID
Authors

Tomer Shlamkovich, Lidan Aharon, Dana Koslawsky, Yulia Einav, Niv Papo

Abstract

Increased activity of the receptor tyrosine kinase Tie2 has been implicated in the promotion of pathological angiogenesis. This activity is mainly mediated through angiopoietin (Ang)1- and Ang2-dependent activation of integrins by Tie2, rendering the Ang/Tie2/integrin axis an attractive putative target for cancer therapeutics. To target this axis, we developed single domain, non-immunoglobulin high-affinity bi-specific protein inhibitors against both Tie2 and αvβ3 integrin. We have previously engineered the Ang2-binding domain of Tie2 (Ang2-BD) as a Tie2 inhibitor. Here, we engineered an exposed loop in Ang2-BD to generate variants that include an integrin-binding Arg-Gly-Asp (RGD) motif and used flow cytometry screening of a yeast-displayed Ang2-BD RGD loop library to identify the integrin antagonists. The bi-specific antagonists targeting both Tie2 and αvβ3 integrin inhibited adhesion and proliferation of endothelial cells cultured together with the αvβ3 integrin ligand vitronectin, as well as endothelial cell invasion and tube formation. The bi-specific reagents inhibited downstream signaling by Tie2 intracellularly in response to its agonist Ang1 more effectively than the wild-type Ang2 BD that binds Tie2 alone. Collectively, this study-the first to describe inhibitors targeting all the known functions resulting from Tie2/integrin αvβ3 cross-talk-has created new tools for studying Tie2- and integrin αvβ3-dependent molecular pathways and provides the basis for the rational and combinatorial engineering of ligand-Tie2 and ligand-integrin αvβ3 receptor interactions. Given the roles of these pathways in cancer angiogenesis and metastasis, this proof of principle study paves the route to create novel Tie2/integrin αvβ3-targeting proteins for clinical use as imaging and therapeutic agents.

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Mendeley readers

The data shown below were compiled from readership statistics for 32 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 32 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 6 19%
Student > Doctoral Student 4 13%
Student > Ph. D. Student 4 13%
Student > Bachelor 2 6%
Other 2 6%
Other 3 9%
Unknown 11 34%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 13 41%
Agricultural and Biological Sciences 2 6%
Pharmacology, Toxicology and Pharmaceutical Science 1 3%
Unspecified 1 3%
Immunology and Microbiology 1 3%
Other 4 13%
Unknown 10 31%