T-cadherin (T-cad) promotes survival, proliferation, and migration of endothelial cells and induces angiogenesis. We aimed to identify domains of T-cad functionally relevant to its effects on endothelial cell behavior. To specifically target the functional properties of the 5 cadherin repeat domains (EC1–EC5) of T-cad, endothelial cells were transduced with lentivectors containing specific T-cad-domain-deletion mutant constructs (ΔI, ΔII, ΔIII, ΔIV, ΔV). Empty (E) lentivector-transduced cells served as control. Similarly to overexpression of native T-cad, cells expressing ΔII, ΔIII, or ΔIV displayed elevated levels of p-Akt and p-GSK3β and increased proliferation rates (for ΔII, ΔIII) vs. E. ΔI- and ΔV-transduced cells exhibited reduced levels of p-Akt and p-GSK3β and retarded growth rates vs. E. Stimulatory effects of native T-cad overexpression on Akt and GSK3β phosphorylation were dose dependently inhibited by coexpression of ΔI or ΔV. Subsequent functional analyses compared only ΔI-, ΔII-, and ΔV-mutant constructs with E as a negative control. Unlike ΔII cells, ΔI and ΔV cells failed to exhibit homophilic ligation and deadhesion responses on a substratum of T-cad protein. In the wound assay, migration was increased for ΔII cells but impaired for ΔI and ΔV cells. In endothelial cell-spheroid assay, angiogenic sprouting was augmented for ΔII cells but inhibited for ΔI and ΔV cells. We conclude that EC1 and EC5 domains of T-cad are essential for its proangiogenic effects. ΔI and ΔV constructs may serve as dominant-negative mutants and as potential tools targeting excessive angiogenesis.—Joshi, M. B., Kyriakakis, E., Pfaff, D., Rupp, K., Philippova, M., Erne, P., Resink, T. J. Extracellular cadherin repeat domains EC1 and EC5 of T-cadherin are essential for its ability to stimulate angiogenic behavior of endothelial cells.
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Extracellular cadherin repeat domains EC1 and EC5 of T-cadherin are essential for its ability to stimulate angiogenic behavior of endothelial cells
Joshi, Manjunath B.; Kyriakakis, Emmanouil; Pfaff, Dennis; Rupp, Katharina; Philippova, Maria; Erne, Paul; Resink, Thérèse J.
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, Volume 23 (11): 4011
Fed of American Socs for Experimental Biology – Nov 1, 2009
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