Glycosylphosphatidylinositol-anchored T-cadherin (T-cad) influences several parameters of angiogenesis including endothelial cell (EC) differentiation, migration, proliferation, and survival. This presupposes signal transduction networking via mediatory regulators and molecular adaptors since T-cad lacks transmembrane and cytosolic domains. Here, using pharmacological inhibition of PI3K, adenoviral-mediated T-cad-overexpression, siRNA-mediated T-cad-depletion, and agonistic antibody-mediated ligation, we demonstrate signaling by T-cad through PI3K-Akt-GSK3 pathways in EC. T-cad-overexpressing EC exhibited increased levels and nuclear accumulation of active -catenin, which was transcriptionally active as shown by increased Lef/Tcf reporter activity and cyclin D1 levels. Cotransduction of EC with constitutively active GSK3 (S9A-GSK3) abrogated the stimulatory effects of T-cad on active -catenin accumulation, proliferation, and survival. Integrin-linked kinase (ILK), a membrane proximal upstream regulator of Akt and GSK3, was considered a candidate signaling mediator for T-cad. T-cad was present in anti-ILK immunoprecipitates, and confocal microscopy revealed colocalization of T-cad and ILK within lamellipodia of migrating cells. ILK-siRNA abolished T-cad-dependent effects on ^Ser-473Akt/^Ser-9GSK3 phosphorylation, active -catenin accumulation, and survival. We conclude ILK is an essential mediator for T-cad signaling via Akt and GSK3 in EC. This is the first demonstration that ILK can regulate inward signaling by GPI-anchored proteins. Furthermore, ILK-GSK3-dependent modulation of active -catenin levels by GPI-anchored T-cad represents a novel mechanism for controlling cellular -catenin activity.--Joshi, M. B., Ivanov, D., Philippova, M., Erne, P., Resink, T. J. Integrin-linked kinase is an essential mediator for T-cadherin-dependent signaling via Akt and GSK3 in endothelial cells.