Glycosylphosphatidylinositol‐anchored T‐cadherin (T‐cad) influences several parameters of angio‐genesis 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‐GSK3β pathways in EC. T‐cad‐overexpressing EC exhibited increased levels and nuclear accumulation of active β‐catenin, which was transcriptionally active as shown by increased Lef/Tcf reporter activity and cyclin D1 levels. Cotransduction of EC with constitutively active GSK3β (S9A‐GSK3β) abrogated the stimulatory effects of T‐cad on active β‐catenin accumulation, proliferation, and survival. Integrin‐linked kinase (ILK), a membrane proximal upstream regulator of Akt and GSK3β, was considered a candidate signaling mediator for T‐cad. T‐cad was present in anti‐ILK immunopre‐cipitates, and confocal microscopy revealed colocal‐ization of T‐cad and ILK within lamellipodia of migrating cells. ILK‐siRNA abolished T‐cad‐dependent effects on ^Ser‐473Akt/^Ser‐9GSK3β phosphorylation, active β‐catenin accumulation, and survival. We conclude ILK is an essential mediator for T‐cad signaling via Akt and GSK3β in EC. This is the first demonstration that ILK can regulate inward signaling by GPI‐anchored proteins. Furthermore, ILK‐GSK3β‐dependent modulation of active β ‐catenin levels by GPI‐anchored T‐cad represents a novel mechanism for controlling cellular β‐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 GSK3β in endothelial cells. FASEB J. 21, 3083–3095 (2007)