Integrin-linked kinase is an essential mediator for T-cadherin-dependent signaling via Akt and GSK3β in endothelial cells

Manjunath B. Joshi, Danila Ivanov, Maria Philippova, Paul Erne, Thérèse J. Resink

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46 Citations (Scopus)

Abstract

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-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 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-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.

Original languageEnglish
Pages (from-to)3083-3095
Number of pages13
JournalFASEB Journal
Volume21
Issue number12
DOIs
Publication statusPublished - 10-2007

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All Science Journal Classification (ASJC) codes

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology
  • Medicine(all)

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