CELL-ADHESION AND THE INTEGRIN-LINKED KINASE REGULATE THE LEF-1 AND BETA-CATENIN SIGNALING PATHWAYS

The integrin-linked kinase (ILK) is an ankyrin repeat containing serin e-threonine protein kinase that can interact directly with the cytopla smic domains of the beta 1 and beta 3 integrin subunits and whose kina se activity is modulated by cell-extracellular matrix interactions, Ov erexpression of constitutively active ILK results in loss of cell-cell adhesion, anchorage-independent growth, and tumorigenicity in nude mi ce. We now show that modest overexpression of ILK in intestinal epithe lial cells as well as in mammary epithelial cells results in an invasi ve phenotype concomitant with a down-regulation of E-cadherin expressi on, translocation of beta-catenin to the nucleus, formation of a compl ex between beta-catenin and the high mobility group transcription fact or, LEF-1, and transcriptional activation by this LEF-1/beta-catenin c omplex We also find that LEF-1 protein expression is rapidly modulated by cell detachment from the extracellular matrix, and that LEF-1 prot ein levels are constitutively up-regulated at ILK overexpression. Thes e effects are specific for ILK because transformation by activated H-r ns or v-src oncogenes do not result in the activation of LEF-1/beta-ca tenin, The results demonstrate that the oncogenic properties of ILK in volve activation of the LEF-1/beta-catenin signaling pathway, and also suggest ILK-mediated cross-talk between cell-matrix interactions and cell-cell adhesion as well as components of the Wnt signaling pathway.