Cell adhesion and the integrin-linked kinase regulate the LEF-1 and β-catenin signaling pathways

Cell adhesion and the integrin-linked kinase regulate the LEF-1 and β-catenin signaling pathways

^*Division of Cancer Research, Sunnybrook Health Science Centre, Research Building, S-218, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5; ^†Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M4N 3M5; ^‡Howard Hughes Medical Institute, and Departments of Microbiology and Biochemistry, University of California, San Francisco CA, 94143-0414; ^§Megabios Corporation, 863A Mitten Road, Burlingame, CA 94010; ^¶Department of Morphology, University Medical Centre, 1211 Geneva, Switzerland; and ^‖Department of Anatomy, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3

Communicated by Harold E. Varmus, National Institutes of Health, Bethesda, MD (received for review December 8, 1997)

Abstract

The integrin-linked kinase (ILK) is an ankyrin repeat containing serine-threonine protein kinase that can interact directly with the cytoplasmic domains of the β1 and β3 integrin subunits and whose kinase activity is modulated by cell–extracellular matrix interactions. Overexpression of constitutively active ILK results in loss of cell–cell adhesion, anchorage-independent growth, and tumorigenicity in nude mice. We now show that modest overexpression of ILK in intestinal epithelial cells as well as in mammary epithelial cells results in an invasive phenotype concomitant with a down-regulation of E-cadherin expression, translocation of β-catenin to the nucleus, formation of a complex between β-catenin and the high mobility group transcription factor, LEF-1, and transcriptional activation by this LEF-1/β-catenin complex. We also find that LEF-1 protein expression is rapidly modulated by cell detachment from the extracellular matrix, and that LEF-1 protein levels are constitutively up-regulated at ILK overexpression. These effects are specific for ILK, because transformation by activated H-ras or v-src oncogenes do not result in the activation of LEF-1/β-catenin. The results demonstrate that the oncogenic properties of ILK involve activation of the LEF-1/β-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.

Footnotes

↵ ** To whom reprint requests should be sent at the present address: Vancouver Hospital and Health Science Centre/University of British Columbia Jack Bell Research Centre and British Columbia Cancer Agency, Department of Biochemistry, University of British Columbia, 2660 Oak Street, Vancouver, BC Vancouver, BC Canada V6H 3Z6. e-mail: sdedhar{at}interchange.ubc.ca.
ABBREVIATIONS:

ILK,

integrin-linked kinase;

TCF,

T cell factor;

IEC,

intestinal epithelial cell;

wt,

wild type