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 serine-threonine protein kinase that can interact directly with the cytoplasmic domains of the beta1 and beta3 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 beta-catenin to the nucleus, formation of a complex between beta-catenin and the high mobility group transcription factor, LEF-1, and transcriptional activation by this LEF-1/beta-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/beta-catenin. The results demonstrate that the oncogenic properties of ILK involve 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.
Novak
A
A
Division of Cancer Research, Sunnybrook Health Science Centre, Research Building, S-218, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
Hsu
S C
SC
Leung-Hagesteijn
C
C
Radeva
G
G
Papkoff
J
J
Montesano
R
R
Roskelley
C
C
Grosschedl
R
R
Dedhar
S
S
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005109:Extracellular Matrix / Q000502:physiology; D011905:Genes, ras; D016391:Genes, src; D051821:Lymphoid Enhancer-Binding Factor 1; D051379:Mice; D008819:Mice, Nude; D016297:Mutagenesis, Site-Directed; D009361:Neoplasm Invasiveness; D015688:Oncogene Protein pp60(v-src) / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic; D014162:Transfection; D051176:beta Catenin; D000099200:Scaffold Protein ILK
D015820:Cadherins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D015688:Oncogene Protein pp60(v-src); D017346:Protein Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D000099200:Scaffold Protein ILK; C495267:CTNNB1 protein, mouse; C495268:Ctnnb1 protein, rat; C497574:Lef1 protein, mouse; C497575:Lef1 protein, rat