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Vol. 273, Issue 1, 528-536, January 2, 1998

Integrin-linked Protein Kinase Regulates Fibronectin Matrix Assembly, E-cadherin Expression, and Tumorigenicity

Chuanyue WuDagger §, Sarah Y. KeightleyDagger , Chungyee Leung-Hagesteijnpar , Galena Radevapar , Marc Coppolinopar , Silvia Goicoechea§, John A. McDonaldDagger , and Shoukat Dedharpar

From the Dagger  Samuel C. Johnson Medical Research Center, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259, the par  Cancer Biology Research Program, Sunnybrook Health Science Centre, and Department of Medical Biophysics, University of Toronto, Toronto M4N 3M5, Ontario, Canada, and the § Department of Cell Biology and The Cell Adhesion and Matrix Research Center, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019

Fibronectin (Fn) matrix plays important roles in many biological processes including morphogenesis and tumorigenesis. Recent studies have demonstrated a critical role of integrin cytoplasmic domains in regulating Fn matrix assembly, implying that intracellular integrin-binding proteins may be involved in controlling extracellular Fn matrix assembly. We report here that overexpression of integrin-linked kinase (ILK), a newly identified serine/threonine kinase that binds to the integrin beta 1 cytoplasmic domain, dramatically stimulated Fn matrix assembly in epithelial cells. The integrin-linked kinase activity is involved in transducing signals leading to the up-regulation of Fn matrix assembly, as overexpression of a kinase-inactive ILK mutant failed to enhance the matrix assembly. Moreover, the increase in Fn matrix assembly induced by ILK overexpression was accompanied by a substantial reduction in the cellular E-cadherin. Finally, we show that ILK-overexpressing epithelial cells readily formed tumors in nude mice, despite forming an extensive Fn matrix. These results identify ILK as an important regulator of pericellular Fn matrix assembly, and suggest a novel critical role of this integrin-linked kinase in cell growth, cell survival, and tumorigenesis.

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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Tumor Dormancy Induced by Downregulation of Urokinase Receptor in Human Carcinoma Involves Integrin and MAPK Signaling
J. Cell Biol., October 4, 1999; 147(1): 89 - 104.
[Abstract] [Full Text] [PDF]

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 JCBHome page
K. Orford, C. C. Orford, and S. W. Byers
Exogenous Expression of {beta}-Catenin Regulates Contact Inhibition, Anchorage-independent Growth, Anoikis, and Radiation-induced Cell Cycle Arrest
J. Cell Biol., August 23, 1999; 146(4): 855 - 868.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
E. Pötter, C. Bergwitz, and G. Brabant
The Cadherin-Catenin System: Implications for Growth and Differentiation of Endocrine Tissues
Endocr. Rev., April 1, 1999; 20(2): 207 - 239.
[Abstract] [Full Text]

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 J. Biol. Chem.Home page
K. J. Langenbach and J. Sottile
Identification of Protein-disulfide Isomerase Activity in Fibronectin
J. Biol. Chem., March 12, 1999; 274(11): 7032 - 7038.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
Y. Tu, F. Li, S. Goicoechea, and C. Wu
The LIM-Only Protein PINCH Directly Interacts with Integrin-Linked Kinase and Is Recruited to Integrin-Rich Sites in Spreading Cells
Mol. Cell. Biol., March 1, 1999; 19(3): 2425 - 2434.
[Abstract] [Full Text] [PDF]

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 J. Cell Sci.Home page
C Wu
Integrin-linked kinase and PINCH: partners in regulation of cell-extracellular matrix interaction and signal transduction
J. Cell Sci., January 12, 1999; 112(24): 4485 - 4489.
[Abstract] [PDF]

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 J. Cell Sci.Home page
F Li, Y Zhang, and C Wu
Integrin-linked kinase is localized to cell-matrix focal adhesions but not cell-cell adhesion sites and the focal adhesion localization of integrin-linked kinase is regulated by the PINCH-binding ANK repeats
J. Cell Sci., January 12, 1999; 112(24): 4589 - 4599.
[Abstract] [PDF]

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 J. Cell Sci.Home page
M. Deugnier, M. Faraldo, P Rousselle, J. Thiery, and M. Glukhova
Cell-extracellular matrix interactions and EGF are important regulators of the basal mammary epithelial cell phenotype
J. Cell Sci., January 4, 1999; 112(7): 1035 - 1044.
[Abstract] [PDF]

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 Mol. Biol. CellHome page
Y. Tu, F. Li, and C. Wu
Nck-2, a Novel Src Homology2/3-containing Adaptor Protein That Interacts with the LIM-only Protein PINCH and Components of Growth Factor Receptor Kinase-signaling Pathways
Mol. Biol. Cell, December 1, 1998; 9(12): 3367 - 3382.
[Abstract] [Full Text]

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 Proc. Natl. Acad. Sci. USAHome page
M. Delcommenne, C. Tan, V. Gray, L. Rue, J. Woodgett, and S. Dedhar
Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase
PNAS, September 15, 1998; 95(19): 11211 - 11216.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
A. Novak, S.-C. Hsu, C. Leung-Hagesteijn, G. Radeva, J. Papkoff, R. Montesano, C. Roskelley, R. Grosschedl, and S. Dedhar
Cell adhesion and the integrin-linked kinase regulate the LEF-1 and beta -catenin signaling pathways
PNAS, April 14, 1998; 95(8): 4374 - 4379.
[Abstract] [Full Text] [PDF]

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 J. Cell Sci.Home page
J Sottile, D. Hocking, and P. Swiatek
Fibronectin matrix assembly enhances adhesion-dependent cell growth
J. Cell Sci., January 10, 1998; 111(19): 2933 - 2943.
[Abstract] [PDF]

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 J. Biol. Chem.Home page
M. D'Amico, J. Hulit, D. F. Amanatullah, B. T. Zafonte, C. Albanese, B. Bouzahzah, M. Fu, L. H. Augenlicht, L. A. Donehower, K.-I. Takemaru, et al.
The Integrin-linked Kinase Regulates the Cyclin D1 Gene through Glycogen Synthase Kinase 3beta and cAMP-responsive Element-binding Protein-dependent Pathways
J. Biol. Chem., October 13, 2000; 275(42): 32649 - 32657.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
P. A. Klekotka, S. A. Santoro, and M. M. Zutter
alpha 2 Integrin Subunit Cytoplasmic Domain-dependent Cellular Migration Requires p38 MAPK
J. Biol. Chem., March 16, 2001; 276(12): 9503 - 9511.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
S. N. Nikolopoulos and C. E. Turner
Integrin-linked Kinase (ILK) Binding to Paxillin LD1 Motif Regulates ILK Localization to Focal Adhesions
J. Biol. Chem., June 22, 2001; 276(26): 23499 - 23505.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
X.-Q. Wang, P. Sun, and A. S. Paller
Inhibition of Integrin-linked Kinase/Protein Kinase B/Akt Signaling. MECHANISM FOR GANGLIOSIDE-INDUCED APOPTOSIS
J. Biol. Chem., November 21, 2001; 276(48): 44504 - 44511.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
S. N. Nikolopoulos and C. E. Turner
Molecular Dissection of Actopaxin-Integrin-linked Kinase-Paxillin Interactions and Their Role in Subcellular Localization
J. Biol. Chem., January 4, 2002; 277(2): 1568 - 1575.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
S. Persad, S. Attwell, V. Gray, M. Delcommenne, A. Troussard, J. Sanghera, and S. Dedhar
Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells
PNAS, March 28, 2000; 97(7): 3207 - 3212.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
L. Gonzalez-Santiago, S. Lopez-Ongil, M. Rodriguez-Puyol, and D. Rodriguez-Puyol
Decreased Nitric Oxide Synthesis in Human Endothelial Cells Cultured on Type I Collagen
Circ. Res., March 22, 2002; 90(5): 539 - 545.
[Abstract] [Full Text] [PDF]


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