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A more recent version of this article appeared on December 1, 2003
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Submitted on May 15, 2003
Revised on July 31, 2003
Accepted on July 31, 2003
1 BC Cancer Agency, Jack Bell Research Centre,
Vancouver, BC, V6H 3Z6
2 Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
3 BC Cancer Agency, Jack Bell Research Centre,
Vancouver, BC, V6H 3Z6, Department
of Biochemistry and Molecular Biology, University of British Columbia,
Vancouver, BC
* Corresponding author. E-mail address: sdedhar{at}interchange.ubc.ca.
Cell attachment and the assembly of cytoskeletal and signaling
complexes downstream of integrins are intimately linked and
coordinated. Although many intracellular proteins have been implicated
in these processes, a new paradigm is emerging from biochemical and
genetic studies which implicates integrin-linked kinase (ILK)
and its interacting proteins, such as CH-ILKBP (
-parvin), paxillin
and PINCH in coupling integrins to the actin cytoskeleton and
signaling complexes. Genetic studies in Drosophila, C.
elegans and mice point to an essential role of ILK as an
adaptor protein in mediating integrin dependent cell attachment
and cytoskeletal organization. Here we demonstrate, using several
different approaches, that inhibiting ILK kinase activity, or
expression, results in the inhibition of cell attachment, cell
migration, F-actin organization, and the specific cytoskeletal
localization of CH-ILKBP and paxillin in human cells. We also
demonstrate that the kinase activity of ILK is elevated in the
cytoskeletal fraction, and that the interaction of CH-ILKBP with ILK
within the cytoskeleton stimulates ILK activity and downstream
signaling to PKB/Akt and GSK-3. Interestingly, the interaction of
CH-ILKBP with ILK is regulated by the Pi3 Kinase pathway, since
inhibition of Pi3 Kinase activity by pharmacological inhibitors, or by
the tumor suppressor PTEN, inhibits this interaction as well as cell
attachment and signaling. These data demonstrate that the kinase and
adaptor properties of ILK function together, in a Pi3 Kinase-dependent
manner, to regulate integrin-mediated cell attachment and
signal transduction.
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