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The Journal of Neuroscience, March 1, 2003, 23(5):1638
Role of Integrin-Linked Kinase in Nerve Growth Factor-Stimulated Neurite Outgrowth
Julia Mills1, Murat Digicaylioglu5, Arthur T. Legg2, Clint E. Young4, Sean S. Young1, Alasdair M. Barr3, Lauren Fletcher5, Timothy P. O'Connor2, and Shoukat Dedhar1 1 Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada V6T 123, and British Columbia Cancer Agency, British Columbia, Canada V6H 326, 2 Department of Anatomy and Cell Biology, University of British Columbia, Vancouver, British Columbia, Canada V6T 123, 3 Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada V6T 124, 4 Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada V6T 2A1, and 5 Center for Neuroscience and Aging Research, The Burnham Institute, La Jolla, California 92037
The role of integrin-linked kinase (ILK), a kinase that is involved in various cellular processes, including adhesion and migration, has not been studied in primary neurons. Using mRNA dot blot and Western blot analysis of ILK in rat and human brain tissue, we found that ILK is expressed in various regions of the CNS. Immunohistochemical and immunocytochemical techniques revealed granular ILK staining that is enriched in neurons and colocalizes with the
1 integrin subunit. The role of ILK in neurite growth promotion by NGF was studied in rat pheochromocytoma cells and dorsal root ganglion neurons using a pharmacological inhibitor of ILK (KP-392) or after overexpression of dominant-negative ILK (ILK-DN). Both molecular and pharmacological inhibition of ILK activity significantly reduced NGF-induced neurite outgrowth. Survival assays indicate that KP-392-induced suppression of neurite outgrowth occurred in the absence of cell death. ILK kinase activity was stimulated by NGF. NGF-mediated stimulation of phosphorylation of both AKT and the Tau kinase glycogen synthase kinase-3 (GSK-3) was inhibited in the presence of KP-392 and after overexpression of ILK-DN. Consequently, ILK inhibition resulted in an increase in the hyperphosphorylation of Tau, a substrate of GSK-3. Together these findings indicate that ILK is an important effector in NGF-mediated neurite outgrowth.
Key words: integrin-linked kinase; glycogen synthase kinase-3; NGF; neurite growth; AKT;
Copyright © 2003 Society for Neuroscience 0270-6474/03/2351638-11$05.00/0
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