Inactivation of integrin-linked kinase induces aberrant tau phosphorylation via sustained activation of glycogen synthase kinase 3beta in N1E-115 neuroblastoma cells.

Abstract

Integrin-linked kinase (ILK) is a focal adhesion serine/threonine protein kinase with an important role in integrin and growth factor signaling pathways. Recently, we demonstrated that ILK is expressed in N1E-115 neuroblastoma cells and controls integrin-dependent neurite outgrowth in serum-starved cells grown on laminin (Ishii, T., Satoh, E., and Nishimura, M. (2001) J. Biol. Chem. 276, 42994-43003). Here we report that ILK controls tau phosphorylation via regulation of glycogen synthase kinase-3beta (GSK-3beta) activity in N1E-115 cells. Stable transfection of a kinase-deficient ILK mutant (DN-ILK) resulted in aberrant tau phosphorylation in N1E-115 cells at sites recognized by the Tau-1 antibody that are identical to some of the phosphorylation sites in paired helical filaments, PHF-tau, in brains of patients with Alzheimer's disease. The tau phosphorylation levels in the DN-ILK-expressing cells are constant under normal and differentiating conditions. On the other hand, aberrant tau phosphorylation was not observed in the parental control cells. ILK inactivation resulted in an increase in the active form but a decrease in the inactive form of GSK-3beta, which is a candidate kinase involved in PHF-tau formation. Moreover, inhibition of GSK-3beta with lithium prevented aberrant tau phosphorylation in the DN-ILK-expressing cells. These results suggest that ILK inactivation results in aberrant tau phosphorylation via sustained activation of GSK-3beta in N1E-115 Cells. ILK directly phosphorylates GSK-3beta and inhibits its activity. Therefore, endogenous ILK protects against GSK-3beta-induced aberrant tau phosphorylation via inhibition of GSK-3beta activity in N1E-115 cells.

• Authors: Toshiaki Ishii, Hidefumi Furuoka, Yoshikage Muroi, Masakazu Nishimura
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 29 Pg. 26970-5 (Jul 18 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12714590 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Culture Media, Serum-Free
• Laminin
• Recombinant Proteins
• tau Proteins
• Lithium
• integrin-linked kinase
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Protein Serine-Threonine Kinases
• Glycogen Synthase Kinase 3

Topics

• Animals
• Cell Adhesion
• Culture Media, Serum-Free
• Enzyme Activation
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Laminin
• Lithium (pharmacology)
• Mice
• Models, Neurological
• Neurites (drug effects, metabolism, ultrastructure)
• Neuroblastoma (metabolism)
• Neurons (cytology, drug effects, metabolism)
• Phosphorylation
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Recombinant Proteins (genetics, metabolism)
• Transfection
• Tumor Cells, Cultured
• tau Proteins (chemistry, metabolism)