Rapid tyrosine phosphorylation of neuronal proteins including tau and focal adhesion kinase in response to amyloid-beta peptide exposure: Involvement of src family protein kinases

Williamson, R., Scales, T., Clark, B. R., Gibb, G., Reynolds, C. H., Kellie, S., Bird, I. N., Varndell, I. M., Sheppard, P. W., Everall, I. and Anderton, B. H. (2002) Rapid tyrosine phosphorylation of neuronal proteins including tau and focal adhesion kinase in response to amyloid-beta peptide exposure: Involvement of src family protein kinases. Journal of Neuroscience, 22 1: 10-20.

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Author Williamson, R.
Scales, T.
Clark, B. R.
Gibb, G.
Reynolds, C. H.
Kellie, S.
Bird, I. N.
Varndell, I. M.
Sheppard, P. W.
Everall, I.
Anderton, B. H.
Title Rapid tyrosine phosphorylation of neuronal proteins including tau and focal adhesion kinase in response to amyloid-beta peptide exposure: Involvement of src family protein kinases
Journal name Journal of Neuroscience   Check publisher's open access policy
ISSN 0270-6474
Publication date 2002
Sub-type Article (original research)
Open Access Status File (Publisher version)
Volume 22
Issue 1
Start page 10
End page 20
Total pages 11
Place of publication Washington
Publisher Soc Neuroscience
Language eng
Abstract The increased production of amyloid beta -peptide (A beta) in Alzheimer's disease is acknowledged to be a key pathogenic event. In this study, we examined the response of primary human and rat brain cortical cultures to A beta administration and found a marked increase in the tyrosine phosphorylation content of numerous neuronal proteins, including tau and putative microtubule-associated protein 2c (MAP2c). We also found that paired helical filaments of aggregated and hyperphosphorylated tau are tyrosine phosphorylated, indicating that changes in the phosphotyrosine content of cytoplasmic proteins in response to A beta are potentially an important process. Increased tyrosine phosphorylation of cytoskeletal and other neuronal proteins was specific to fibrillar A beta (25-35) and A beta (1-42). The tyrosine phosphorylation was blocked by addition of the Src family tyrosine kinase inhibitor 4-amino-5-( 4-chlorophenyl)- 7(t-butyl) pyrazol(3,4-D) pyramide (PP2) and the phosphatidylinositol 3-kinase inhibitor LY 294002. Tyrosine phosphorylation of tau and MAP2c was concomitant with an increase in the tyrosine phosphorylation and subsequent putative activation of the non-receptor kinase, focal adhesion kinase (FAK). Immunoprecipitation of Fyn, a member of the Src family, from A beta (25-35)-treated neurons showed an increased association of Fyn with FAK. A beta treatment of cells also stimulated the sustained activation of extracellular regulated kinase-2, which was blocked by addition of PP2 and LY 294002, suggesting that FAK/Fyn/PI3-kinase association is upstream of mitogen-activated protein (MAP) kinase signaling in A beta -treated neurons. This cascade of signaling events contains the earliest biochemical changes in neurons to be described in response to A beta exposure and may be critical for subsequent neurodegenerative changes.
Keyword Neurosciences
Alzheimer's disease
amyloid beta-peptide
cortical neurons
tyrosine phosphorylation
FAK
Fyn
ERK2
tau
MAP2c
Helical Filament-tau
Glycogen-synthase Kinase-3-beta
Central-nervous-system
Alzheimers-disease
Phosphatidylinositol 3-kinase
Physiological Levels
Hippocampal-neurons
Cortical-neurons
Induced Neurodegeneration
Microtubule-binding
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Chemistry and Molecular Biosciences
 
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Created: Wed, 19 Sep 2007, 16:06:40 EST