Phosphorylation of Tau by Fyn: Implications for Alzheimer's Disease

Abstract

The abnormal phosphorylation of tau protein on serines and threonines is a hallmark characteristic of the neurofibrillary tangles of Alzheimer's disease (AD). The discovery that tau could be phosphorylated on tyrosine and evidence that A␤ signal transduction involved tyrosine phosphorylation led us to question whether tyrosine phosphorylation of tau occurred during the neurodegenerative process. In this study we determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn. By developing both polyclonal and monoclonal probes specific for phospho-tyr18, we found that the phosphorylation of tau at tyr18 occurred at early developmental stages in mouse but was absent in the adult. Our phosphospecific probes also revealed that paired helical filament preparations exhibited phospho-tyr18 reactivity that was sensitive to phosphotyrosine-specific protein phosphatase treatment. Moreover, immunocytochemical studies indicated that tyrosine phosphorylated tau was present in the neurofibrillary tangles in AD brain. However, the staining pattern excluded neuropil threads and dystrophic neurites indicating that tyrosine phosphorylated tau was distributed in AD brain in a manner dissimilar from other abnormally phosphorylated tau. We also found evidence suggesting that differentially phosphorylated tau existed within degenerating neurons. Our data add new support for a role for fyn in the neurodegenerative process.

Increase in tau tyrosine phosphorylation correlates with the formation of tau aggregates

“…Furthermore, Williamson et al showed that treatment of primary rat and human cortical neurons with Aβ peptides promotes a transient activation of various signaling proteins including fyn, and tyrosine phosphorylation of neuronal proteins, such as tau [19]. These reports have suggested that fyn kinase may mediate tau tyrosine phosphorylation at Y18 and Y29 and have a role in neurodegeneration [10,12,19]. We did not detect Y18 and Y29 phosphorylation by mass spectrometry.…”

“…Thus, we cannot rule out the presence of phosphorylated Y18 and Y29 based on mass spectrometry. In JNPL3 mice, we did not uncover the phosphorylation of Y18 (anti-pY18; [12]) and Y29 (anti-pY29; [19]) by Western blotting of total lysates and Tau12-immunopurified preparations from S1 and P3 fractions (data not shown). Furthermore, we did not detect a differential increase in expression or co-localization of fyn kinase and intraneuronal tau aggregates, or detect tyrosine-phosphorylated fyn kinase in brain extracts (data not shown).…”

“…No information is available regarding the kinases involved in abnormal tyrosine phosphorylation of tau in human tauopathy. In their studies of COS7 cells co-transfected with tau and fyn, Lee et al demonstrated the association of tau proteins with fyn tyrosine kinase and tyrosine phosphorylation of tau at Y18 [10,12]. Furthermore, Williamson et al showed that treatment of primary rat and human cortical neurons with Aβ peptides promotes a transient activation of various signaling proteins including fyn, and tyrosine phosphorylation of neuronal proteins, such as tau [19].…”

A low molecular weight protein tyrosine phosphatase from Synechocystis sp. strain PCC 6803: enzymatic characterization and identification of its potential substrates

“…This reversible phosphorylation/dephosphorylation process is catalysed by opposing reactions of protein kinases and protein phosphatases (1,2). It has been well studied that in eukaryotes protein phosphorylation on tyrosine residues plays a key role in the regulatory mechanism of various cellular processes including growth, differentiation, cell cycle regulation and cytoskeletal function (3,4), and as well as controls many diseases (5,6) including infectious diseases (7,8). In comparison to eukaryotes, the occurrence of protein tyrosine kinases (PTKs)/protein tyrosine phosphatases (PTPs) in bacteria including photosynthetic cyanobacteria, was suggested much later (9 15).…”

Developing Therapeutic Approaches to Tau, Selected Kinases, and Related Neuronal Protein Targets

“…Tau can also undergo tyrosine phosphorylation (Lee et al 2004), sumoylation, and nitration (Gong et al 2005;Reynolds et al 2006), although the consequences of these modifications are presently unclear. Finally, it has recently been shown that tau can undergo acetylation on multiple lysines (Min et al 2010;Cohen et al 2011), including lysine residues (K280/K281) within a MT binding repeat.…”