Tài liệu Báo cáo khoa học:Tyrosine phosphorylation of tau regulates its interactions with Fyn SH2

Tyrosine phosphorylation of tau regulates its interactions

with Fyn SH2 domains, but not SH3 domains, altering the

cellular localization of tau

Alessia Usardi1

, Amy M. Pooler1

, Anjan Seereeram1

, C. Hugh Reynolds1

, Pascal Derkinderen1

,

Brian Anderton1

, Diane P. Hanger1

, Wendy Noble1,* and Ritchie Williamson1,2,*

1 Department of Neuroscience, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King’s College London, UK

2 Biomedical Research Institute, Ninewells Medical School, University of Dundee, UK

Keywords

Fyn-SH2; Fyn-SH3; phosphorylation; tau;

tyrosine

Correspondence

R. Williamson, Biomedical Research

Institute, Ninewells Medical School,

University of Dundee, Dundee DD1 9SY, UK

Fax: +44 1382 740 359

Tel: +44 1382 740 347

E-mail: [email protected]

*These authors contributed equally to this

work

(Received 19 April 2011, revised 20 May

2011, accepted 16 June 2011)

doi:10.1111/j.1742-4658.2011.08218.x

Recent reports have demonstrated that interactions between the microtu￾bule-associated protein tau and the nonreceptor tyrosine kinase Fyn play a

critical role in mediating synaptic toxicity and neuronal loss in response to

b-amyloid (Ab) in models of Alzheimer’s disease. Disruption of interactions

between Fyn and tau may thus have the potential to protect neurons from

Ab-induced neurotoxicity. Here, we investigated tau and Fyn interactions

and the potential implications for positioning of these proteins in membrane

microdomains. Tau is known to bind to Fyn via its Src-homology (SH)3

domain, an association regulated by phosphorylation of PXXP motifs in tau.

Here, we show that Pro216 within the PXXP(213–216) motif in tau plays an

important role in mediating the interaction of tau with Fyn-SH3. We also

show that tau interacts with the SH2 domain of Fyn, and that this associa￾tion, unlike that of Fyn-SH3, is influenced by Fyn-mediated tyrosine phos￾phorylation of tau. In particular, phosphorylation of tau at Tyr18, a reported

target of Fyn, is important for mediating Fyn-SH2–tau interactions. Finally,

we show that tyrosine phosphorylation influences the localization of tau to

detergent-resistant membrane microdomains in primary cortical neurons,

and that this trafficking is Fyn-dependent. These findings may have implica￾tions for the development of novel therapeutic strategies aimed at disrupting

the tau ⁄Fyn-mediated synaptic dysfunction that occurs in response to ele￾vated Ab levels in neurodegenerative disease.

Structured digital abstract

l Fyn physically interacts with tau by pull down (View interaction)

l Fyn physically interacts with tau by pull down (View interaction)

Introduction

The microtubule-associated protein tau is a predomi￾nantly neuronal soluble phosphoprotein that is mainly

cytoplasmic, but is also present in nuclear [1,2]

and membrane [3–5] compartments of various cell

types. Abnormalities in tau, including its aberrant

phosphorylation, truncation and aggregation, are

causally associated with neuronal loss in a family of

neurodegenerative disorders named the tauopathies,

which include Alzheimer’s disease (AD), progressive

supranuclear palsy and frontotemporal dementia with

Abbreviations

AD, Alzheimer’s disease; Ab, b-amyloid; CHO, Chinese hamster ovary; CNS, central nervous system; DRM, detergent-resistant

microdomain; GST, glutathione-S-transferase; NMDA, N-methyl-D-aspartate; PSD, postsynaptic density; SEM, standard error of the mean;

SH, Src homology.

FEBS Journal 278 (2011) 2927–2937 ª 2011 The Authors Journal compilation ª 2011 FEBS 2927