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J. Biol. Chem., Vol. 283, Issue 26, 18177-18186, June 27, 2008

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Phosphorylation Regulates Tau Interactions with Src Homology 3 Domains of Phosphatidylinositol 3-Kinase, Phospholipase C1, Grb2, and Src Family Kinases^*

C. Hugh Reynolds¹, Claire J. Garwood, Selina Wray, Caroline Price², Stuart Kellie^¶, Timothy Perera³, Marketa Zvelebil^||**, Alice Yang^||, Paul W. Sheppard, Ian M. Varndell, Diane P. Hanger, and Brian H. Anderton

From the The MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, London SE5 8AF, United Kingdom, Yamanouchi Research Institute, Oxford, OX4 4XS, United Kingdom, ^¶School of Molecular and Microbial Sciences, University of Queensland, St. Lucia, Brisbane 4072, Australia, ^||Ludwig Institute for Cancer Research, University College London, London WC1E 6BT, United Kingdom, ^**The Institute of Cancer Research, London SW3 6JB, United Kingdom, and Biomol International LP, Exeter, EX2 8NL, United Kingdom

The microtubule-associated protein tau can associate with various other proteins in addition to tubulin, including the SH3 domains of Src family tyrosine kinases. Tau is well known to aggregate to form hyperphosphorylated filamentous deposits in several neurodegenerative diseases (tauopathies) including Alzheimer disease. We now report that tau can bind to SH3 domains derived from the p85 subunit of phosphatidylinositol 3-kinase, phospholipase C1, and the N-terminal (but not the C-terminal) SH3 of Grb2 as well as to the kinases Fyn, cSrc, and Fgr. However, the short inserts found in neuron-specific isoforms of Src prevented the binding of tau. The experimentally determined binding of tau peptides is well accounted for when modeled into the peptide binding cleft in the SH3 domain of Fyn. After phosphorylation in vitro or in transfected cells, tau showed reduced binding to SH3 domains; no binding was detected with hyperphosphorylated tau isolated from Alzheimer brain, but SH3 binding was restored by phosphatase treatment. Tau mutants with serines and threonines replaced by glutamate, to mimic phosphorylation, showed reduced SH3 binding. These results strongly suggest that tau has a potential role in cell signaling in addition to its accepted role in cytoskeletal assembly, with regulation by phosphorylation that may be disrupted in the tauopathies including Alzheimer disease.

Received for publication, November 28, 2007 , and in revised form, April 24, 2008.

^* This work was supported by the Medical Research Council, UK under their LINK scheme and by the Yamanouchi Research Institute (Astellas Pharma Europe Ltd (UK)) and Biomol International LP. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Present address: Current Medicine Group, 4th Floor, 11–21 Paul St., London EC2A 4JU, UK.

³ Present address: Johnson and Johnson Pharmaceutical Research and Development, Turnhoutsweg 30, B-2340 Beerse, Belgium.

¹ To whom correspondence should be addressed: MRC Centre for Neurodegeneration Research, Dept. of Neuroscience, Box O37, King's College London, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK. Tel.: 44-20-7848-0261; Fax: 44-20-7708-0017; E-mail: h.reynolds{at}iop.kcl.ac.uk.

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