title: Tyrosine phosphorylation of tau regulates its interactions with Fyn SH2 domains, but not SH3 domains, altering the cellular localization of tau.
abstract: Recent reports have demonstrated that interactions between the microtubule-associated protein tau and the nonreceptor tyrosine kinase Fyn play a critical role in mediating synaptic toxicity and neuronal loss in response to β-amyloid (Aβ) in models of Alzheimer's disease. Disruption of interactions between Fyn and tau may thus have the potential to protect neurons from Aβ-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 association, unlike that of Fyn-SH3, is influenced by Fyn-mediated tyrosine phosphorylation 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 implications for the development of novel therapeutic strategies aimed at disrupting the tau/Fyn-mediated synaptic dysfunction that occurs in response to elevated Aβ levels in neurodegenerative disease.
authors.affiliation: Department of Neuroscience, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, UK.
authors.forename: Alessia
authors.initials: A
authors.lastname: Usardi
authors.forename: Amy M
authors.initials: AM
authors.lastname: Pooler
authors.forename: Anjan
authors.initials: A
authors.lastname: Seereeram
authors.forename: C Hugh
authors.initials: CH
authors.lastname: Reynolds
authors.forename: Pascal
authors.initials: P
authors.lastname: Derkinderen
authors.forename: Brian
authors.initials: B
authors.lastname: Anderton
authors.forename: Diane P
authors.initials: DP
authors.lastname: Hanger
authors.forename: Wendy
authors.initials: W
authors.lastname: Noble
authors.forename: Ritchie
authors.initials: R
authors.lastname: Williamson
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D010766:Phosphorylation; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*; D018909:src Homology Domains; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins; D014443:Tyrosine; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn