TY - JOUR
T1 - Tyrosine phosphorylation of tau regulates its interactions with Fyn SH2 domains, but not SH3 domains, altering the cellular localization of tau
AU - Usardi, Alessia
AU - Pooler, Amy M.
AU - Seereeram, Anjan
AU - Reynolds, C. Hugh
AU - Derkinderen, Pascal
AU - Anderton, Brian
AU - Hanger, Diane P.
AU - Noble, Wendy
AU - Williamson, Ritchie
PY - 2011/8
Y1 - 2011/8
N2 - 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 beta-amyloid (A beta) in models of Alzheimer's disease. Disruption of interactions between Fyn and tau may thus have the potential to protect neurons from A beta-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 A beta levels in neurodegenerative disease.
AB - 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 beta-amyloid (A beta) in models of Alzheimer's disease. Disruption of interactions between Fyn and tau may thus have the potential to protect neurons from A beta-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 A beta levels in neurodegenerative disease.
U2 - 10.1111/j.1742-4658.2011.08218.x
DO - 10.1111/j.1742-4658.2011.08218.x
M3 - Article
VL - 278
SP - 2927
EP - 2937
JO - FEBS Journal
JF - FEBS Journal
IS - 16
ER -