title: Phosphorylation regulates tau interactions with Src homology 3 domains of phosphatidylinositol 3-kinase, phospholipase Cgamma1, Grb2, and Src family kinases.
abstract: 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 p85alpha subunit of phosphatidylinositol 3-kinase, phospholipase Cgamma1, 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.
authors.affiliation: The MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, London, UK. h.reynolds@iop.kcl.ac.uk
authors.forename: C Hugh
authors.initials: CH
authors.lastname: Reynolds
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Garwood
authors.forename: Selina
authors.initials: S
authors.lastname: Wray
authors.forename: Caroline
authors.initials: C
authors.lastname: Price
authors.forename: Stuart
authors.initials: S
authors.lastname: Kellie
authors.forename: Timothy
authors.initials: T
authors.lastname: Perera
authors.forename: Marketa
authors.initials: M
authors.lastname: Zvelebil
authors.forename: Alice
authors.initials: A
authors.lastname: Yang
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sheppard
authors.forename: Ian M
authors.initials: IM
authors.lastname: Varndell
authors.forename: Diane P
authors.initials: DP
authors.lastname: Hanger
authors.forename: Brian H
authors.initials: BH
authors.lastname: Anderton
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D006801:Humans; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018909:src Homology Domains; D019061:src-Family Kinases / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D051380:GRB2 Adaptor Protein; D010455:Peptides; D016875:tau Proteins; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D051966:Phospholipase C gamma