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1.
J Biol Chem ; 274(36): 25490-8, 1999 Sep 03.
Article in English | MEDLINE | ID: mdl-10464280

ABSTRACT

Hyperphosphorylated forms of the neuronal microtubule (MT)-associated protein tau are major components of Alzheimer's disease paired helical filaments. Previously, we reported that ABalphaC, the dominant brain isoform of protein phosphatase 2A (PP2A), is localized on MTs, binds directly to tau, and is a major tau phosphatase in cells. We now describe direct interactions among tau, PP2A, and MTs at the submolecular level. Using tau deletion mutants, we found that ABalphaC binds a domain on tau that is indistinguishable from its MT-binding domain. ABalphaC binds directly to MTs through a site that encompasses its catalytic subunit and is distinct from its binding site for tau, and ABalphaC and tau bind to different domains on MTs. Specific PP2A isoforms bind to MTs with distinct affinities in vitro, and these interactions differentially inhibit the ability of PP2A to dephosphorylate various substrates, including tau and tubulin. Finally, tubulin assembly decreases PP2A activity in vitro, suggesting that PP2A activity can be modulated by MT dynamics in vivo. Taken together, these findings indicate how structural interactions among ABalphaC, tau, and MTs might control the phosphorylation state of tau. Disruption of these normal interactions could contribute significantly to development of tauopathies such as Alzheimer's disease.


Subject(s)
Microtubules/metabolism , Neurons/metabolism , Phosphoprotein Phosphatases/metabolism , tau Proteins/metabolism , Alzheimer Disease/metabolism , Animals , Cattle , Humans , Neurons/ultrastructure , Phosphorylation , Protein Phosphatase 2
2.
Neuron ; 17(6): 1201-7, 1996 Dec.
Article in English | MEDLINE | ID: mdl-8982166

ABSTRACT

Recently, we reported that a pool of protein phosphatase 2A (PP2A) is associated with microtubules. Here, we demonstrate that specific isoforms of PP2A bind and dephosphorylate the neuronal microtubule-associated protein tau. Coexpression of tau and SV40 small t, a specific inhibitor of PP2A, in CV-1, NIH 3T3, or NT2 cells induced the phosphorylation of tau at multiple sites, including Ser-199, Ser-202, Thr-205, Ser-396, and Ser-404. Immunofluorescent and biochemical analyses revealed that hyperphosphorylation correlated with dissociation of tau from microtubules and a loss of tau-induced microtubule stabilization. Taken together, these results support the hypothesis that PP2A controls the phosphorylation state of tau in vivo.


Subject(s)
Microtubules/metabolism , Phosphoprotein Phosphatases/metabolism , tau Proteins/metabolism , 3T3 Cells , Animals , Cell Line , Drug Stability , Epitopes , Isoenzymes/metabolism , Mice , Phosphorylation , Protein Phosphatase 2 , tau Proteins/chemistry , tau Proteins/immunology
3.
J Cell Biol ; 128(6): 1131-44, 1995 Mar.
Article in English | MEDLINE | ID: mdl-7896877

ABSTRACT

Immunofluorescence microscopy revealed the presence of protein phosphatase 2A (PP2A) on microtubules in neuronal and nonneuronal cells. Interphase and mitotic spindle microtubules, as well as centrosomes, were all labeled with antibodies against individual PP2A subunits, showing that the AB alpha C holoenzyme is associated with microtubules. Biochemical analysis showed that PP2A could be reversibly bound to microtubules in vitro and that approximately 75% of the PP2A in cytosolic extracts could interact with microtubules. The activity of microtubule-associated PP2A was differentially regulated during the cell cycle. Enzymatic activity was high during S phase and intermediate during G1, while the activity in G2 and M was 20-fold lower than during S phase. The amount of microtubule-bound PP2A remained constant throughout the cell cycle, implying that cell cycle regulation of its enzymatic activity involves factors other than microtubules. These results raise the possibility that PP2A regulates cell cycle-dependent microtubule functions, such as karyokinesis and membrane transport.


Subject(s)
Microtubules/metabolism , Phosphoprotein Phosphatases/metabolism , Animals , Cattle , Cell Cycle , Cells, Cultured , Fluorescent Antibody Technique , Haplorhini , Mice , Protein Binding , Protein Phosphatase 2 , Rats
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