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The protein phosphatase PP2A/Bα binds to the microtubule-associated proteins Tau and MAP2 at a motif also recognized by the kinase Fyn: implications for tauopathies.

Abstract
The predominant brain microtubule-associated proteins MAP2 and tau play a critical role in microtubule cytoskeletal organization and function. We have previously reported that PP2A/Bα, a major protein phosphatase 2A (PP2A) holoenzyme, binds to and dephosphorylates tau, and regulates microtubule stability. Here, we provide evidence that MAP2 co-purifies with and is dephosphorylated by endogenous PP2A/Bα in bovine gray matter. It co-localizes with PP2A/Bα in immature and mature human neuronal cell bodies. PP2A co-immunoprecipitates with and directly interacts with MAP2. Using in vitro binding assays, we show that PP2A/Bα binds to MAP2c isoforms through a region encompassing the microtubule-binding domain and upstream proline-rich region. Tau and MAP2 compete for binding to and dephosphorylation by PP2A/Bα. Remarkably, the protein-tyrosine kinase Fyn, which binds to the proline-rich RTPPKSP motif conserved in both MAP2 and tau, inhibits the interaction of PP2A/Bα with either tau or MAP2c. The corresponding synthetic RTPPKSP peptide, but not the phosphorylated RpTPPKSP version, competes with Tau and MAP2c for binding to PP2A/Bα. Significantly, down-regulation of PP2A/Bα and deregulation of Fyn-Tau protein interactions have been linked to enhanced tau phosphorylation in Alzheimer disease. Together, our results suggest that PP2A/Bα is part of segregated MAP2 and tau signaling scaffolds that can coordinate the action of key kinases and phosphatases involved in modulating neuronal plasticity. Deregulation of these compartmentalized multifunctional protein complexes is likely to contribute to tau deregulation, microtubule disruption, and altered signaling in tauopathies.
AuthorsJean-Marie Sontag, Viyada Nunbhakdi-Craig, Charles L White 3rd, Shelley Halpain, Estelle Sontag
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 18 Pg. 14984-93 (Apr 27 2012) ISSN: 1083-351X [Electronic] United States
PMID22403409 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • MAP2 protein, human
  • MAPT protein, human
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Peptides
  • Protein Isoforms
  • tau Proteins
  • FYN protein, human
  • Proto-Oncogene Proteins c-fyn
  • Protein Phosphatase 2
Topics
  • Alzheimer Disease (metabolism, pathology)
  • Amino Acid Motifs
  • Animals
  • Cattle
  • Cell Line
  • Microtubule-Associated Proteins (metabolism)
  • Nerve Tissue Proteins (metabolism)
  • Neurons (metabolism, pathology)
  • Peptides (pharmacology)
  • Protein Binding (drug effects)
  • Protein Isoforms (metabolism)
  • Protein Phosphatase 2 (metabolism)
  • Proto-Oncogene Proteins c-fyn (metabolism)
  • Signal Transduction (drug effects)
  • tau Proteins (metabolism)

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