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Monoubiquitination Promotes Calpain Cleavage of the Protein Phosphatase 2A (PP2A) Regulatory Subunit alpha 4, Altering PP2A Stability and Microtubule-associated Protein Phosphorylation

Monoubiquitination Promotes Calpain Cleavage of the Protein Phosphatase 2A (PP2A) Regulatory Subunit alpha 4, Altering PP2A Stability and Microtubule-associated Protein Phosphorylation

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Authors

  • Guy R. Watkins
  • Ning Wang
  • Matthew D. Mazalouskas
  • Rey J. Gomez
  • Chris R. Guthrie
  • Brian C. Kraemer
  • Susann Schweiger
  • Benjamin W. Spiller
  • Brian E. Wadzinski

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Info

Original languageEnglish
Pages24207-24215
Number of pages9
JournalJournal of Biological Chemistry
Journal publication date13 Jul 2012
Volume287
Issue29
DOIs
StatePublished

Abstract

Multiple neurodegenerative disorders are linked to aberrant phosphorylation of microtubule-associated proteins (MAPs). Protein phosphatase 2A (PP2A) is the major MAP phosphatase; however, little is known about its regulation at microtubules. alpha 4 binds the PP2A catalytic subunit (PP2Ac) and the microtubule-associated E3 ubiquitin ligase MID1, and through unknown mechanisms can both reduce and enhance PP2Ac stability. We show MID1-dependent monoubiquitination of alpha 4 triggers calpain-mediated cleavage and switches alpha 4's activity from protective to destructive, resulting in increased Tau phosphorylation. This regulatory mechanism appears important in MAP-dependent pathologies as levels of cleaved alpha 4 are decreased in Opitz syndrome and increased in Alzheimer disease, disorders characterized by MAP hypophosphorylation and hyperphosphorylation, respectively. These findings indicate that regulated inter-domain cleavage controls the dual functions of alpha 4, and dysregulation of alpha 4 cleavage may contribute to Opitz syndrome and Alzheimer disease.

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