Monoubiquitination Promotes Calpain Cleavage of the Protein Phosphatase 2A (PP2A) Regulatory Subunit alpha 4, Altering PP2A Stability and Microtubule-associated Protein Phosphorylation. / Watkins, Guy R.; Wang, Ning; Mazalouskas, Matthew D.; Gomez, Rey J.; Guthrie, Chris R.; Kraemer, Brian C.; Schweiger, Susann; Spiller, Benjamin W.; Wadzinski, Brian E.
In: Journal of Biological Chemistry, Vol. 287, No. 29, 13.07.2012, p. 24207-24215.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Monoubiquitination Promotes Calpain Cleavage of the Protein Phosphatase 2A (PP2A) Regulatory Subunit alpha 4, Altering PP2A Stability and Microtubule-associated Protein Phosphorylation
A1 - Watkins,Guy R.
A1 - Wang,Ning
A1 - Mazalouskas,Matthew D.
A1 - Gomez,Rey J.
A1 - Guthrie,Chris R.
A1 - Kraemer,Brian C.
A1 - Schweiger,Susann
A1 - Spiller,Benjamin W.
A1 - Wadzinski,Brian E.
AU - Watkins,Guy R.
AU - Wang,Ning
AU - Mazalouskas,Matthew D.
AU - Gomez,Rey J.
AU - Guthrie,Chris R.
AU - Kraemer,Brian C.
AU - Schweiger,Susann
AU - Spiller,Benjamin W.
AU - Wadzinski,Brian E.
PY - 2012/7/13
Y1 - 2012/7/13
N2 - <p>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.</p>
AB - <p>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.</p>
U2 - 10.1074/jbc.M112.368613
DO - 10.1074/jbc.M112.368613
M1 - Article
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 29
VL - 287
SP - 24207
EP - 24215
ER -