Altered phosphorylation of cytoskeletal proteins in mutant protein phosphatase 2A transgenic mice.
Protein phosphatase 2A (PP2A) is a family of heterotrimeric enzymes with diverse functions under physiologic and pathologic conditions such as Alzheimer's disease. All PP2A holoenzymes have in common a catalytic subunit C and a structural scaffolding subunit A. These core subunits assemble with various regulatory B subunits to form heterotrimers with distinct functions in the cell. Substrate specificity of PP2A in vitro is determined by regulatory subunits with leucine 309 of the catalytic subunit C playing a crucial role in the recruitment of regulatory subunits into the complex. Here we expressed a mutant form of Calpha, L309A, in brain and Harderian (lacrimal) gland of transgenic mice. We found an altered recruitment of regulatory subunits into the complex, demonstrating a role for the carboxyterminal leucine of Calpha in regulating holoenzyme assembly in vivo. This was associated with an increased phosphorylation of tau in brain and an impaired dephosphorylation of vimentin demonstrating that both cytoskeletal proteins are in vivo substrates of distinct PP2A holoenzyme complexes.
Division of Psychiatry Research, University of Zürich, 8008 Zürich, Switzerland.
Andreas
A
Schild
Lars M
LM
Ittner
Jürgen
J
Götz
D000818:Animals; D001921:Brain / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D006243:Harderian Gland / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D021122:Protein Subunits / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D021122:Protein Subunits; D014746:Vimentin; D016875:tau Proteins; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D007930:Leucine