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Regulation of protein phosphatase 2A methylation by LCMT1 and PME‐1 plays a critical role in differentiation of neuroblastoma cells
Author(s) -
Sontag JeanMarie,
NunbhakdiCraig Viyada,
Mitterhuber Martina,
Ogris Egon,
Sontag Estelle
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.07049.x
Subject(s) - protein phosphatase 2 , methylation , protein subunit , phosphatase , neurite , biology , gene knockdown , cellular differentiation , microbiology and biotechnology , chemistry , biochemistry , phosphorylation , gene , in vitro
J. Neurochem. (2010) 115, 1455–1465. Abstract Neuritic alterations are a major feature of many neurodegenerative disorders. Methylation of protein phosphatase 2A (PP2A) catalytic C subunit by the leucine carboxyl methyltransferase (LCMT1), and demethylation by the protein phosphatase methylesterase 1, is a critical PP2A regulatory mechanism. It modulates the formation of PP2A holoenzymes containing the Bα subunit, which dephosphorylate key neuronal cytoskeletal proteins, including tau. Significantly, we have reported that LCMT1, methylated C and Bα expression levels are down‐regulated in Alzheimer disease‐affected brain regions. In this study, we show that enhanced expression of LCMT1 in cultured N2a neuroblastoma cells, which increases endogenous methylated C and Bα levels, induces changes in F‐actin organization. It promotes serum‐independent neuritogenesis and development of extended tau‐positive processes upon N2a cell differentiation. These stimulatory effects can be abrogated by LCMT1 knockdown and S ‐adenosylhomocysteine, an inhibitor of methylation reactions. Expression of protein phosphatase methylesterase 1 and the methylation‐site L309Δ C subunit mutant, which decrease intracellular methylated C and Bα levels, block N2a cell differentiation and LCMT1‐mediated neurite formation. Lastly, inducible and non‐inducible knockdown of Bα in N2a cells inhibit process outgrowth. Altogether, our results establish a novel mechanistic link between PP2A methylation and development of neurite‐like processes.