- Title
- Regulation of protein phosphatase 2A methylation by LCMT1 and PME-1 plays a critical role in differentiation of neuroblastoma cells
- Creator
- Sontag, Jean-Marie; Nunbhakdi-Craig, Viyada; Mitterhuber, Martina; Ogris, Egon; Sontag, Estelle
- Relation
- Journal of Neurochemistry Vol. 115, Issue 6, p. 1455-1465
- Publisher Link
- http://dx.doi.org/10.1111/j.1471-4159.2010.07049.x
- Publisher
- Wiley-Blackwell Publishing
- Resource Type
- journal article
- Date
- 2010
- Description
- 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 methylationsite L309Δ C subunit mutant, which decrease intracellular methylated C and Bα levels, block N2a cell differentiation and LCMT1-mediated neurite formation. Lastly, inducible and noninducible knockdown of Bα in N2a cells inhibit process outgrowth. Altogether, our results establish a novel mechanistic link between PP2A methylation and development of neuritelike processes.
- Subject
- differentiation; methylation; methylesterase; methyltransferase; protein phosphatase 2A
- Identifier
- uon:9584
- Identifier
- http://hdl.handle.net/1959.13/922549
- Identifier
- ISSN:0022-3042
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