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Details on Person The reversible methylation of the PP2A C subunit is a highly...

Class:Id	Summation:8964124
_displayName	The reversible methylation of the PP2A C subunit is a highly...
_timestamp	2017-02-15 15:05:41
created	[InstanceEdit:8964123] Jupe, Steve, 2017-02-15
literatureReference	[LiteratureReference:8857630] A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain [LiteratureReference:8964075] PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail) [LiteratureReference:8856944] Structural mechanism of demethylation and inactivation of protein phosphatase 2A [LiteratureReference:8964117] A protein phosphatase methylesterase (PME-1) is one of several novel proteins stably associating with two inactive mutants of protein phosphatase 2A [LiteratureReference:8964091] The structural basis for tight control of PP2A methylation and function by LCMT-1 [LiteratureReference:8964120] Leucine Carboxyl Methyltransferase 1 (LCMT-1) Methylates Protein Phosphatase 4 (PP4) and Protein Phosphatase 6 (PP6) and Differentially Regulates the Stable Formation of Different PP4 Holoenzymes [LiteratureReference:8964093] Mechanisms of the scaffold subunit in facilitating protein phosphatase 2A methylation [LiteratureReference:8964071] Spatial control of protein phosphatase 2A (de)methylation [LiteratureReference:8964121] Selection of protein phosphatase 2A regulatory subunits is mediated by the C terminus of the catalytic Subunit [LiteratureReference:8857610] A new role for protein methylation: switching partners at the phosphatase ball [LiteratureReference:8857621] Carboxyl methylation of the phosphoprotein phosphatase 2A catalytic subunit promotes its functional association with regulatory subunits in vivo [LiteratureReference:8857625] Regulation of protein phosphatase 2A methylation by LCMT1 and PME-1 plays a critical role in differentiation of neuroblastoma cells [LiteratureReference:8857627] Protein phosphatase 2A catalytic subunit is methyl-esterified at its carboxyl terminus by a novel methyltransferase [LiteratureReference:8964078] Targeted disruption of the PME-1 gene causes loss of demethylated PP2A and perinatal lethality in mice [LiteratureReference:8964080] Differential methylation and altered conformation of cytoplasmic and nuclear forms of protein phosphatase 2A during cell cycle progression [LiteratureReference:8857618] Purification of porcine brain protein phosphatase 2A leucine carboxyl methyltransferase and cloning of the human homologue [LiteratureReference:8857601] Leucine carboxyl methyltransferase-1 is necessary for normal progression through mitosis in mammalian cells [LiteratureReference:8857611] An inactive protein phosphatase 2A population is associated with methylesterase and can be re-activated by the phosphotyrosyl phosphatase activator [LiteratureReference:8964113] Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies [LiteratureReference:8964107] Regulation of protein phosphatase 2A (PP2A) tumor suppressor function by PME-1 [LiteratureReference:8964088] Protein Phosphatase Methyl-Esterase PME-1 Protects Protein Phosphatase 2A from Ubiquitin/Proteasome Degradation
modified	[InstanceEdit:8964126] Jupe, Steve, 2017-02-15
text	The reversible methylation of the PP2A C subunit is a highly conserved and essential regulatory mechanism (Lee et al. 1996). Methylation of the carboxy-termius of PP2A C enhances the affinity of the PP2A core enzyme for some regulatory subunits (Xing et al. 2008). Changes in PP2A methylation appear to regulate formation of PP2A complexes and alter the specificity of PP2A phosphatase activity (Mumby 2001). Blockade of PP2A methylation in yeast causes a set of phenotypes that are consistent with decreased formation of PP2A holoenzymes (Wu et al. 2000). Reversible methylation of PP2A is catalyzed by two highly conserved enzymes, a 38 kDa leucine carboxyl methyltransferase (LCMT1) (De Baere et al. 1999, Lee & Stock 1993) and a 42 kDa methylesterase (PPME1) (Lee et al. 1996, Ogris et al. 1999). PP2A carboxy-methylation by LCMT1 requires an active PP2A conformation and is significantly facilitated by the PP2A scaffold (or A) subunit (Stanevich et al. 2011, Stanevich et al. 2014). LCMT1 also methylates the PP2A-like phosphatases PP4 and PP6 (Hwang et al. 2016). PPME1 catalyzes removal of the methyl group, thus reversing the activity of LCMT1 (Lee et al. 1996). Overexpression of yeast PPME caused phenotypes similar to those associated with loss of the methyltransferase gene (Wu et al. 2000). Methylation and demethylation are spatially separated within mammalian cells, as the majority of LCMT1 is cytoplasmic and PPME1 predominantly localizes in the nucleus (Longin et al. 2008). In mammalian cells, LCMT1 knockdown results in apoptotic cell death (Longin et al. 2007). In mice, LCMT1 or PPME1 knockout are lethal (Lee & Pallas 2007, Ortega-Gutiérrez et al. 2008). Methylation levels of PP2A change during the cell cycle, suggesting a critical role of methylation in cell-cycle regulation (Turowski et al. 1995, Lee & Pallas 2007). Regulation of PP2A methylation by LCMT1 and PPME1 plays a critical role in differentiation of neuroblastoma cells (Sontag et al. 2010). Decreased PP2A methylation in Alzheimer’s and Parkinson’s disease patients contributes to PP2A inactivation and increased phosphorylation of tau and alpha-synuclein (Sontag & Sontag 2014, Park et al. 2016). PPME1 may also inhibit PP2A by sequestration (Longin et al. 2004) and/or by evicting catalytic metal ions from the PP2A active site (Xing et al. 2008). As such, increased PPME1 expression suppresses PP2A tumor suppressive function and promotes oncogenic MAPK/ERK and AKT pathway activities in various cancer types (Kaur & Westermarck 2016). PPME1 may also protect PP2A from ubiquitin/proteasome degradation (Yabe et al. 2015).
(summation)	[Reaction:8856951] PP2A demethylation by PPME1 [Homo sapiens]
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