p(HGNC:LCMT1)

Entity

Name

LCMT1

Namespace

hgnc

Namespace Version

20180906

Namespace URL

https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/hgnc-names.belns

Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases. PubMed:29281045

Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases. PubMed:29281045

PME-1 catalyzes removal of the methyl group, thus reversing the activity of LCMT1 PubMed:19277525

Like all methyltransferases,LCMT1 activity depends on the supply of the universal methyl donor, S-adenosylmethionine (SAM),and is inhibited by S-adenosylhomocysteine (SAH; Leulliot et al.,2004; Sontag et al.,2007). PubMed:24653673

Like all methyltransferases,LCMT1 activity depends on the supply of the universal methyl donor, S-adenosylmethionine (SAM),and is inhibited by S-adenosylhomocysteine (SAH; Leulliot et al.,2004; Sontag et al.,2007). PubMed:24653673

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a). PubMed:24653673

Notably, methylation of PP2A catalytic C subunit on the Leu- 309 residue by leucine carboxyl methyltransferase 1 (LCMT1) promotes the biogenesis and stabilization of PP2A/B
enzymes (20). We have shown that decreased LCMT1 activity and/or expression levels correlate with down-regulation of PP2A methylation and PP2A/B
expression levels and with concomitant accumulation of phospho-Tau in AD-affected brain regions (21), in cultured N2a neuroblastoma cells and in vivo PubMed:23943618

Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases. PubMed:29281045

The addition of a methyl group by LCMT1 at L309 enhances the binding affinity of the core dimer (A&C subunit) toward distinct regulatory subunits and provides specific activity to the holoenzyme [56]. PubMed:23454242

Reversible methylation of PP2A is catalyzed by two highly conserved and PP2A-specific enzymes, leucine carboxyl methyltransferase (LCMT1)[21,33] and PP2A methylesterase (PME-1)[17] (Figure 1). PubMed:19277525

Furthermore, formation of a stable complex between PP2A and PME-1 likely blocks LCMT1-catalyzed methylation. PubMed:19277525

PME-1 catalyzes removal of the methyl group, thus reversing the activity of LCMT1 PubMed:19277525

A portion of cellular PP2A stably associated with PME-1 and was catalytically inactive [80]; intriguingly, this inactive portion of PP2A could be re-activated by PP2A phosphatase activator (PTPA), but not by LCMT1, ruling out the possibility that inactivation was solely caused by demethylation PubMed:19277525

Proteinphosphatase 2A catalytic subunit is uniquely methylated on Leu-309 by the dedicated leucine carboxyl methyltransferase-1 (LCMT-1; Lee et al.,1996; De Baere et al.,1999). PubMed:24653673

Significantly, downregulation of LCMT1 expression leads to a significant decrease of PP2A methylation and concomitant loss of PP2A holoenzymes containing the regulatory Bα (or PPP2R2A) subunit (PP2A/Bα; Lee and Pallas,2007; Sontag et al.,2008; MacKay et al.,2013). PubMed:24653673

For example, PME-1 stabilizes a nuclear pool of inactive PP2A enzymes (Longin et al., 2008), while methylation by LCMT1 influences the amounts of PP2A enzymes bound to plasma membrane microdomains (Sontag et al.,2013). PubMed:24653673

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a). PubMed:24653673

Proteinphosphatase 2A catalytic subunit is uniquely methylated on Leu-309 by the dedicated leucine carboxyl methyltransferase-1 (LCMT-1; Lee et al.,1996; De Baere et al.,1999). PubMed:24653673

Significantly, downregulation of LCMT1 expression leads to a significant decrease of PP2A methylation and concomitant loss of PP2A holoenzymes containing the regulatory Bα (or PPP2R2A) subunit (PP2A/Bα; Lee and Pallas,2007; Sontag et al.,2008; MacKay et al.,2013). PubMed:24653673

For example, PME-1 stabilizes a nuclear pool of inactive PP2A enzymes (Longin et al., 2008), while methylation by LCMT1 influences the amounts of PP2A enzymes bound to plasma membrane microdomains (Sontag et al.,2013). PubMed:24653673

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a). PubMed:24653673

For example, PME-1 stabilizes a nuclear pool of inactive PP2A enzymes (Longin et al., 2008), while methylation by LCMT1 influences the amounts of PP2A enzymes bound to plasma membrane microdomains (Sontag et al.,2013). PubMed:24653673

Significantly, down-regulation of LCMT1 protein expression parallels the deficits in PP2A methylation observed in AD (Sontag et al.,2004a). PubMed:24653673