p(HGNC:PPP2CA, pmod(Me, Leu, 309))

Entity

Name

PPP2CA

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

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

Deletion of PTPA homologs in yeast, rrd1/rrd2, resulted in elevated levels of stable PP2A-PME-1 complexes, accompanied by decreased methylation PubMed:19277525

Interestingly, although PME-1 is activated by PP2A binding, the catalytic subunit of PP2A is inactivated in this process, not just through demethylation but also by loss of the catalytic metal ions PubMed:19277525

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

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

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

Recent evidence suggests a broader role for PME-1 than just being a demethylating enzyme for the catalytic subunit of PP2A PubMed:19277525

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

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

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

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 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

Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the catalytic subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits PubMed:19277525

Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the catalytic subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits PubMed:19277525

Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the catalytic subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits PubMed:19277525

Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the catalytic subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits PubMed:19277525

Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the catalytic subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits PubMed:19277525

Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the catalytic subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits PubMed:19277525

Interestingly, although PME-1 is activated by PP2A binding, the catalytic subunit of PP2A is inactivated in this process, not just through demethylation but also by loss of the catalytic metal ions PubMed:19277525

Methylation is thought to play a critical role in the biogenesis of PP2A holoenzymes. 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

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