PPP2R2D

PPP2R2D encodes the B55delta regulatory subunit that directs the PP2A serine/threonine phosphatase toward CDK phosphosites during cell-cycle and meiotic control (PMID:19793917, PMID:33758202). During mitotic entry, PP2A-B55delta opposes Cdk1-driven phosphorylation and is itself inactivated downstream of Greatwall kinase, such that removing PP2A-B55delta activity rescues M-phase entry in Greatwall-depleted extracts (PMID:19793917). In meiosis, PP2A-B55delta acts on two distinct Arpp19 sites: it dephosphorylates Arpp19-S109 (the PKA site) to release prophase arrest upon the progesterone-induced fall in PKA activity, while being inhibited by Greatwall-phosphorylated Arpp19-S67 to permit Cdk1 activation at M-phase entry (PMID:33758202). This TORC1–Greatwall–PP2A-B55delta module is conserved to yeast, where it governs fermentation rate (PMID:30341081). Beyond the cell cycle, PPP2R2D dephosphorylates and inactivates AMPKalpha; hepatic AhR transcriptionally upregulates Ppp2r2d to drive this axis, inhibiting autophagy and causing mitochondrial dysfunction in alcohol-induced steatosis (PMID:36241614). In T cells, PPP2R2D restrains immune activation by maintaining closed chromatin at the IL-2 locus and at immune-checkpoint/exhaustion loci, suppressing IL-2 and pCREB and limiting Treg expansion (PMID:32897879, PMID:35831019). Its expression is tuned post-transcriptionally by miRNAs in cancer and disease contexts (PMID:27074866, PMID:38442987).

1. 2009 High

   Placed PP2A-B55delta in the mitotic-entry pathway as the CDK-phosphosite phosphatase inactivated downstream of Greatwall kinase, explaining how M-phase phosphorylations are stabilized.

   Evidence Xenopus egg extract immunodepletion and epistasis rescue of Gwl and PP2A-B55delta

   PMID:19793917

   Open questions at the time

   • Mechanism by which Greatwall output inactivates the B55delta holoenzyme not resolved at this step
   • Specific CDK substrates dephosphorylated by B55delta not enumerated
2. 2021 High

   Identified PP2A-B55delta as the Arpp19-S109 (PKA-site) phosphatase, showing it integrates PKA and Greatwall inputs through two distinct Arpp19 sites to control meiotic resumption.

   Evidence Xenopus oocyte meiosis assays with site-specific Arpp19 phosphorylation biochemistry and PKA/Greatwall epistasis

   PMID:33758202

   Open questions at the time

   • Structural basis for dual-site recognition of Arpp19 unresolved
   • Whether the same holoenzyme acts on both sites simultaneously in vivo not established
3. 2018 Medium

   Demonstrated conservation of the TORC1–Greatwall–PP2A-B55delta module by linking it to metabolic (fermentation) control in yeast, extending its role beyond animal cell-cycle regulation.

   Evidence S. cerevisiae genetics with CDC55 deletion and fermentation assays, confirmed in S. pombe

   PMID:30341081

   Open questions at the time

   • Molecular substrate linking B55delta to glycolytic control not identified
   • Relevance to mammalian metabolism not tested here
4. 2016 Medium

   Connected PPP2R2D-mediated CDK1 counteraction to chemosensitivity, and showed its expression is set post-transcriptionally by miR-133b.

   Evidence Luciferase 3'UTR reporter for miR-133b, knockdown/overexpression cell lines, cisplatin cell-cycle and in vivo tumorigenicity assays in hepatocellular carcinoma

   PMID:27074866

   Open questions at the time

   • Direct CDK1 dephosphorylation by B55delta not reconstituted in this context
   • Single cancer type
5. 2020 Medium

   Established an immunoregulatory role: PPP2R2D restrains IL-2 production by keeping the IL-2 locus and pCREB low, linking the phosphatase subunit to T-cell tolerance.

   Evidence T cell-specific conditional KO (LckCre), chromatin accessibility, IL-2 and pCREB measurement, Treg suppression and TLR7 autoimmunity models

   PMID:32897879

   Open questions at the time

   • Direct substrate at the IL-2 locus not biochemically defined
   • Single lab, no reconstitution
6. 2022 Medium

   Defined a hepatic AhR→PPP2R2D→AMPKalpha axis, showing PPP2R2D dephosphorylates AMPKalpha to inhibit autophagy and drive alcohol-induced steatosis.

   Evidence Alcohol-fed mouse model, hepatocyte-specific AhR KO, PPP2R2D gain/loss, AMPKalpha phosphorylation assays and lipidomics

   PMID:36241614

   Open questions at the time

   • Direct PP2A-B55delta dephosphorylation of AMPKalpha not reconstituted in vitro
   • Single lab
7. 2022 Medium

   Extended the T-cell role to checkpoint and exhaustion control, showing PPP2R2D loss opens chromatin at exhaustion loci and expands intratumoral Tregs.

   Evidence T cell-specific conditional KO, melanoma xenograft, chromatin accessibility at exhaustion loci, adoptive transfer, flow cytometry

   PMID:35831019

   Open questions at the time

   • Mechanistic link between phosphatase activity and chromatin state at checkpoint loci undefined
   • Direct substrate unknown
8. 2024 Low

   Reinforced the PPP2R2D–AMPKalpha link in renal epithelium and added miR-5010-5p as a second post-transcriptional regulator tuning the axis under high glucose.

   Evidence Dual-luciferase reporter, miRNA mimic transfection, AMPKalpha and NF-kappaB phosphorylation western blots, cytokine measurement

   PMID:38442987

   Open questions at the time

   • Indirect evidence that PPP2R2D dephosphorylates AMPKalpha — no direct biochemistry
   • Single lab

• The molecular determinants of B55delta substrate selection across its cell-cycle (CDK/Arpp19) and metabolic/immune (AMPKalpha, chromatin) roles remain unresolved.
• No structural model of how B55delta recruits distinct substrates
• Direct reconstitution of AMPKalpha dephosphorylation lacking
• Mechanism connecting phosphatase activity to chromatin accessibility at immune loci unknown