PPP2R5E

PPP2R5E (B56epsilon) is a regulatory subunit of protein phosphatase 2A (PP2A) that confers substrate specificity on the holoenzyme to control developmental signaling, cytoskeletal organization, and tumor cell fate (PMID:14522869, PMID:39284558). During vertebrate embryogenesis it acts as a positive regulator of multiple pathways: it is required for Wnt/beta-catenin signaling upstream of Dishevelled and downstream of the Wnt ligand, and it promotes eye induction through the IGF/PI3K/Akt pathway and eye field separation through the Hedgehog pathway (PMID:14522869, PMID:17074314). The subunit is alternatively translated into a full-length, nuclear-competent form bearing an N-terminal nuclear localization signal and a C-terminal nuclear export signal, and a shorter cytoplasmic isoform lacking the NLS; the cytoplasmic isoform is specifically required for Wnt signaling and midbrain-hindbrain boundary formation (PMID:19129191). Through PP2A phosphatase activity, PPP2R5E physically binds and stabilizes the microtubule crosslinking factor MTCL1 against proteasomal degradation, supporting proper microtubule organization (PMID:27521566). Holoenzyme assembly depends on PPP2R5E contacting the PP2A A and C subunits; the de novo Glu191Lys variant in a conserved motif weakens these contacts and is associated with a neurodevelopmental and myopathic phenotype (PMID:39284558). PPP2R5E functions as a tumor suppressor: it is a direct target of miR-23a and miR-19b, whose elevation suppresses PPP2R5E and drives proliferation, survival, and chemoresistance (PMID:24997345, PMID:37175484), whereas restoring PPP2R5E in glioblastoma induces nuclear ROS-driven genotoxic stress, senescence, and ferroptosis to sensitize cells to temozolomide (PMID:42203893).

1. 2003 High

   Established that a specific PP2A regulatory subunit positively gates Wnt signaling, defining where PP2A:B56epsilon acts within the pathway rather than treating PP2A as a generic phosphatase.

   Evidence Loss-of-function and epistasis in Xenopus embryos placing B56epsilon upstream of Dishevelled and downstream of Wnt ligand

   PMID:14522869

   Open questions at the time

   • Direct phosphatase substrate within the Wnt pathway not identified
   • Mechanism connecting PP2A activity to Dishevelled regulation unresolved
2. 2006 High

   Extended B56epsilon's developmental role beyond Wnt to IGF/PI3K/Akt and Hedgehog signaling, showing it is a multi-pathway node in eye development.

   Evidence Loss-of-function in Xenopus with epistasis using PI3K/Akt inhibitors and Hedgehog pathway components

   PMID:17074314

   Open questions at the time

   • Molecular substrates in PI3K/Akt and Hedgehog pathways not defined
   • Whether the same isoform mediates all three pathways unknown at this stage
3. 2009 High

   Resolved that distinct subcellular pools of B56epsilon carry distinct functions, showing alternative translation produces a cytoplasm-restricted isoform required specifically for Wnt signaling.

   Evidence Alternative translation mapping, NLS/NES mutagenesis, subcellular localization, and rescue in Xenopus

   PMID:19129191

   Open questions at the time

   • Regulation of isoform choice in mammalian tissues not characterized
   • Nuclear function of the full-length form not assigned a substrate
4. 2014 Medium

   Connected PPP2R5E to oncogenic miRNA regulation, establishing it as a growth-suppressive effector silenced by miR-23a in gastric cancer.

   Evidence Overexpression/knockdown with functional rescue in gastric cancer cells and xenografts

   PMID:24997345

   Open questions at the time

   • Phosphatase substrates mediating the anti-growth effect not identified
   • Direct binding of miR-23a to the PPP2R5E transcript not shown here
5. 2016 Medium

   Identified a non-signaling, cytoskeletal role: PPP2R5E-directed PP2A activity protects MTCL1 from proteasomal turnover to maintain microtubule organization.

   Evidence Mass spectrometry interactome, co-IP, siRNA, okadaic acid/MG132 rescue, and microtubule immunofluorescence

   PMID:27521566

   Open questions at the time

   • The phosphosite on MTCL1 dephosphorylated by PP2A not mapped
   • Single-lab interaction without reciprocal in vivo validation
6. 2023 Medium

   Generalized miRNA control of PPP2R5E to a second cancer type and linked it to PP2A enzymatic output, with miR-19b directly repressing PPP2R5E to drive chemoresistance.

   Evidence Luciferase reporter, PP2A activity assay, and knockdown phenotypes in colorectal cancer cells

   PMID:37175484

   Open questions at the time

   • Downstream PP2A substrates driving 5-FU resistance not defined
   • Single lab, in vitro only
7. 2024 Medium

   Provided a direct biochemical mechanism for human disease by showing a de novo variant disrupts PPP2R5E incorporation into the PP2A holoenzyme.

   Evidence Whole exome sequencing and biochemical interaction assays for A/C subunit binding in a patient

   PMID:39284558

   Open questions at the time

   • Single case; genotype-phenotype causality not established in a cohort
   • Downstream signaling consequence of holoenzyme loss not measured
8. 2026 High

   Demonstrated that restoring PPP2R5E actively reprograms tumor cell fate, inducing nuclear ROS, senescence, and ferroptosis to sensitize glioblastoma to temozolomide.

   Evidence miRNA screens, γH2AX foci, senescence/ferroptosis assays, FTY720 phenocopy, knockdown rescue, and orthotopic/syngeneic mouse models

   PMID:42203893

   Open questions at the time

   • Phosphatase substrate linking PPP2R5E to nuclear ROS generation unknown
   • Whether the nuclear full-length isoform specifically drives this effect untested
9. 2025 Low

   Raised the possibility that PPP2R5E abundance is set post-transcriptionally by the RNA exosome via EXOSC2 across stem and cancer cells.

   Evidence EXOSC2 perturbation with PPP2R5E monitoring in embryonic stem and cancer cells (preprint)

   Open questions at the time

   • Preprint with limited methodological detail; mechanism of regulation not described
   • Direct exosome targeting of the PPP2R5E transcript not demonstrated

• The specific phosphoprotein substrates dephosphorylated by PPP2R5E-containing PP2A across its Wnt, PI3K/Akt, Hedgehog, cytoskeletal, and tumor-suppressive roles remain unidentified.
• No direct PP2A:B56epsilon substrate mapped in any pathway
• Structural basis of substrate selection not resolved