Affinage

PPP2R1B

Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform · UniProt P30154

Length
601 aa
Mass
66.2 kDa
Annotated
2026-06-10
25 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPP2R1B (PP2A-Abeta) encodes the beta isoform of the PP2A scaffold A subunit, which assembles the PP2A heterotrimer and functions as a tumor suppressor that restrains oncogenic signaling (PMID:17540176). Its C-terminal HEAT-repeat region (amino acids 412–601, repeats 11–15) is required to bind the catalytic C subunit, and tumor-derived deletions and missense variants in this region abolish that interaction (PMID:9765152, PMID:14767517, PMID:40178903); an independent N-terminal interface selectively recruits regulatory subunits B56gamma, PR72, and PR48 but not B55alpha, B56alpha, or B56beta, and the cancer-associated G90D mutation disrupts B56gamma binding (PMID:16276521). The assembled Abeta holoenzyme dephosphorylates multiple signaling substrates: RalA at Ser183/Ser194 to inactivate its transforming function (PMID:17540176), AKT to limit XIAP-driven 5-FU resistance (PMID:26247730), AMPKalpha and AKT in hepatocytes (PMID:35320000), and ERK to suppress MAPK-driven EMT and liver metastasis (PMID:38429738); cancer-associated mutants that fail to form these complexes lose tumor-suppressive activity (PMID:17540176, PMID:40178903). PPP2R1B abundance is set transcriptionally by SP1/SP3 and RXRalpha/beta activators and Ets-1 repression at its promoter (PMID:22827437) and by hepatic IRF3 induction that amplifies PP2A activity to suppress glucose production (PMID:35320000), and its protein stability is controlled by CRL4A-DCAF6–mediated ubiquitination opposed by USP5 deubiquitination (PMID:33913576). Loss of Ppp2r1b in mice impairs meiotic recombination and causes spermatocyte meiotic arrest and male infertility (PMID:33913576).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 Medium

    Established which region of the scaffold subunit is needed to engage the catalytic core, defining the structural basis of holoenzyme assembly.

    Evidence Sequencing and functional binding assay on a tumor-derived deletion mutant

    PMID:9765152

    Open questions at the time
    • Did not map the interface at residue resolution
    • No functional consequence for downstream signaling tested
  2. 2004 Medium

    Localized the catalytic-subunit binding determinant to HEAT repeats 11–15 (aa 412–601), showing tumor mutations there break the A–C interaction.

    Evidence Reciprocal Co-IP of endogenous PP2A-Abeta and PP2A-C from mutation-bearing colorectal tumors

    PMID:14767517

    Open questions at the time
    • Did not assess effect on regulatory subunit recruitment
    • Phosphatase activity of mutant holoenzymes not measured
  3. 2006 Medium

    Defined an isoform-selective regulatory-subunit interface, distinguishing Abeta from Aalpha by its subset of B-subunit partners.

    Evidence In vitro binding assay with recombinant B subunits plus G90D mutagenesis

    PMID:16276521

    Open questions at the time
    • Selectivity not confirmed in cells
    • Functional output of B56gamma- vs PR72-containing holoenzymes unresolved
  4. 2007 High

    Identified RalA as a direct substrate and demonstrated that loss of Abeta enables transformation, establishing its tumor-suppressor mechanism.

    Evidence Co-IP, phosphorylation assay, and transformation rescue with WT/mutant Abeta plus shRNA knockdown

    PMID:17540176

    Open questions at the time
    • Did not establish Abeta-specific regulatory subunit for RalA dephosphorylation in vivo
    • Other transformation-relevant substrates not surveyed
  5. 2007 Low

    Linked the exon 2/3-encoded N-terminal region to full enzymatic function via splice variants seen in B-CLL.

    Evidence RT-PCR detection of aberrant splicing with PP2A activity assay

    PMID:17449237

    Open questions at the time
    • Association only; causal effect of splicing on activity not reconstituted
    • Single method, limited mechanistic detail
  6. 2012 Medium

    Mapped the transcriptional control of PPP2R1B, identifying activating and repressing factors at its proximal promoter.

    Evidence EMSA, promoter mutagenesis, luciferase reporters, and ChIP

    PMID:22827437

    Open questions at the time
    • Physiological contexts driving each factor not defined
    • No link to downstream phosphatase output
  7. 2015 Medium

    Connected PPP2R1B loss to AKT-driven chemoresistance, extending its substrate repertoire beyond RalA.

    Evidence siRNA knockdown/rescue, pAKT and XIAP western blots, apoptosis assays, and xenografts

    PMID:26247730

    Open questions at the time
    • Direct dephosphorylation of AKT by Abeta holoenzyme not biochemically shown
    • Regulatory subunit involved not identified
  8. 2021 Medium

    Revealed post-translational control of PPP2R1B abundance and a required in vivo role in male meiosis.

    Evidence Ppp2r1b knockout mice with meiotic phenotype plus identification of CRL4A-DCAF6 and USP5 as ubiquitin writer/eraser

    PMID:33913576

    Open questions at the time
    • Substrates relevant to meiotic recombination not identified
    • How ubiquitination is signaled is unknown
  9. 2021 Low

    Proposed translational control of PPP2R1B by eIF3a as a determinant of ERK activity and BRAF-inhibitor resistance.

    Evidence eIF3a overexpression with PPP2R1B/p-ERK western blots and drug sensitivity assays

    PMID:34512348

    Open questions at the time
    • Translational mechanism not directly reconstituted
    • Single method, single lab
  10. 2022 High

    Placed PPP2R1B in a hepatic metabolic axis, showing IRF3-driven induction amplifies PP2A to dephosphorylate AMPKalpha/AKT and suppress glucose production.

    Evidence Hepatocyte IRF3 knockout, cistrome integration, PP2A activity and phosphorylation assays, in vivo ASO suppression in obese mice

    PMID:35320000

    Open questions at the time
    • Direct biochemical demonstration of Abeta holoenzyme acting on AMPKalpha not isolated from total PP2A
    • Regulatory subunit mediating metabolic substrates unidentified
  11. 2024 Medium

    Identified ERK as a direct substrate, linking PPP2R1B to suppression of MAPK-driven metastasis.

    Evidence Co-IP with p-ERK, LC-MS/MS substrate ID, EMT marker blots, invasion assays, and in vivo liver metastasis model

    PMID:38429738

    Open questions at the time
    • Dephosphorylation site on ERK not mapped
    • Holoenzyme composition for ERK targeting not defined
  12. 2025 Medium

    Showed germline variants impair PP2A function through two distinct routes—loss of catalytic binding and accelerated protein degradation.

    Evidence Protein turnover, catalytic subunit binding, and phosphatase activity assays on R233C and truncating variants

    PMID:40178903

    Open questions at the time
    • Associated human phenotype not mechanistically connected to a specific substrate
    • In vivo consequences of these germline variants not modeled

Open questions

Synthesis pass · forward-looking unresolved questions
  • Which regulatory B subunit pairs with Abeta to direct each substrate (RalA, AKT, AMPKalpha, ERK) in a given tissue context remains unresolved.
  • No reconstituted holoenzyme assigned to specific substrates
  • Tissue-specific subunit usage undefined
  • Structural basis of substrate selectivity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0005198 structural molecule activity 3 GO:0098772 molecular function regulator activity 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-1430728 Metabolism 1 R-HSA-1474165 Reproduction 1 R-HSA-392499 Metabolism of proteins 1
Partners
AKT1DCAF6MAPK1PPP2R3APPP2R5CRALAUSP5
Complex memberships
PP2A holoenzyme

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 A truncated PP2A-Abeta (PPP2R1B) protein generated by a deletion mutation was unable to bind to the catalytic (C) subunit of the PP2A holoenzyme, establishing that the C-terminal region of PPP2R1B is required for catalytic subunit interaction. Sequencing of tumor-derived deletion mutant; functional binding assay showing loss of catalytic subunit interaction Science Medium 9765152
2004 Missense mutations and deletions within amino acids 412–601 of PPP2R1B (the PP2A-C binding region, encompassing HEAT repeats 11–15) inhibit co-immunoprecipitation of PP2A-Abeta and PP2A-C proteins, demonstrating that this domain mediates catalytic subunit binding. Co-immunoprecipitation of PP2A-Abeta and PP2A-C from colorectal cancer tissues harboring PPP2R1B mutations Oncology reports Medium 14767517
2006 Wild-type PP2A-Abeta (PPP2R1B) binds B56gamma (PPP2R5C), PR72 (PPP2R3A), and PR48 regulatory subunits but not B55alpha (PPP2R2A), B56alpha (PPP2R5A), or B56beta (PPP2R5B) in an in vitro binding assay. The cancer-associated G90D mutation inhibits interaction with B56gamma but does not affect binding to PR72, identifying an isoform-selective regulatory subunit interface. In vitro binding assay with recombinant regulatory subunits; site-directed mutagenesis (G90D) Genes, chromosomes & cancer Medium 16276521
2007 PP2A-Abeta (PPP2R1B) forms a complex with the small GTPase RalA and dephosphorylates RalA at Ser183 and Ser194, inactivating RalA and abolishing its transforming function. Cancer-associated Abeta mutants fail to form this complex, and suppression of PP2A Abeta permits immortalized human cells to achieve tumorigenic transformation. Co-immunoprecipitation (PP2A-Abeta/RalA complex), phosphorylation assay, cell transformation assays with wild-type and mutant Abeta re-expression, shRNA knockdown Cell High 17540176
2015 PPP2R1B negatively regulates AKT activation; knockdown of PPP2R1B increases AKT phosphorylation, leading to elevated XIAP expression and enhanced 5-FU resistance, while rescue of PPP2R1B expression decreases AKT phosphorylation and XIAP levels and re-sensitizes colon cancer cells to 5-FU-induced apoptosis. siRNA knockdown and rescue overexpression of PPP2R1B; western blotting for pAKT and XIAP; cell viability and apoptosis assays; xenograft mouse model Cell death & disease Medium 26247730
2007 Alternative splicing of PPP2R1B (skipping of exons 2/3 or 3) in B-CLL was associated with reduced PP2A phosphatase activity, indicating that the exon 2/3-encoded region is required for full enzymatic function of the PP2A holoenzyme. RT-PCR detection of aberrant splicing; PP2A activity assay European journal of cancer Low 17449237
2012 The proximal promoter of the PP2A-Abeta (PPP2R1B) gene contains functional binding sites for Ets-1 (negative regulator), SP1/SP3 (positive regulators), and RXRalpha/beta (positive regulators), as demonstrated by gel mobility shift assays, in vitro mutagenesis, luciferase reporter assays, and chromatin immunoprecipitation. Gel mobility shift assay, in vitro mutagenesis, luciferase reporter gene assay, ChIP Current molecular medicine Medium 22827437
2021 Homozygous deletion of Ppp2r1b in mice impairs meiotic recombination and causes meiotic arrest in spermatocytes, resulting in male infertility. PPP2R1B protein stability is regulated by ubiquitination: E3 ligase CRL4A-DCAF6 promotes polyubiquitination and degradation of PPP2R1B, while ubiquitin-specific protease 5 (USP5) counteracts this by deubiquitination. Homozygous mouse knockout (phenotype: meiotic arrest, infertility); identification of CRL4A-DCAF6 as E3 ligase and USP5 as deubiquitinase via functional assays FASEB journal Medium 33913576
2022 Hepatic IRF3 directly transcriptionally induces Ppp2r1b expression; IRF3-mediated induction of Ppp2r1b amplifies PP2A activity, leading to dephosphorylation of AMPKalpha and AKT, thereby suppressing hepatic glucose production and contributing to dysglycemia in obesity. Hepatocyte-specific IRF3 knockout mice; integration of IRF3-dependent transcriptome and cistrome (ChIP-seq); PP2A activity assay; phosphorylation assays for AMPKalpha and AKT; antisense oligonucleotide suppression of hepatic Irf3 in obese mice Science translational medicine High 35320000
2024 PPP2R1B co-immunoprecipitates with phospho-ERK (p-ERK) in colorectal cancer cells, and PPP2R1B expression negatively correlates with p-ERK levels; PPP2R1B induces dephosphorylation of ERK, inhibiting the MAPK/ERK signaling pathway and suppressing EMT-mediated liver metastasis. Co-immunoprecipitation (PPP2R1B with p-ERK); LC-MS/MS substrate identification; western blotting for p-ERK and EMT markers; wound healing/invasion assays; in vivo liver metastasis model (spleen injection) Cancer cell international Medium 38429738
2025 Germline missense variant R233C in PPP2R1B disrupts binding of PP2A catalytic subunit to the scaffold, resulting in loss of phosphatase activity. Additionally, germline loss-of-function truncating variants produce rapidly degraded protein, establishing that PPP2R1B protein stability and catalytic subunit binding are both required for PP2A phosphatase function. Functional characterization of mutant Abeta overexpression (protein turnover assay); catalytic subunit binding assay; phosphatase activity assay JCI insight Medium 40178903
2021 eIF3a controls ERK activity by regulating PPP2R1B expression via a translational mechanism; downregulation of eIF3a reduces PPP2R1B protein levels, thereby increasing p-ERK and conferring resistance to vemurafenib (BRAF inhibitor) in melanoma cells. Overexpression of eIF3a in resistant cells; western blotting for PPP2R1B and p-ERK; cell sensitivity assays Frontiers in pharmacology Low 34512348

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Alterations of the PPP2R1B gene in human lung and colon cancer. Science (New York, N.Y.) 340 9765152
2000 Low frequency of alterations of the alpha (PPP2R1A) and beta (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms. Oncogene 188 10713707
2007 The tumor suppressor PP2A Abeta regulates the RalA GTPase. Cell 171 17540176
2015 MicroRNA-587 antagonizes 5-FU-induced apoptosis and confers drug resistance by regulating PPP2R1B expression in colorectal cancer. Cell death & disease 80 26247730
2000 Alterations of the PPP2R1B gene located at 11q23 in human colorectal cancers. Gut 78 10896920
2007 Analysis of 11q22-q23 deletion target genes in B-cell chronic lymphocytic leukaemia: evidence for a pathogenic role of NPAT, CUL5, and PPP2R1B. European journal of cancer (Oxford, England : 1990) 60 17449237
2004 PPP2R1B gene alterations inhibit interaction of PP2A-Abeta and PP2A-C proteins in colorectal cancers. Oncology reports 47 14767517
2020 Exosomal miR-200c suppresses chemoresistance of docetaxel in tongue squamous cell carcinoma by suppressing TUBB3 and PPP2R1B. Aging 41 32310826
2000 Identification of a 6-cM minimal deletion at 11q23.1-23.2 and exclusion of PPP2R1B gene as a deletion target in cervical cancer. Cancer research 37 11118052
2006 The glycine 90 to aspartate alteration in the Abeta subunit of PP2A (PPP2R1B) associates with breast cancer and causes a deficit in protein function. Genes, chromosomes & cancer 36 16276521
2022 Hepatic IRF3 fuels dysglycemia in obesity through direct regulation of Ppp2r1b. Science translational medicine 34 35320000
2007 Alterations of tumour suppressor gene PPP2R1B in hepatocellular carcinoma. Cancer letters 24 17324501
1999 Absence of PPP2R1B gene alterations in primary ovarian cancers. Oncogene 19 10597236
2022 LncRNA-IQCH-AS1 sensitizes thyroid cancer cells to doxorubicin via modulating the miR-196a-5p/PPP2R1B signalling pathway. Journal of chemotherapy (Florence, Italy) 16 35972306
2021 PPP2R1B is modulated by ubiquitination and is essential for spermatogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 33913576
2001 PPP2R1B gene in chronic lymphocytic leukemias and mantle cell lymphomas. Leukemia & lymphoma 16 11342371
2012 The PP2A-Aβ gene is regulated by multiple transcriptional factors including Ets-1, SP1/SP3, and RXRα/β. Current molecular medicine 14 22827437
2024 PPP2R1B abolishes colorectal cancer liver metastasis and sensitizes Oxaliplatin by inhibiting MAPK/ERK signaling pathway. Cancer cell international 11 38429738
2007 Mutation analysis of the tumor suppressor gene PPP2R1B in human cervical cancer. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 10 17343570
1999 Somatic mutations of the PPP2R1B candidate tumor suppressor gene at chromosome 11q23 are infrequent in ovarian carcinomas. Neoplasia (New York, N.Y.) 10 10935485
2023 Lnc-PPP2R1B Mediates the Alternative Splicing of PPP2R1B by Interacting and Stabilizing HNRNPLL and Promotes Osteogenesis of MSCs. Stem cell reviews and reports 8 37243830
2002 Alterations in the suppressor gene PPP2R1B in parathyroid hyperplasias and adenomas. Cancer genetics and cytogenetics 7 11996789
2013 Infrequent mutations of the PPP2R1A and PPP2R1B genes in patients with ovarian cancer. Molecular medicine reports 6 23588898
2021 The Downregulation of eIF3a Contributes to Vemurafenib Resistance in Melanoma by Activating ERK via PPP2R1B. Frontiers in pharmacology 5 34512348
2025 Germline mutations in PPP2R1B in patients with a personal and family history of cancer. JCI insight 2 40178903

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