PPP4R1 encodes PP4 regulatory subunit 1, a HEAT/ARM-repeat scaffolding subunit of the serine/threonine protein phosphatase 4 holoenzyme. PPP4R1 binds the catalytic subunit PPP4C to form a PP4C-PPP4R1 complex that directs phosphatase activity toward selected targets. The best-supported PPP4R1-specific process is dampening canonical NF-kappaB signaling through PP4-dependent regulation of TRAF2/TRAF6 and the IKK/NEMO axis. Broader PP4 roles in DNA damage response are well established for PP4 complexes, but the strongest DDR substrate evidence is not specific to the PPP4R1-containing holoenzyme.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005737
cytoplasm
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Cytoplasmic localization is consistent with PPP4R1 acting in PP4 signaling complexes, although precise compartment-specific localization is not strongly resolved.
Reason: Falcon research notes sparse direct localization evidence but supports cytoplasm as a reasonable broad location for PPP4R1-containing PP4 signaling complexes.
Supporting Evidence:
file:human/PPP4R1/PPP4R1-deep-research-falcon.md
Direct localization data for human PPP4R1 are comparatively sparse; available evidence indicates PP4 regulatory subunits help determine holoenzyme subcellular localization.
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GO:0019888
protein phosphatase regulator activity
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: PPP4R1 is a non-catalytic regulatory/scaffolding subunit of PP4 that binds PPP4C and helps define holoenzyme substrate targeting.
Reason: This is the most appropriate molecular-function annotation for PPP4R1: it regulates a protein phosphatase rather than catalyzing dephosphorylation itself.
Supporting Evidence:
file:human/PPP4R1/PPP4R1-deep-research-falcon.md
PPP4R1 is a regulatory/scaffolding subunit of the serine/threonine phosphatase PP4.
PMID:10026142
The PP4R1 cDNA clone engineered with an N-terminal Myc tag was expressed in COS M6 cells and PP4C co-immunoprecipitated with Myc-tagged PP4R1.
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GO:0005515
protein binding
|
IPI
PMID:16085932 A novel, evolutionarily conserved protein phosphatase comple... |
MODIFY |
Summary: This IPI annotation captures PPP4R1 binding to PPP4C, but generic protein binding is less informative than the known PP4 regulatory subunit activity.
Reason: PPP4R1's PPP4C interaction should be represented as protein phosphatase regulator activity rather than the uninformative protein binding term.
Proposed replacements:
protein phosphatase regulator activity
Supporting Evidence:
PMID:16085932
Using a combination of tandem affinity purification tagging and mass spectrometry, we characterized a novel, evolutionarily conserved protein phosphatase 4 (PP4)-containing complex.
file:human/PPP4R1/PPP4R1-deep-research-falcon.md
A foundational proteomics analysis of human PP4 complexes reported mutually exclusive PP4C assemblies that include a binary PP4C-PPP4R1 complex.
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|
GO:0005515
protein binding
|
IPI
PMID:17353931 Large-scale mapping of human protein-protein interactions by... |
MODIFY |
Summary: This high-throughput interactome annotation reports PPP4C binding, but the biologically meaningful interpretation is PPP4 regulator/scaffold activity.
Reason: Replace generic protein binding with the more informative protein phosphatase regulator activity term supported by the PPP4R1-PPP4C complex literature.
Proposed replacements:
protein phosphatase regulator activity
Supporting Evidence:
PMID:17353931
Mapping protein-protein interactions is an invaluable tool for understanding protein function.
file:human/PPP4R1/PPP4R1-deep-research-falcon.md
PPP4R1 defines a specific PP4 holoenzyme class rather than being a generic interactor.
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GO:0005515
protein binding
|
IPI
PMID:18614045 A PP4-phosphatase complex dephosphorylates gamma-H2AX genera... |
REMOVE |
Summary: This interaction entry concerns PP4 complex biology, but the cited gamma-H2AX paper primarily supports a PP4R2/PP4R3-containing complex rather than a PPP4R1-specific DDR role.
Reason: The local publication text supports a PP4C/PP4R2/PP4R3beta gamma-H2AX phosphatase complex rather than a PPP4R1-containing complex, so this PMID should not support a PPP4R1 functional annotation.
Supporting Evidence:
PMID:18614045
Here we describe a three-protein PP4 phosphatase complex in mammalian cells, containing PP4C, PP4R2, and PP4R3beta, that specifically dephosphorylates ATR-mediated gamma-H2AX.
file:human/PPP4R1/PPP4R1-deep-research-falcon.md
DDR substrate assignments are most often attributed to PP4 complexes broadly or to PP4R2/PP4R3-containing assemblies rather than being conclusively mapped to the PPP4R1-containing heterodimer.
|
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GO:0005515
protein binding
|
IPI
PMID:18715871 PP4R4/KIAA1622 forms a novel stable cytosolic complex with p... |
MODIFY |
Summary: This PP4 regulatory-subunit study distinguishes PP4R4 from PP4R1 complexes; the PPP4R1-PPP4C interaction should still be represented by the regulator activity term rather than protein binding.
Reason: Generic protein binding does not capture the role of PPP4R1 as a PP4 regulatory/scaffolding subunit.
Proposed replacements:
protein phosphatase regulator activity
Supporting Evidence:
PMID:18715871
PP4c interacts with regulatory proteins, which specify substrate targeting and intracellular localization.
file:human/PPP4R1/PPP4R1-deep-research-falcon.md
PP4 holoenzymes are members of the PP2A-like phosphoprotein phosphatase family, in which a catalytic subunit associates with regulatory proteins that shape substrate selection, localization, and signaling outputs.
|
|
GO:0005515
protein binding
|
IPI
PMID:26496610 A human interactome in three quantitative dimensions organiz... |
MODIFY |
Summary: This quantitative interactome annotation is compatible with PPP4R1 interacting with PPP4C, but protein binding is not the best GO representation of the established function.
Reason: Replace with protein phosphatase regulator activity to capture the regulatory-subunit role.
Proposed replacements:
protein phosphatase regulator activity
Supporting Evidence:
PMID:26496610
Using quantitative proteomics, we detect specific interactions, estimate interaction stoichiometries, and measure cellular abundances of interacting proteins.
file:human/PPP4R1/PPP4R1-deep-research-falcon.md
PPP4R1 is a repeat-rich scaffold protein with PP2A-A-like HEAT repeats, consistent with a regulatory subunit that presents binding surfaces for catalytic subunit and substrates/adaptors.
|
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GO:0005515
protein binding
|
IPI
PMID:27880917 Phenotypic and Interaction Profiling of the Human Phosphatas... |
MODIFY |
Summary: The phosphatase interactome result is consistent with PP4 complex membership, but the actionable GO annotation should be PPP4R1's phosphatase regulator role.
Reason: PPP4R1 is not merely a binding protein; it is the regulatory/scaffolding subunit of a PP4 holoenzyme.
Proposed replacements:
protein phosphatase regulator activity
Supporting Evidence:
PMID:27880917
We identified 1,335 high-confidence interactions (1,104 previously unreported), implicating these phosphatases in the regulation of a variety of cellular processes.
file:human/PPP4R1/PPP4R1-deep-research-falcon.md
PPP4R1's functional contribution is to form a PPP4C-PPP4R1 holoenzyme that can direct PP4 dephosphorylation activity toward specific signaling modules.
|
|
GO:0005515
protein binding
|
IPI
PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... |
MODIFY |
Summary: This proteome-scale interaction supports PPP4C association but is still too generic as a protein binding annotation.
Reason: The PPP4C interaction should be curated as protein phosphatase regulator activity in the PP4 complex context.
Proposed replacements:
protein phosphatase regulator activity
Supporting Evidence:
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
file:human/PPP4R1/PPP4R1-deep-research-falcon.md
PPP4R1 is a regulatory/scaffolding subunit of the serine/threonine phosphatase PP4.
|
|
GO:0005515
protein binding
|
IPI
PMID:40205054 Multimodal cell maps as a foundation for structural and func... |
MODIFY |
Summary: This recent multimodal cell-map interaction should not leave PPP4R1 with a generic protein binding function when the PP4 regulatory role is known.
Reason: Use protein phosphatase regulator activity to capture the functional consequence of PPP4R1 binding PPP4C.
Proposed replacements:
protein phosphatase regulator activity
Supporting Evidence:
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
file:human/PPP4R1/PPP4R1-deep-research-falcon.md
PPP4R1 defines a specific PP4 holoenzyme class rather than being a generic interactor.
|
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GO:0004721
phosphoprotein phosphatase activity
|
ISS
GO_REF:0000024 |
MODIFY |
Summary: This annotation is acceptable only with the contributes_to qualifier, but the broad phosphoprotein phosphatase term should be replaced with the more specific protein serine/threonine phosphatase activity term.
Reason: PPP4R1 forms a complex with serine/threonine phosphatase PPP4C, so contributes_to protein serine/threonine phosphatase activity is defensible, while enables would be misleading.
Proposed replacements:
protein serine/threonine phosphatase activity
Supporting Evidence:
PMID:10026142
These data indicate that one form of PP4 is similar to the core complex of PP2A in that it consists of a catalytic subunit and a PP2AA-like structural subunit.
file:human/PPP4R1/PPP4R1-deep-research-falcon.md
PPP4R1 itself is not an enzyme; the catalytic activity resides in PPP4C.
|
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GO:0006468
protein phosphorylation
|
ISS
GO_REF:0000024 |
REMOVE |
Summary: This is an opposite-reaction misannotation. PPP4R1 is a regulatory subunit of protein phosphatase 4, which removes phosphate groups from phosphoproteins rather than phosphorylating them.
Reason: PPP4R1 is not a kinase, and the supported PP4 biology concerns dephosphorylation or regulation of phosphatase activity, not protein phosphorylation.
Supporting Evidence:
file:human/PPP4R1/PPP4R1-deep-research-falcon.md
PPP4R1 itself is not an enzyme; the catalytic activity resides in PPP4C, which hydrolyzes phosphate esters on phosphoserine/ phosphothreonine residues.
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GO:0030289
protein phosphatase 4 complex
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: PPP4R1 is a component of the PP4C-PPP4R1 protein phosphatase 4 holoenzyme.
Reason: Multiple sources support PPP4R1 as a stable regulatory subunit in a PP4C-PPP4R1 complex.
Supporting Evidence:
PMID:10026142
The final product contained two major proteins: the PP4 catalytic subunit plus a protein that migrated as a doublet of 120-125 kDa.
file:human/PPP4R1/PPP4R1-deep-research-falcon.md
In mammals, PP4 can form a heterodimer with PPP4R1 (PP4C/PP4R1) and other distinct assemblies with other regulatory subunits.
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GO:0007165
signal transduction
|
NAS
PMID:10026142 Purification and identification of a novel subunit of protei... |
MODIFY |
Summary: The broad signal transduction annotation should be replaced by the specific PPP4R1-supported process: negative regulation of canonical NF-kappaB signal transduction.
Reason: PPP4R1-specific pathway evidence supports inhibition of canonical NF-kappaB signaling through TRAF2/TRAF6 and IKK/NEMO, not generic signal transduction.
Proposed replacements:
negative regulation of canonical NF-kappaB signal transduction
Supporting Evidence:
PMID:25134449
Exogenous expression of PP4R1 inhibited NF-kappaB activation by TRAF2, TRAF6, TNF and the Epstein-Barr virus oncoprotein LMP1.
PMID:28445980
Formation of a complex with PP4R1 and PP4c is required to bridge MCPyV tAg to the NEMO adaptor protein, allowing deactivation of the NF-kB pathway.
file:human/PPP4R1/PPP4R1-deep-research-falcon.md
The best-supported direct biological function of this holoenzyme is negative regulation of inflammatory NF-kappaB signaling.
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GO:0019888
protein phosphatase regulator activity
|
NAS
PMID:10026142 Purification and identification of a novel subunit of protei... |
ACCEPT |
Summary: The founding biochemical study supports PPP4R1 as a PP4 regulatory subunit that binds PPP4C.
Reason: This is a direct, specific annotation for PPP4R1's core molecular function.
Supporting Evidence:
PMID:10026142
Amino acid sequence information of several peptides derived from the 105 kDa protein was utilized to isolate a human cDNA clone.
file:human/PPP4R1/PPP4R1-deep-research-falcon.md
PPP4R1 encodes a HEAT-repeat scaffold regulatory subunit that forms a PP4C-PPP4R1 holoenzyme.
|
Q: Which endogenous human substrates are specifically directed by the PPP4R1-containing PP4 holoenzyme rather than by PP4R2/PP4R3 or PP4R4 complexes?
Q: In which cell types is PPP4R1-dependent negative regulation of canonical NF-kappaB signaling physiologically dominant?
Q: Does PPP4R1 have a reproducible nuclear function through HDAC3 regulation, or is its best-supported role cytoplasmic signaling through PP4C?
Experiment: Endogenous PPP4R1 and PPP4C co-immunoprecipitation after TNF stimulation, followed by phosphoproteomics in PPP4R1 knockout and rescue cells.
Hypothesis: PPP4R1 directs PP4C toward a limited set of NF-kappaB pathway substrates, including TRAF2/TRAF6 and IKK/NEMO-associated targets.
Type: phosphoproteomics
Experiment: Compare wild-type PPP4R1 rescue with PPP4C-binding-defective PPP4R1 mutants in NF-kappaB reporter, IL8/CCL20 secretion, and IKK phosphorylation assays.
Hypothesis: PPP4R1-dependent PP4C recruitment is required for negative regulation of canonical NF-kappaB signaling.
Type: cell-based pathway assay
Experiment: Subcellular fractionation and live-cell imaging of endogenously tagged PPP4R1 under basal, TNF-stimulated, and DNA replication stress conditions.
Hypothesis: PPP4R1 is primarily cytoplasmic during NF-kappaB regulation, with any nuclear/chromatin pool representing a context-dependent non-core function.
Type: localization assay
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The requested target is the human gene PPP4R1 (a.k.a. PP4R1, also reported as regulatory subunit R1 of protein phosphatase 4). The literature in this report consistently uses PP4R1/PPP4R1 to denote a regulatory (non-catalytic) subunit of protein phosphatase 4 (PP4) that forms a complex with the PP4 catalytic subunit PPP4C (PP4c). This is distinct from other PP4 regulatory subunits (PPP4R2/PPP4R3/PPP4R4) that form alternate PP4 holoenzymes. (park2020functionalrolesof pages 1-3, yang2017theserinethreoninephosphatases pages 13-17)
PPP4R1 is a regulatory/scaffolding subunit of the serine/threonine phosphatase PP4. PP4 holoenzymes are members of the PP2A-like phosphoprotein phosphatase family, in which a catalytic subunit associates with regulatory proteins that shape substrate selection, localization, and signaling outputs. In mammals, PP4 can form a heterodimer with PPP4R1 (PP4C/PP4R1) and other distinct assemblies with other regulatory subunits. (park2020functionalrolesof pages 1-3)
A foundational proteomics analysis of human PP4 complexes reported mutually exclusive PP4C assemblies that include a binary PP4C–PPP4R1 complex as one major form, emphasizing that PPP4R1 defines a specific PP4 holoenzyme class rather than being a generic interactor. (gingras2005anovelevolutionarily media 59a70f55, gingras2005anovelevolutionarily media 0cab0373)
Evidence supports that PPP4R1 is a repeat-rich scaffold protein with PP2A-A-like HEAT repeats (often discussed as ARM/HEAT-type repeats in the broader literature), consistent with a regulatory subunit that presents binding surfaces for catalytic subunit and substrates/adaptors rather than catalyzing reactions itself. A review of serine/threonine phosphatases notes that PPP4R1 contains HEAT repeats similar to PP2A structural subunits and that PPP4R1 can form a heterodimeric complex with PPP4C. (yang2017theserinethreoninephosphatases pages 13-17)
Historically, biochemical fractionation of PP4-containing complexes identified a ~105 kDa PP4-associated protein with sequence similarity to the repeat region of the PP2A A (PR65) subunit, consistent with the later understanding of a PP2A-A-like repeat scaffold in the PP4 system (which aligns with the general properties expected for PPP4R1). (hastie2000anovel50 pages 9-10)
PPP4R1 itself is not an enzyme; the catalytic activity resides in PPP4C, which hydrolyzes phosphate esters on phosphoserine/phosphothreonine residues of protein substrates. PPP4R1’s functional contribution is to form a PPP4C–PPP4R1 holoenzyme that can direct PP4 dephosphorylation activity toward specific signaling modules.
The strongest and most PPP4R1-specific mechanistic evidence in the retrieved corpus links PPP4R1-containing PP4 to negative regulation of NF-κB signaling, centered on the IKK complex and upstream adaptor/E3 ligases.
TRAF2/TRAF6 targeting: A primary study reported that PP4R1 interacts with TRAF2 (initially identified by yeast two-hybrid) and also with TRAF6 in a RING-domain dependent manner. Functionally, PP4R1 expression inhibited NF-κB activation driven by TRAF2/TRAF6 and upstream stimuli (e.g., TNF, EBV LMP1), while PP4R1 knockdown enhanced inflammatory outputs (e.g., IL8 induction). Mechanistically, PP4R1 mediated TRAF2 Ser11 dephosphorylation and reduced TRAF6 polyubiquitination, consistent with suppression of NF-κB activation at an early signaling node. (hadweh2014thepp4r1subunit pages 1-2)
IKK/NEMO bridging and viral immune evasion: In the context of Merkel polyomavirus small T antigen (tAg), PP4R1 was shown to form a complex with PP4c and to be required to bridge viral tAg to NEMO, enabling deactivation of the NF-κB pathway. PP4R1 depletion prevented tAg-mediated NF-κB inhibition and reduced suppression of pro-inflammatory cytokine production, demonstrating PPP4R1 is functionally required for this PP4-dependent NF-κB regulatory mechanism. (abdulsada2017thepp4r1subunit pages 1-2)
2024 mechanistic advance—AMBRA1 competition model in intestinal inflammation: A 2024 Cell Death & Differentiation study extends this axis into inflammatory disease biology. It reports that PP4R1 interacts with PP4c and references the known mechanism in which PP4R1 bridges IKK to PP4c to promote IKK dephosphorylation/inactivation. The study provides evidence that AMBRA1 can bind PP4R1 and PP4c to disrupt the PP4R1/PP4c–IKK module, thereby antagonizing IKK dephosphorylation, increasing IKK phosphorylation, and promoting intestinal inflammation. This positions the PP4R1/PP4c–IKK node as a regulatory checkpoint in inflammatory signaling with potential therapeutic implications. (xu2024ambra1promotesintestinal pages 1-3)
Expert synthesis: An authoritative PP4 review summarizes that a PP4C–PP4R1 complex can inactivate IKK via dephosphorylation, thereby preventing downstream NF-κB activation. (park2020functionalrolesof pages 7-8)
Multiple authoritative reviews describe PP4 as a regulator of DDR, including dephosphorylation of substrates such as γ-H2AX, RPA2, KAP1, and 53BP1, which can influence checkpoint recovery, homologous recombination, and chromatin dynamics. However, within the evidence retrieved here, these DDR substrate assignments are most often attributed to PP4 complexes broadly or to PP4R2/PP4R3-containing assemblies rather than being conclusively mapped to the PPP4R1-containing heterodimer. Thus, DDR can be included as a plausible broader PP4 functional context but should be treated as indirect for PPP4R1 unless additional PPP4R1-specific DDR data are introduced. (park2020functionalrolesof pages 3-4, park2020functionalrolesof pages 1-3, ramos2019roleofprotein pages 5-6)
A DDR-focused review reports that Ppp4-R1 decreases HDAC3 activity through dephosphorylation of Ser424, linking PPP4R1-containing PP4 activity to chromatin regulation (via histone deacetylase control). This is one of the more specific substrate-level statements involving a PPP4R1-defined PP4 complex in the retrieved evidence, although it is presented in review form rather than as primary experimental text in this run. (ramos2019roleofprotein pages 5-6)
Direct PPP4R1 localization evidence in the retrieved corpus is limited compared with pathway evidence. Early PP4 complex work explicitly noted that the subcellular location of PPP4R1 had not been clearly established at that time (contrasting with centrosome-enriched PP4R2-associated assemblies). (hastie2000anovel50 pages 9-10)
Nonetheless, the PP4 complex architecture literature emphasizes that regulatory subunits determine subcellular targeting and that PP4 complexes can operate across compartments; the PPP4R1-defined PP4C assembly is one of the major cellular PP4C complexes. (park2020functionalrolesof pages 1-3, gingras2005anovelevolutionarily media 59a70f55)
The 2024 Xu et al. study provides a current mechanistic model: AMBRA1 competes for PP4R1 and PP4c binding, disrupting PP4R1/PP4c-mediated IKK dephosphorylation and thereby enhancing NF-κB signaling and intestinal inflammation. The work links this signaling logic to therapeutic response context (reported improvement of infliximab therapy upon AMBRA1 deletion in the experimental system described). (xu2024ambra1promotesintestinal pages 1-3)
A 2024 Translational Cancer Research paper (LIHC-focused) reported that PPP4R1 is overexpressed in cancer tissues versus adjacent tissues (including experimental verification of higher PPP4R1 protein in tumor vs paracancerous tissue in LIHC) and proposed clinical utility: diagnostic significance for 14 tumors with AUC > 0.7, prognostic associations in five tumor types, and PPP4R1 as an independent prognostic factor in LIHC (P < 0.05). It also reported a positive correlation between PPP4R1 expression and fludarabine IC50, suggesting potential relevance to drug sensitivity/resistance. (li2024thediagnosticprognostic pages 1-2)
The 2024 AMBRA1–PP4R1/PP4c mechanism supports a therapeutic concept: modulating the PP4R1/PP4c–IKK dephosphorylation axis could tune NF-κB-driven inflammation. While not yet a clinical intervention directed at PPP4R1, this is a concrete disease-proximal mechanism with treatment-response framing (infliximab) in a contemporary study. (xu2024ambra1promotesintestinal pages 1-3)
The 2024 LIHC study positions PPP4R1 as a candidate diagnostic/prognostic biomarker and explores drug sensitivity correlations. Such analyses are currently most consistent with translational bioinformatics and validation workflows (e.g., ROC/AUC and survival modeling) rather than deployed clinical practice, but they represent the present state of “real-world implementation” efforts around PPP4R1. (li2024thediagnosticprognostic pages 1-2)
Authoritative reviews emphasize two points relevant to functional annotation:
1) Holoenzyme logic: PP4’s regulatory subunits (including PPP4R1) define function by determining target substrates and complex composition (heterodimers vs heterotrimers). (park2020functionalrolesof pages 1-3)
2) Signal integration: PP4 is repeatedly described as participating in multiple critical pathways (DDR, immune/NF-κB signaling, metabolism), and PPP4R1-containing PP4 is specifically represented as an NF-κB suppressor module through IKK regulation. (park2020functionalrolesof pages 7-8, park2020functionalrolesof pages 1-3)
From LIHC/pan-cancer analyses (2024):
- PPP4R1 diagnostic significance reported for 14 tumors with ROC AUC > 0.7. (li2024thediagnosticprognostic pages 1-2)
- PPP4R1 identified as an independent prognostic factor in LIHC (P < 0.05, multivariable Cox regression reported). (li2024thediagnosticprognostic pages 1-2)
- PPP4R1 expression positively correlated with fludarabine IC50 (drug sensitivity association). (li2024thediagnosticprognostic pages 1-2)
From inflammatory signaling mechanism (2024):
- Mechanistic/phenotypic outcomes are presented as functional effects (e.g., antagonism of IKK dephosphorylation; increased inflammatory signaling; improved infliximab response upon AMBRA1 deletion), though specific numeric effect sizes are not extractable from the current evidence snippets in this run. (xu2024ambra1promotesintestinal pages 1-3)
PPP4R1 encodes a HEAT-repeat scaffold regulatory subunit that forms a PP4C–PPP4R1 holoenzyme. The best-supported direct biological function of this holoenzyme is negative regulation of inflammatory NF-κB signaling, mediated through interactions with upstream adaptors (TRAF2/TRAF6) and the IKK/NEMO axis, and modulated by competitive binding partners such as AMBRA1 (a 2024 mechanistic advance). Evidence for PPP4’s broader roles in DNA damage responses is strong at the PP4-complex level, but PPP4R1-specific DDR substrate assignment is less definitive in the retrieved sources and should be treated cautiously. (hadweh2014thepp4r1subunit pages 1-2, xu2024ambra1promotesintestinal pages 1-3, abdulsada2017thepp4r1subunit pages 1-2, park2020functionalrolesof pages 3-4)
A foundational schematic of human PP4C complexes (including the PP4C–PPP4R1 binary complex and other mutually exclusive PP4 assemblies) is available from Gingras et al. 2005 and supports the complex-composition framework used in this report. (gingras2005anovelevolutionarily media 59a70f55, gingras2005anovelevolutionarily media 0cab0373)
| Aspect | Key finding | Evidence type | Representative source with year | URL | PaperQA citation id |
|---|---|---|---|---|---|
| Identity/complex | PPP4R1 (PP4R1/MEG1) is the human regulatory subunit 1 of protein phosphatase 4 and forms a heterodimeric PP4 holoenzyme with catalytic PPP4C/PP4c; reviews distinguish this PP4C–PPP4R1 complex from PP4R2/PP4R3-containing heterotrimers. | Review + primary | Park & Lee 2020; Yang & Arrizabalaga 2017 | https://doi.org/10.5483/bmbrep.2020.53.4.019 ; https://doi.org/10.1111/mmi.13715 | (park2020functionalrolesof pages 1-3, yang2017theserinethreoninephosphatases pages 13-17) |
| Identity/complex | Foundational proteomics mapped PP4C into mutually exclusive complexes, including a binary PP4C–PPP4R1 complex and the PP4cs complex with PP4R2/PP4R3, establishing core architecture for human PP4 assemblies. | Primary | Gingras et al. 2005 | https://doi.org/10.1074/mcp.m500231-mcp200 | (gingras2005anovelevolutionarily media 59a70f55) |
| Domains | PPP4R1 has PP2A-A-like HEAT repeats/ARM-like architecture, consistent with a scaffold/adaptor role rather than catalytic activity. | Review | Yang & Arrizabalaga 2017 | https://doi.org/10.1111/mmi.13715 | (yang2017theserinethreoninephosphatases pages 13-17) |
| Domains | A ~105 kDa PP4-associated protein with sequence similarity to repeats in the PP2A A/PR65 subunit was identified early in PP4 fractionation studies, supporting the long-repeat scaffold nature later assigned to PPP4R1. | Primary | Hastie et al. 2000 | https://doi.org/10.1042/bj3470845 | (hastie2000anovel50 pages 9-10) |
| Pathways/substrates | PP4 complexes broadly regulate DNA-damage signaling by dephosphorylating substrates including γ-H2AX, RPA2, KAP1, and 53BP1; however, many of these assignments are strongest for PP4 holoenzymes generally or PP4R2/PP4R3-containing complexes, not always specifically PPP4R1-directed. | Review | Ramos et al. 2019; Park & Lee 2020 | https://doi.org/10.15698/cst2019.03.178 ; https://doi.org/10.5483/bmbrep.2020.53.4.019 | (ramos2019roleofprotein pages 5-6, park2020functionalrolesof pages 3-4) |
| Pathways/substrates | PPP4R1-containing PP4 directly suppresses NF-κB by targeting the IKK axis; PP4R1 bridges PP4c to IKK/NEMO and is required for dephosphorylation-dependent inactivation of the complex. | Primary | Abdul-Sada et al. 2017 | https://doi.org/10.18632/oncotarget.15836 | (abdulsada2017thepp4r1subunit pages 1-2) |
| Pathways/substrates | PPP4R1 also targets TRAF2 and TRAF6 to inhibit NF-κB activation, including TRAF2 Ser11 dephosphorylation and reduced TRAF6 polyubiquitination, linking the subunit to upstream inflammatory signal dampening. | Primary | Hadweh et al. 2014 | https://doi.org/10.1016/j.cellsig.2014.08.001 | (hadweh2014thepp4r1subunit pages 1-2) |
| Pathways/substrates | A key 2024 advance showed AMBRA1 promotes intestinal inflammation by antagonizing PP4R1/PP4c-mediated IKK dephosphorylation; AMBRA1 competitively binds PP4R1 and PP4c, disrupts the PP4R1–PP4c–IKK module, and increases NF-κB signaling. | Primary | Xu et al. 2024 | https://doi.org/10.1038/s41418-024-01275-9 | (xu2024ambra1promotesintestinal pages 1-3) |
| Pathways/substrates | PPP4R1-containing PP4 can also regulate chromatin-associated signaling outside canonical NF-κB, including decreased HDAC3 activity via dephosphorylation of HDAC3 Ser424. | Review | Ramos et al. 2019 | https://doi.org/10.15698/cst2019.03.178 | (ramos2019roleofprotein pages 5-6) |
| Localization | Direct localization data for human PPP4R1 are comparatively sparse; available evidence indicates PP4 regulatory subunits help determine holoenzyme subcellular localization, and PPP4R1 has been reported as present in both cytoplasm and nucleus rather than a strictly compartment-restricted factor. | Primary/review | Chen et al. 2008; general PP4 reviews | https://doi.org/10.1074/jbc.m803443200 ; https://doi.org/10.5483/bmbrep.2020.53.4.019 | (park2020functionalrolesof pages 1-3) |
| Localization | Earlier PP4 work noted that, unlike centrosomal PPP4R2, the subcellular location of PPP4R1 had not yet been clearly established, underscoring a persistent evidence gap in precise compartment-specific annotation. | Primary | Hastie et al. 2000 | https://doi.org/10.1042/bj3470845 | (hastie2000anovel50 pages 9-10) |
| Disease/application | PPP4R1 is increasingly studied as a disease-relevant signaling regulator: inflammatory bowel disease data in 2024 position the PP4R1/PP4c–IKK node as a potential therapeutic leverage point, with AMBRA1 loss reducing pro-inflammatory cytokines and improving infliximab response in the reported model. | Primary | Xu et al. 2024 | https://doi.org/10.1038/s41418-024-01275-9 | (xu2024ambra1promotesintestinal pages 1-3) |
| Disease/application | A 2024 LIHC study reported PPP4R1 overexpression in tumor tissue, diagnostic value across 14 tumors with AUC >0.7, prognostic significance in five tumors, independent prognostic value in LIHC (P<0.05), and positive correlation with fludarabine IC50, supporting biomarker potential though mainly from bioinformatic/validation analyses. | Primary + database-style bioinformatics | Li et al. 2024 | https://doi.org/10.21037/tcr-23-1744 | (li2024thediagnosticprognostic pages 1-2) |
| Disease/application | Open Targets lists current, relatively low-to-moderate evidence disease associations for PPP4R1 including Alzheimer disease, multiple sclerosis, neurodegenerative disease, smoking initiation, and mathematical ability; these are hypothesis-generating rather than definitive functional annotations. | Database | Open Targets search (current platform result) | https://platform.opentargets.org | (li2024thediagnosticprognostic pages 1-2) |
Table: This table summarizes verified functional-annotation evidence for human PPP4R1/PP4R1 (UniProt Q8TF05), emphasizing recent 2024 studies and foundational PP4 complex architecture papers. It highlights what is well supported, where evidence is indirect, and where localization or substrate specificity remains less resolved.
References
(park2020functionalrolesof pages 1-3): Jaehong Park and Dong-Hyun Lee. Functional roles of protein phosphatase 4 in multiple aspects of cellular physiology: a friend and a foe. BMB Reports, 53:181-190, Apr 2020. URL: https://doi.org/10.5483/bmbrep.2020.53.4.019, doi:10.5483/bmbrep.2020.53.4.019. This article has 52 citations and is from a peer-reviewed journal.
(yang2017theserinethreoninephosphatases pages 13-17): Chunlin Yang and Gustavo Arrizabalaga. The serine/threonine phosphatases of apicomplexan parasites. Molecular Microbiology, 106:1-21, Oct 2017. URL: https://doi.org/10.1111/mmi.13715, doi:10.1111/mmi.13715. This article has 53 citations and is from a domain leading peer-reviewed journal.
(gingras2005anovelevolutionarily media 59a70f55): Anne-Claude Gingras, Michael Caballero, Marcel Zarske, Amy Sanchez, Tony R. Hazbun, Stanley Fields, Nahum Sonenberg, Ernst Hafen, Brian Raught, and Ruedi Aebersold. A novel, evolutionarily conserved protein phosphatase complex involved in cisplatin sensitivity. Molecular & Cellular Proteomics, 4:1725-1740, Nov 2005. URL: https://doi.org/10.1074/mcp.m500231-mcp200, doi:10.1074/mcp.m500231-mcp200. This article has 236 citations and is from a domain leading peer-reviewed journal.
(gingras2005anovelevolutionarily media 0cab0373): Anne-Claude Gingras, Michael Caballero, Marcel Zarske, Amy Sanchez, Tony R. Hazbun, Stanley Fields, Nahum Sonenberg, Ernst Hafen, Brian Raught, and Ruedi Aebersold. A novel, evolutionarily conserved protein phosphatase complex involved in cisplatin sensitivity. Molecular & Cellular Proteomics, 4:1725-1740, Nov 2005. URL: https://doi.org/10.1074/mcp.m500231-mcp200, doi:10.1074/mcp.m500231-mcp200. This article has 236 citations and is from a domain leading peer-reviewed journal.
(hastie2000anovel50 pages 9-10): C. James HASTIE, Graeme K. CARNEGIE, Nick MORRICE, and Patricia T. W. COHEN. A novel 50 kda protein forms complexes with protein phosphatase 4 and is located at centrosomal microtubule organizing centres. The Biochemical journal, 347 Pt 3:845-55, May 2000. URL: https://doi.org/10.1042/bj3470845, doi:10.1042/bj3470845. This article has 95 citations.
(hadweh2014thepp4r1subunit pages 1-2): Paul Hadweh, Hasem Habelhah, Elliott Kieff, George Mosialos, and Eudoxia Hatzivassiliou. The pp4r1 subunit of protein phosphatase pp4 targets traf2 and traf6 to mediate inhibition of nf-κb activation. Cellular signalling, 26 12:2730-7, Dec 2014. URL: https://doi.org/10.1016/j.cellsig.2014.08.001, doi:10.1016/j.cellsig.2014.08.001. This article has 32 citations and is from a peer-reviewed journal.
(abdulsada2017thepp4r1subunit pages 1-2): Hussein Abdul-Sada, Marietta Müller, Rajni Mehta, Rachel Toth, J. Simon C. Arthur, Adrian Whitehouse, and Andrew Macdonald. The pp4r1 sub-unit of protein phosphatase pp4 is essential for inhibition of nf-κb by merkel polyomavirus small tumour antigen. Oncotarget, 8:25418-25432, Mar 2017. URL: https://doi.org/10.18632/oncotarget.15836, doi:10.18632/oncotarget.15836. This article has 53 citations.
(xu2024ambra1promotesintestinal pages 1-3): Weimin Xu, Zhebin Hua, Yaosheng Wang, Wenbo Tang, Weijun Ou, Fangyuan Liu, Yiqing Yang, Wenjun Ding, Zhongchuan Wang, Long Cui, Wensong Ge, Yubei Gu, Xiaolei Wang, YingWei Chen, Chen-Ying Liu, and Peng Du. Ambra1 promotes intestinal inflammation by antagonizing pp4r1/pp4c mediated ikk dephosphorylation in an autophagy-independent manner. Cell death and differentiation, 31:618-634, Feb 2024. URL: https://doi.org/10.1038/s41418-024-01275-9, doi:10.1038/s41418-024-01275-9. This article has 11 citations and is from a domain leading peer-reviewed journal.
(park2020functionalrolesof pages 7-8): Jaehong Park and Dong-Hyun Lee. Functional roles of protein phosphatase 4 in multiple aspects of cellular physiology: a friend and a foe. BMB Reports, 53:181-190, Apr 2020. URL: https://doi.org/10.5483/bmbrep.2020.53.4.019, doi:10.5483/bmbrep.2020.53.4.019. This article has 52 citations and is from a peer-reviewed journal.
(park2020functionalrolesof pages 3-4): Jaehong Park and Dong-Hyun Lee. Functional roles of protein phosphatase 4 in multiple aspects of cellular physiology: a friend and a foe. BMB Reports, 53:181-190, Apr 2020. URL: https://doi.org/10.5483/bmbrep.2020.53.4.019, doi:10.5483/bmbrep.2020.53.4.019. This article has 52 citations and is from a peer-reviewed journal.
(ramos2019roleofprotein pages 5-6): Facundo Ramos, María Teresa Villoria, Esmeralda Alonso-Rodríguez, and Andrés Clemente-Blanco. Role of protein phosphatases pp1, pp2a, pp4 and cdc14 in the dna damage response. Cell Stress, 3:70-85, Mar 2019. URL: https://doi.org/10.15698/cst2019.03.178, doi:10.15698/cst2019.03.178. This article has 77 citations.
(li2024thediagnosticprognostic pages 1-2): Xiaowei Li, Yinglian Pan, Siren Feng, Weimei Xing, Bo Lin, Wei Li, Mengsen Li, and Mingyue Zhu. The diagnostic, prognostic, drug sensitivity and cerna internet of ppp4r1 in liver hepatocellular carcinoma (lihc). Translational Cancer Research, 13:594-612, Feb 2024. URL: https://doi.org/10.21037/tcr-23-1744, doi:10.21037/tcr-23-1744. This article has 3 citations.
(campos2020cellcycleand pages 6-8): Adrián Campos and Andrés Clemente-Blanco. Cell cycle and dna repair regulation in the damage response: protein phosphatases take over the reins. International Journal of Molecular Sciences, 21:446, Jan 2020. URL: https://doi.org/10.3390/ijms21020446, doi:10.3390/ijms21020446. This article has 126 citations.
id: Q8TF05
gene_symbol: PPP4R1
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
PPP4R1 encodes PP4 regulatory subunit 1, a HEAT/ARM-repeat scaffolding
subunit of the serine/threonine protein phosphatase 4 holoenzyme. PPP4R1
binds the catalytic subunit PPP4C to form a PP4C-PPP4R1 complex that directs
phosphatase activity toward selected targets. The best-supported
PPP4R1-specific process is dampening canonical NF-kappaB signaling through
PP4-dependent regulation of TRAF2/TRAF6 and the IKK/NEMO axis. Broader PP4
roles in DNA damage response are well established for PP4 complexes, but the
strongest DDR substrate evidence is not specific to the PPP4R1-containing
holoenzyme.
alternative_products:
- name: 1 (PP4Rmeg)
id: Q8TF05-1
- name: '2'
id: Q8TF05-2
sequence_note: VSP_009469
existing_annotations:
- term:
id: GO:0005737
label: cytoplasm
qualifier: is_active_in
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: >-
Cytoplasmic localization is consistent with PPP4R1 acting in PP4
signaling complexes, although precise compartment-specific localization
is not strongly resolved.
action: ACCEPT
reason: >-
Falcon research notes sparse direct localization evidence but supports
cytoplasm as a reasonable broad location for PPP4R1-containing PP4
signaling complexes.
supported_by:
- reference_id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
supporting_text: >-
Direct localization data for human PPP4R1 are comparatively sparse;
available evidence indicates PP4 regulatory subunits help determine
holoenzyme subcellular localization.
- term:
id: GO:0019888
label: protein phosphatase regulator activity
qualifier: enables
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: >-
PPP4R1 is a non-catalytic regulatory/scaffolding subunit of PP4 that
binds PPP4C and helps define holoenzyme substrate targeting.
action: ACCEPT
reason: >-
This is the most appropriate molecular-function annotation for PPP4R1:
it regulates a protein phosphatase rather than catalyzing
dephosphorylation itself.
supported_by:
- reference_id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
supporting_text: >-
PPP4R1 is a regulatory/scaffolding subunit of the serine/threonine
phosphatase PP4.
- reference_id: PMID:10026142
supporting_text: >-
The PP4R1 cDNA clone engineered with an N-terminal Myc tag was
expressed in COS M6 cells and PP4C co-immunoprecipitated with
Myc-tagged PP4R1.
- term:
id: GO:0005515
label: protein binding
qualifier: enables
evidence_type: IPI
original_reference_id: PMID:16085932
review:
summary: >-
This IPI annotation captures PPP4R1 binding to PPP4C, but generic
protein binding is less informative than the known PP4 regulatory
subunit activity.
action: MODIFY
reason: >-
PPP4R1's PPP4C interaction should be represented as protein phosphatase
regulator activity rather than the uninformative protein binding term.
proposed_replacement_terms:
- id: GO:0019888
label: protein phosphatase regulator activity
supported_by:
- reference_id: PMID:16085932
supporting_text: >-
Using a combination of tandem affinity purification tagging and mass
spectrometry, we characterized a novel, evolutionarily conserved
protein phosphatase 4 (PP4)-containing complex.
- reference_id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
supporting_text: >-
A foundational proteomics analysis of human PP4 complexes reported
mutually exclusive PP4C assemblies that include a binary
PP4C-PPP4R1 complex.
- term:
id: GO:0005515
label: protein binding
qualifier: enables
evidence_type: IPI
original_reference_id: PMID:17353931
review:
summary: >-
This high-throughput interactome annotation reports PPP4C binding, but
the biologically meaningful interpretation is PPP4 regulator/scaffold
activity.
action: MODIFY
reason: >-
Replace generic protein binding with the more informative protein
phosphatase regulator activity term supported by the PPP4R1-PPP4C
complex literature.
proposed_replacement_terms:
- id: GO:0019888
label: protein phosphatase regulator activity
supported_by:
- reference_id: PMID:17353931
supporting_text: >-
Mapping protein-protein interactions is an invaluable tool for
understanding protein function.
- reference_id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
supporting_text: >-
PPP4R1 defines a specific PP4 holoenzyme class rather than being a
generic interactor.
- term:
id: GO:0005515
label: protein binding
qualifier: enables
evidence_type: IPI
original_reference_id: PMID:18614045
review:
summary: >-
This interaction entry concerns PP4 complex biology, but the cited
gamma-H2AX paper primarily supports a PP4R2/PP4R3-containing complex
rather than a PPP4R1-specific DDR role.
action: REMOVE
reason: >-
The local publication text supports a PP4C/PP4R2/PP4R3beta gamma-H2AX
phosphatase complex rather than a PPP4R1-containing complex, so this
PMID should not support a PPP4R1 functional annotation.
supported_by:
- reference_id: PMID:18614045
supporting_text: >-
Here we describe a three-protein PP4 phosphatase complex in
mammalian cells, containing PP4C, PP4R2, and PP4R3beta, that
specifically dephosphorylates ATR-mediated gamma-H2AX.
- reference_id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
supporting_text: >-
DDR substrate assignments are most often attributed to PP4
complexes broadly or to PP4R2/PP4R3-containing assemblies rather
than being conclusively mapped to the PPP4R1-containing heterodimer.
- term:
id: GO:0005515
label: protein binding
qualifier: enables
evidence_type: IPI
original_reference_id: PMID:18715871
review:
summary: >-
This PP4 regulatory-subunit study distinguishes PP4R4 from PP4R1
complexes; the PPP4R1-PPP4C interaction should still be represented by
the regulator activity term rather than protein binding.
action: MODIFY
reason: >-
Generic protein binding does not capture the role of PPP4R1 as a PP4
regulatory/scaffolding subunit.
proposed_replacement_terms:
- id: GO:0019888
label: protein phosphatase regulator activity
supported_by:
- reference_id: PMID:18715871
supporting_text: >-
PP4c interacts with regulatory proteins, which specify substrate
targeting and intracellular localization.
- reference_id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
supporting_text: >-
PP4 holoenzymes are members of the PP2A-like phosphoprotein
phosphatase family, in which a catalytic subunit associates with
regulatory proteins that shape substrate selection, localization,
and signaling outputs.
- term:
id: GO:0005515
label: protein binding
qualifier: enables
evidence_type: IPI
original_reference_id: PMID:26496610
review:
summary: >-
This quantitative interactome annotation is compatible with PPP4R1
interacting with PPP4C, but protein binding is not the best GO
representation of the established function.
action: MODIFY
reason: >-
Replace with protein phosphatase regulator activity to capture the
regulatory-subunit role.
proposed_replacement_terms:
- id: GO:0019888
label: protein phosphatase regulator activity
supported_by:
- reference_id: PMID:26496610
supporting_text: >-
Using quantitative proteomics, we detect specific interactions,
estimate interaction stoichiometries, and measure cellular
abundances of interacting proteins.
- reference_id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
supporting_text: >-
PPP4R1 is a repeat-rich scaffold protein with PP2A-A-like HEAT
repeats, consistent with a regulatory subunit that presents binding
surfaces for catalytic subunit and substrates/adaptors.
- term:
id: GO:0005515
label: protein binding
qualifier: enables
evidence_type: IPI
original_reference_id: PMID:27880917
review:
summary: >-
The phosphatase interactome result is consistent with PP4 complex
membership, but the actionable GO annotation should be PPP4R1's
phosphatase regulator role.
action: MODIFY
reason: >-
PPP4R1 is not merely a binding protein; it is the regulatory/scaffolding
subunit of a PP4 holoenzyme.
proposed_replacement_terms:
- id: GO:0019888
label: protein phosphatase regulator activity
supported_by:
- reference_id: PMID:27880917
supporting_text: >-
We identified 1,335 high-confidence interactions (1,104 previously
unreported), implicating these phosphatases in the regulation of a
variety of cellular processes.
- reference_id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
supporting_text: >-
PPP4R1's functional contribution is to form a PPP4C-PPP4R1
holoenzyme that can direct PP4 dephosphorylation activity toward
specific signaling modules.
- term:
id: GO:0005515
label: protein binding
qualifier: enables
evidence_type: IPI
original_reference_id: PMID:33961781
review:
summary: >-
This proteome-scale interaction supports PPP4C association but is still
too generic as a protein binding annotation.
action: MODIFY
reason: >-
The PPP4C interaction should be curated as protein phosphatase regulator
activity in the PP4 complex context.
proposed_replacement_terms:
- id: GO:0019888
label: protein phosphatase regulator activity
supported_by:
- reference_id: PMID:33961781
supporting_text: >-
Dual proteome-scale networks reveal cell-specific remodeling of the
human interactome.
- reference_id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
supporting_text: >-
PPP4R1 is a regulatory/scaffolding subunit of the serine/threonine
phosphatase PP4.
- term:
id: GO:0005515
label: protein binding
qualifier: enables
evidence_type: IPI
original_reference_id: PMID:40205054
review:
summary: >-
This recent multimodal cell-map interaction should not leave PPP4R1 with
a generic protein binding function when the PP4 regulatory role is known.
action: MODIFY
reason: >-
Use protein phosphatase regulator activity to capture the functional
consequence of PPP4R1 binding PPP4C.
proposed_replacement_terms:
- id: GO:0019888
label: protein phosphatase regulator activity
supported_by:
- reference_id: PMID:40205054
supporting_text: >-
Multimodal cell maps as a foundation for structural and functional
genomics.
- reference_id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
supporting_text: >-
PPP4R1 defines a specific PP4 holoenzyme class rather than being a
generic interactor.
- term:
id: GO:0004721
label: phosphoprotein phosphatase activity
qualifier: contributes_to
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: >-
This annotation is acceptable only with the contributes_to qualifier,
but the broad phosphoprotein phosphatase term should be replaced with
the more specific protein serine/threonine phosphatase activity term.
action: MODIFY
reason: >-
PPP4R1 forms a complex with serine/threonine phosphatase PPP4C, so
contributes_to protein serine/threonine phosphatase activity is
defensible, while enables would be misleading.
proposed_replacement_terms:
- id: GO:0004722
label: protein serine/threonine phosphatase activity
supported_by:
- reference_id: PMID:10026142
supporting_text: >-
These data indicate that one form of PP4 is similar to the core
complex of PP2A in that it consists of a catalytic subunit and a
PP2AA-like structural subunit.
- reference_id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
supporting_text: >-
PPP4R1 itself is not an enzyme; the catalytic activity resides in
PPP4C.
- term:
id: GO:0006468
label: protein phosphorylation
qualifier: involved_in
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: >-
This is an opposite-reaction misannotation. PPP4R1 is a regulatory
subunit of protein phosphatase 4, which removes phosphate groups from
phosphoproteins rather than phosphorylating them.
action: REMOVE
reason: >-
PPP4R1 is not a kinase, and the supported PP4 biology concerns
dephosphorylation or regulation of phosphatase activity, not protein
phosphorylation.
supported_by:
- reference_id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
supporting_text: >-
PPP4R1 itself is not an enzyme; the catalytic activity resides in
PPP4C, which hydrolyzes phosphate esters on phosphoserine/
phosphothreonine residues.
- term:
id: GO:0030289
label: protein phosphatase 4 complex
qualifier: part_of
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: >-
PPP4R1 is a component of the PP4C-PPP4R1 protein phosphatase 4
holoenzyme.
action: ACCEPT
reason: >-
Multiple sources support PPP4R1 as a stable regulatory subunit in a
PP4C-PPP4R1 complex.
supported_by:
- reference_id: PMID:10026142
supporting_text: >-
The final product contained two major proteins: the PP4 catalytic
subunit plus a protein that migrated as a doublet of 120-125 kDa.
- reference_id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
supporting_text: >-
In mammals, PP4 can form a heterodimer with PPP4R1 (PP4C/PP4R1)
and other distinct assemblies with other regulatory subunits.
- term:
id: GO:0007165
label: signal transduction
qualifier: involved_in
evidence_type: NAS
original_reference_id: PMID:10026142
review:
summary: >-
The broad signal transduction annotation should be replaced by the
specific PPP4R1-supported process: negative regulation of canonical
NF-kappaB signal transduction.
action: MODIFY
reason: >-
PPP4R1-specific pathway evidence supports inhibition of canonical
NF-kappaB signaling through TRAF2/TRAF6 and IKK/NEMO, not generic signal
transduction.
proposed_replacement_terms:
- id: GO:0043124
label: negative regulation of canonical NF-kappaB signal transduction
supported_by:
- reference_id: PMID:25134449
supporting_text: >-
Exogenous expression of PP4R1 inhibited NF-kappaB activation by
TRAF2, TRAF6, TNF and the Epstein-Barr virus oncoprotein LMP1.
- reference_id: PMID:28445980
supporting_text: >-
Formation of a complex with PP4R1 and PP4c is required to bridge
MCPyV tAg to the NEMO adaptor protein, allowing deactivation of the
NF-kB pathway.
- reference_id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
supporting_text: >-
The best-supported direct biological function of this holoenzyme is
negative regulation of inflammatory NF-kappaB signaling.
- term:
id: GO:0019888
label: protein phosphatase regulator activity
qualifier: enables
evidence_type: NAS
original_reference_id: PMID:10026142
review:
summary: >-
The founding biochemical study supports PPP4R1 as a PP4 regulatory
subunit that binds PPP4C.
action: ACCEPT
reason: >-
This is a direct, specific annotation for PPP4R1's core molecular
function.
supported_by:
- reference_id: PMID:10026142
supporting_text: >-
Amino acid sequence information of several peptides derived from the
105 kDa protein was utilized to isolate a human cDNA clone.
- reference_id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
supporting_text: >-
PPP4R1 encodes a HEAT-repeat scaffold regulatory subunit that forms
a PP4C-PPP4R1 holoenzyme.
references:
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: PMID:10026142
title: Purification and identification of a novel subunit of protein serine/threonine phosphatase 4.
findings: []
- id: PMID:11729228
title: Cloning and characterization of a novel subunit of protein serine/threonine phosphatase 4 from mesangial cells.
findings: []
- id: PMID:15805470
title: Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4.
findings: []
- id: PMID:16085932
title: A novel, evolutionarily conserved protein phosphatase complex involved in cisplatin sensitivity.
findings: []
- id: PMID:17353931
title: Large-scale mapping of human protein-protein interactions by mass spectrometry.
findings: []
- id: PMID:18614045
title: A PP4-phosphatase complex dephosphorylates gamma-H2AX generated during DNA replication.
findings: []
- id: PMID:18715871
title: PP4R4/KIAA1622 forms a novel stable cytosolic complex with phosphoprotein phosphatase 4.
findings: []
- id: PMID:25134449
title: The PP4R1 subunit of protein phosphatase PP4 targets TRAF2 and TRAF6 to mediate inhibition of NF-kappaB activation.
findings: []
- id: PMID:26496610
title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
findings: []
- id: PMID:27880917
title: Phenotypic and Interaction Profiling of the Human Phosphatases Identifies Diverse Mitotic Regulators.
findings: []
- id: PMID:28445980
title: The PP4R1 sub-unit of protein phosphatase PP4 is essential for inhibition of NF-kappaB by merkel polyomavirus small tumour antigen.
findings: []
- id: PMID:33961781
title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
findings: []
- id: PMID:40205054
title: Multimodal cell maps as a foundation for structural and functional genomics.
findings: []
- id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
title: Falcon deep research report for human PPP4R1
findings: []
core_functions:
- description: >-
Regulatory/scaffolding subunit of the PP4C-PPP4R1 serine/threonine
phosphatase holoenzyme that contributes to phosphoprotein phosphatase
activity and directs PP4-dependent negative regulation of canonical
NF-kappaB signaling.
molecular_function:
id: GO:0019888
label: protein phosphatase regulator activity
directly_involved_in:
- id: GO:0043124
label: negative regulation of canonical NF-kappaB signal transduction
locations:
- id: GO:0005737
label: cytoplasm
in_complex:
id: GO:0030289
label: protein phosphatase 4 complex
supported_by:
- reference_id: PMID:10026142
supporting_text: >-
PP4C co-immunoprecipitated with Myc-tagged PP4R1.
- reference_id: PMID:25134449
supporting_text: >-
Exogenous expression of PP4R1 inhibited NF-kappaB activation by
TRAF2, TRAF6, TNF and the Epstein-Barr virus oncoprotein LMP1.
- reference_id: file:human/PPP4R1/PPP4R1-deep-research-falcon.md
supporting_text: >-
PPP4R1 encodes a HEAT-repeat scaffold regulatory subunit that forms a
PP4C-PPP4R1 holoenzyme.
proposed_new_terms: []
suggested_questions:
- question: Which endogenous human substrates are specifically directed by the PPP4R1-containing PP4 holoenzyme rather than by PP4R2/PP4R3 or PP4R4 complexes?
- question: In which cell types is PPP4R1-dependent negative regulation of canonical NF-kappaB signaling physiologically dominant?
- question: Does PPP4R1 have a reproducible nuclear function through HDAC3 regulation, or is its best-supported role cytoplasmic signaling through PP4C?
suggested_experiments:
- description: Endogenous PPP4R1 and PPP4C co-immunoprecipitation after TNF stimulation, followed by phosphoproteomics in PPP4R1 knockout and rescue cells.
experiment_type: phosphoproteomics
hypothesis: PPP4R1 directs PP4C toward a limited set of NF-kappaB pathway substrates, including TRAF2/TRAF6 and IKK/NEMO-associated targets.
- description: Compare wild-type PPP4R1 rescue with PPP4C-binding-defective PPP4R1 mutants in NF-kappaB reporter, IL8/CCL20 secretion, and IKK phosphorylation assays.
experiment_type: cell-based pathway assay
hypothesis: PPP4R1-dependent PP4C recruitment is required for negative regulation of canonical NF-kappaB signaling.
- description: Subcellular fractionation and live-cell imaging of endogenously tagged PPP4R1 under basal, TNF-stimulated, and DNA replication stress conditions.
experiment_type: localization assay
hypothesis: PPP4R1 is primarily cytoplasmic during NF-kappaB regulation, with any nuclear/chromatin pool representing a context-dependent non-core function.