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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
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Download this section (compressed HTML)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
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