PPP4R4 (PP4R4, KIAA1622) is a noncatalytic regulatory subunit of serine/threonine protein phosphatase 4 (PP4). The 873-residue canonical protein is built largely of HEAT/ARM-type repeats and has weak sequence similarity to the A (scaffolding) subunit of PP2A. It binds the PP4 catalytic subunit PPP4C specifically (not the related PP2A or PP6 catalytic subunits), through an interface analogous to that used by the PP2A A subunit, and forms a stable cytosolic PPP4C-PPP4R4 complex that is separate from the PP4 complexes containing PP4R1, PP4R2-PP4R3 or alpha4. Unlike PP2A A, PP4R4 does not bridge PP4c to other regulatory subunits. In vitro the PPP4C-PPP4R4 complex dephosphorylates a fluorogenic substrate and gammaH2AX with lower activity than free PPP4C, consistent with a regulatory subunit that modulates catalytic activity; its physiological substrates and cellular processes remain unknown.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004864 protein phosphatase inhibitor activity | IDA PMID:18715871 PP4R4/KIAA1622 forms a novel stable cytosolic complex with p... | MODIFY | Summary: protein phosphatase inhibitor activity (IDA, PMID:18715871): in vitro, PP4c-PP4R4 complexes dephosphorylate a fluorogenic substrate and gammaH2AX less efficiently than free PP4c. Reason: The reduced activity is real in the assay but does not distinguish PP4R4 from an ordinary holoenzyme regulatory subunit: the PP4c-PP4R2-PP4R3 complex is likewise less active than free PP4c on the same substrates, and nobody regards PP4R2/PP4R3 as inhibitors. Reduced activity of a PP2A-family holoenzyme toward small/generic substrates relative to the free catalytic subunit is the expected consequence of regulatory-subunit binding, and the physiological substrates of the PP4c-PP4R4 complex are unknown, so 'inhibitor' over-reads the result. The parent term protein phosphatase regulator activity (GO:0019888), already on the gene by IBA, captures what is demonstrated (binds PP4c and modulates its activity). The two inhibitor rows are the same claim and receive the same action. Proposed replacements: protein phosphatase regulator activity Supporting Evidence: PMID:18715871 PP4c.PP4R4 complexes exhibit phosphatase activity toward a fluorogenic substrate and gammaH2AX, but this activity is lower than that associated with the PP4c.PP4R2.PP4R3 complex, which itself is less active than the free PP4c catalytic subunit. |
| GO:0004865 protein serine/threonine phosphatase inhibitor activity | IDA PMID:18715871 PP4R4/KIAA1622 forms a novel stable cytosolic complex with p... | MODIFY | Summary: protein serine/threonine phosphatase inhibitor activity (IDA, PMID:18715871): in vitro, PP4c-PP4R4 complexes dephosphorylate a fluorogenic substrate and gammaH2AX less efficiently than free PP4c. Reason: The reduced activity is real in the assay but does not distinguish PP4R4 from an ordinary holoenzyme regulatory subunit: the PP4c-PP4R2-PP4R3 complex is likewise less active than free PP4c on the same substrates, and nobody regards PP4R2/PP4R3 as inhibitors. Reduced activity of a PP2A-family holoenzyme toward small/generic substrates relative to the free catalytic subunit is the expected consequence of regulatory-subunit binding, and the physiological substrates of the PP4c-PP4R4 complex are unknown, so 'inhibitor' over-reads the result. The parent term protein phosphatase regulator activity (GO:0019888), already on the gene by IBA, captures what is demonstrated (binds PP4c and modulates its activity). The two inhibitor rows are the same claim and receive the same action. Proposed replacements: protein phosphatase regulator activity Supporting Evidence: PMID:18715871 PP4c.PP4R4 complexes exhibit phosphatase activity toward a fluorogenic substrate and gammaH2AX, but this activity is lower than that associated with the PP4c.PP4R2.PP4R3 complex, which itself is less active than the free PP4c catalytic subunit. |
| GO:0005515 protein binding | IPI PMID:18715871 PP4R4/KIAA1622 forms a novel stable cytosolic complex with p... | MODIFY | Summary: IPI with PPP4C (P60510) from PMID:18715871. Low-throughput affinity purification/mass spectrometry with reciprocal and mutational analysis establishes a specific, stable PP4c-PP4R4 complex. Reason: Bare protein binding is uninformative. The partner in every row is the PP4 catalytic subunit PPP4C, and the interaction is the defining property of PP4R4 as a PP4 regulatory subunit, so the informative replacement is protein phosphatase binding (GO:0019903). Interaction specificity (PP4c, not PP2Ac or PP6c) and mutational disruption at the A-subunit-like interface support a direct catalytic-subunit binding mode. Proposed replacements: protein phosphatase binding Supporting Evidence: PMID:18715871 PP4R4 displays weak sequence homology with the A (scaffolding) subunit of the PP2A holoenzyme and specifically associates with PP4c (and not with the related PP2Ac or PP6c phosphatases). PMID:18715871 The PP4c.PP4R4 interaction is disrupted by mutations analogous to those abrogating the association of PP2Ac with PP2A A subunit. |
| GO:0005515 protein binding | IPI PMID:27880917 Phenotypic and Interaction Profiling of the Human Phosphatas... | MODIFY | Summary: IPI with PPP4C (P60510) from PMID:27880917. High-throughput interaction proteomics recovering the same PPP4C partner already established by the dedicated study. Reason: Bare protein binding is uninformative. The partner in every row is the PP4 catalytic subunit PPP4C, and the interaction is the defining property of PP4R4 as a PP4 regulatory subunit, so the informative replacement is protein phosphatase binding (GO:0019903). Interaction specificity (PP4c, not PP2Ac or PP6c) and mutational disruption at the A-subunit-like interface support a direct catalytic-subunit binding mode. The high-throughput study's abstract does not name PPP4R4; the curator's with/from records PPP4C as partner, consistent with the dedicated study, so this row reinforces rather than independently establishes the claim. Proposed replacements: protein phosphatase binding Supporting Evidence: PMID:18715871 PP4R4 displays weak sequence homology with the A (scaffolding) subunit of the PP2A holoenzyme and specifically associates with PP4c (and not with the related PP2Ac or PP6c phosphatases). file:human/PPP4R4/PPP4R4-uniprot.txt Component of the PP4 complex PPP4C-PPP4R4. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: IPI with PPP4C (P60510) from PMID:28514442. High-throughput interaction proteomics recovering the same PPP4C partner already established by the dedicated study. Reason: Bare protein binding is uninformative. The partner in every row is the PP4 catalytic subunit PPP4C, and the interaction is the defining property of PP4R4 as a PP4 regulatory subunit, so the informative replacement is protein phosphatase binding (GO:0019903). Interaction specificity (PP4c, not PP2Ac or PP6c) and mutational disruption at the A-subunit-like interface support a direct catalytic-subunit binding mode. The high-throughput study's abstract does not name PPP4R4; the curator's with/from records PPP4C as partner, consistent with the dedicated study, so this row reinforces rather than independently establishes the claim. Proposed replacements: protein phosphatase binding Supporting Evidence: PMID:18715871 PP4R4 displays weak sequence homology with the A (scaffolding) subunit of the PP2A holoenzyme and specifically associates with PP4c (and not with the related PP2Ac or PP6c phosphatases). file:human/PPP4R4/PPP4R4-uniprot.txt Component of the PP4 complex PPP4C-PPP4R4. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: IPI with PPP4C (P60510) from PMID:33961781. High-throughput interaction proteomics recovering the same PPP4C partner already established by the dedicated study. Reason: Bare protein binding is uninformative. The partner in every row is the PP4 catalytic subunit PPP4C, and the interaction is the defining property of PP4R4 as a PP4 regulatory subunit, so the informative replacement is protein phosphatase binding (GO:0019903). Interaction specificity (PP4c, not PP2Ac or PP6c) and mutational disruption at the A-subunit-like interface support a direct catalytic-subunit binding mode. The high-throughput study's abstract does not name PPP4R4; the curator's with/from records PPP4C as partner, consistent with the dedicated study, so this row reinforces rather than independently establishes the claim. Proposed replacements: protein phosphatase binding Supporting Evidence: PMID:18715871 PP4R4 displays weak sequence homology with the A (scaffolding) subunit of the PP2A holoenzyme and specifically associates with PP4c (and not with the related PP2Ac or PP6c phosphatases). file:human/PPP4R4/PPP4R4-uniprot.txt Component of the PP4 complex PPP4C-PPP4R4. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MODIFY | Summary: IPI with PPP4C (P60510) from PMID:40205054. High-throughput interaction proteomics recovering the same PPP4C partner already established by the dedicated study. Reason: Bare protein binding is uninformative. The partner in every row is the PP4 catalytic subunit PPP4C, and the interaction is the defining property of PP4R4 as a PP4 regulatory subunit, so the informative replacement is protein phosphatase binding (GO:0019903). Interaction specificity (PP4c, not PP2Ac or PP6c) and mutational disruption at the A-subunit-like interface support a direct catalytic-subunit binding mode. The high-throughput study's abstract does not name PPP4R4; the curator's with/from records PPP4C as partner, consistent with the dedicated study, so this row reinforces rather than independently establishes the claim. Proposed replacements: protein phosphatase binding Supporting Evidence: PMID:18715871 PP4R4 displays weak sequence homology with the A (scaffolding) subunit of the PP2A holoenzyme and specifically associates with PP4c (and not with the related PP2Ac or PP6c phosphatases). file:human/PPP4R4/PPP4R4-uniprot.txt Component of the PP4 complex PPP4C-PPP4R4. |
| GO:0005737 cytoplasm | IDA PMID:18715871 PP4R4/KIAA1622 forms a novel stable cytosolic complex with p... | MODIFY | Summary: cytoplasm (IDA). PP4R4 was purified as a stable cytosolic complex with PP4c; UniProt records cytoplasm from the same paper. Reason: Correct but less specific than the evidence: the dedicated study describes a cytosolic complex and the gene already carries cytosol (GO:0005829) by IDA (HPA) and IBA. Refine to cytosol. Proposed replacements: cytosol Supporting Evidence: PMID:18715871 we identify a novel, stable cytosolic PP4c interacting partner, KIAA1622, which we have renamed PP4R4. file:human/PPP4R4/PPP4R4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:18715871}. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: cytoplasm (IEA). PP4R4 was purified as a stable cytosolic complex with PP4c; UniProt records cytoplasm from the same paper. Reason: Correct but less specific than the evidence: the dedicated study describes a cytosolic complex and the gene already carries cytosol (GO:0005829) by IDA (HPA) and IBA. Refine to cytosol. Proposed replacements: cytosol Supporting Evidence: PMID:18715871 we identify a novel, stable cytosolic PP4c interacting partner, KIAA1622, which we have renamed PP4R4. file:human/PPP4R4/PPP4R4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:18715871}. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: cytosol (IBA, GO_REF:0000033). PP4R4 forms a stable cytosolic complex with PP4c ; the IBA reflects PAINT placement at PTN001087371 within PTHR21467, a family whose only experimentally characterised member is human PP4R4 (appearing as its own donor, as expected). Reason: Cytosol is the most specific location supported: the dedicated biochemical study identifies the PP4c-PP4R4 assembly as cytosolic and distinct from the PP4 complexes that act on chromatin-associated substrates. IBA and IDA rows make the same claim and are both accepted. Supporting Evidence: PMID:18715871 we identify a novel, stable cytosolic PP4c interacting partner, KIAA1622, which we have renamed PP4R4. PMID:18715871 Our data demonstrate that PP4R4 forms a novel cytosolic complex with PP4c, independent from the complexes containing PP4R1, PP4R2.PP4R3, and alpha4 |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: cytosol (IDA, GO_REF:0000052). PP4R4 forms a stable cytosolic complex with PP4c; HPA immunofluorescence localisation agrees. Reason: Cytosol is the most specific location supported: the dedicated biochemical study identifies the PP4c-PP4R4 assembly as cytosolic and distinct from the PP4 complexes that act on chromatin-associated substrates. IBA and IDA rows make the same claim and are both accepted. Supporting Evidence: PMID:18715871 we identify a novel, stable cytosolic PP4c interacting partner, KIAA1622, which we have renamed PP4R4. PMID:18715871 Our data demonstrate that PP4R4 forms a novel cytosolic complex with PP4c, independent from the complexes containing PP4R1, PP4R2.PP4R3, and alpha4 |
| GO:0008287 protein serine/threonine phosphatase complex | IBA GO_REF:0000033 | MODIFY | Summary: protein serine/threonine phosphatase complex (IBA). PP4R4 is a component of a PPP4C-PPP4R4 assembly. Reason: Correct but general. The complex in question is specifically a PP4 holoenzyme (PPP4C plus regulatory subunit), for which GO has protein phosphatase 4 complex (GO:0030289, is_a GO:0008287). PP4R4 binds PP4c and not PP2Ac or PP6c, so the PP4-specific child is warranted for both the IDA and IBA rows. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001087371 · PTHR21467 PPPR4R4 family node SUPPORTS TRANSFER Node placement is sound; the only experimental donor is human PP4R4 itself. The transferred term is correct but the PP4-specific child GO:0030289 is warranted. Proposed replacements: protein phosphatase 4 complex Supporting Evidence: PMID:18715871 PP4R4 displays weak sequence homology with the A (scaffolding) subunit of the PP2A holoenzyme and specifically associates with PP4c (and not with the related PP2Ac or PP6c phosphatases). PMID:18715871 Our data demonstrate that PP4R4 forms a novel cytosolic complex with PP4c, independent from the complexes containing PP4R1, PP4R2.PP4R3, and alpha4 file:human/PPP4R4/PPP4R4-uniprot.txt Component of the PP4 complex PPP4C-PPP4R4. |
| GO:0008287 protein serine/threonine phosphatase complex | IDA PMID:18715871 PP4R4/KIAA1622 forms a novel stable cytosolic complex with p... | MODIFY | Summary: protein serine/threonine phosphatase complex (IDA). PP4R4 is a component of a PPP4C-PPP4R4 assembly. Reason: Correct but general. The complex in question is specifically a PP4 holoenzyme (PPP4C plus regulatory subunit), for which GO has protein phosphatase 4 complex (GO:0030289, is_a GO:0008287). PP4R4 binds PP4c and not PP2Ac or PP6c, so the PP4-specific child is warranted for both the IDA and IBA rows. Proposed replacements: protein phosphatase 4 complex Supporting Evidence: PMID:18715871 PP4R4 displays weak sequence homology with the A (scaffolding) subunit of the PP2A holoenzyme and specifically associates with PP4c (and not with the related PP2Ac or PP6c phosphatases). PMID:18715871 Our data demonstrate that PP4R4 forms a novel cytosolic complex with PP4c, independent from the complexes containing PP4R1, PP4R2.PP4R3, and alpha4 file:human/PPP4R4/PPP4R4-uniprot.txt Component of the PP4 complex PPP4C-PPP4R4. |
| GO:0019888 protein phosphatase regulator activity | IBA GO_REF:0000033 | ACCEPT | Summary: protein phosphatase regulator activity (IBA, PTN001087371). PP4R4 binds the PP4 catalytic subunit and modulates its activity in vitro; PAINT placed this function on the PPP4R4 family node with human PP4R4 as donor. Reason: This is the core molecular function: PP4R4 is a noncatalytic HEAT/ARM-repeat partner that binds PP4c specifically, at an interface analogous to PP2A A-subunit binding, and alters the activity of the catalytic subunit. The term is appropriately general given that the physiological substrates and the direction of regulation in vivo are unknown. PTHR21467 is a single-subfamily (SF0) vertebrate-restricted family in which human PP4R4 is the only characterised member, so the IBA is grounded on the target's own experimental data and asserts inheritance across PPP4R4 orthologs. Supporting Evidence: PMID:18715871 PP4R4 displays weak sequence homology with the A (scaffolding) subunit of the PP2A holoenzyme and specifically associates with PP4c (and not with the related PP2Ac or PP6c phosphatases). PMID:18715871 PP4c.PP4R4 complexes exhibit phosphatase activity toward a fluorogenic substrate and gammaH2AX, but this activity is lower than that associated with the PP4c.PP4R2.PP4R3 complex, which itself is less active than the free PP4c catalytic subunit. file:human/PPP4R4/PPP4R4-uniprot.txt PTHR21467:SF0; SERINE_THREONINE-PROTEIN PHOSPHATASE 4 REGULATORY SUBUNIT 4 |
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Download this section (compressed HTML)Q: What are the physiological substrates of the cytosolic PPP4C-PPP4R4 holoenzyme, and does PP4R4 redirect PP4c away from the chromatin-associated substrates (gammaH2AX, RPA2) targeted by PP4R2-PP4R3?
Q: Should the reduced in vitro activity of a PP2A-family holoenzyme relative to its free catalytic subunit be annotated as phosphatase inhibitor activity, given that the same is true of most regulatory subunits?
Experiment: Phosphoproteomics in PPP4R4 knockout versus wild-type cells (e.g., testis or neural lines where PPP4R4 is expressed) to identify substrates whose dephosphorylation depends on PPP4R4 but not PPP4R2/PPP4R3.
Experiment: Cryo-EM or AlphaFold-guided mutagenesis of the PPP4C-PPP4R4 interface to determine whether PP4R4 occludes or shapes the PPP4C active site, distinguishing inhibitory from substrate-targeting roles.
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