ARPP19 (cAMP-regulated phosphoprotein 19) is a small (112-residue), intrinsically disordered member of the endosulfine family, paralogous to ENSA. It is a phosphorylation-controlled inhibitor of protein phosphatase 2A holoenzymes that carry a B55 regulatory subunit (PP2A-B55). At mitotic entry the Greatwall kinase MASTL phosphorylates ARPP19 on Ser62; phospho-Ser62-ARPP19 then binds PP2A-B55 through a tripartite interface on B55 and the catalytic subunit and blocks the phosphatase, so that cyclin B-CDK1 substrate phosphorylation can accumulate and persist through mitosis. Phospho-ARPP19 is also a slowly turned-over substrate of PP2A-B55; its eventual dephosphorylation reactivates the phosphatase and helps time mitotic exit. In mouse, Arpp19 loss is embryonic lethal and Arpp19-null fibroblasts prematurely dephosphorylate CDK1 substrates during mitosis, a defect ENSA does not compensate. A second site, Ser104, is phosphorylated by PKA (and in Xenopus oocytes the equivalent PKA site maintains prophase-I arrest); PKA and MASTL/MAST3 phosphorylation are mutually antagonistic. The shorter splice isoform ARPP-16, enriched in striatal medium spiny neurons, is phosphorylated on the equivalent site (Ser46) by MAST3 kinase to give basal inhibition of B55alpha- and B56delta-containing PP2A that is reversed by dopamine/PKA signalling. ARPP19 is a soluble cytoplasmic and nucleoplasmic protein; earlier reports of GAP-43 mRNA stabilization and alpha-synuclein binding are not well developed.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000086 G2/M transition of mitotic cell cycle | IMP PMID:21164014 The substrate of Greatwall kinase, Arpp19, controls mitosis ... | ACCEPT | Summary: Greatwall-phosphorylated Arpp19 binds and inhibits PP2A to promote mitotic entry; endogenous Arpp19, not ENSA, is the PP2A inhibitor at mitotic entry in egg extracts. Reason: This is the defining function of the gene. The primary evidence is Xenopus egg extract depletion/add-back (abstract-only in cache; the paper also used HeLa cells per its MeSH indexing), and the mechanism was subsequently reconstituted with purified human ARPP19 and human PP2A:B55 (PMID:38123684), whose authors state that inhibition of PP2A:B55 by ARPP19 is essential for mitotic entry. ARPP19 performs the inhibitory step itself, so this is participation, not mere necessity. Supporting Evidence: PMID:21164014 We identified cyclic adenosine monophosphate-regulated phosphoprotein 19 (Arpp19) and Ξ±-Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry. PMID:21164014 Although both proteins can inhibit PP2A, endogenous Arpp19, but not Ξ±-Endosulfine, is responsible for PP2A inhibition at mitotic entry in Xenopus egg extracts. PMID:38123684 The inhibition of PP2A:B55 by two B55-specific inhibitors, FAM122A and ARPP19, is essential for mitotic entry |
| GO:0000278 mitotic cell cycle | IMP PMID:21164014 The substrate of Greatwall kinase, Arpp19, controls mitosis ... | ACCEPT | Summary: Broad parent of GO:0000086 from the same paper; ARPP19 also sustains the mitotic phosphorylation state after entry and its dephosphorylation times mitotic exit. Reason: Correct but general. It is not redundant with the G2/M annotation because ARPP19 acts throughout mitosis, first as PP2A:B55 inhibitor and later as its substrate, so that its dephosphorylation enables mitotic exit (PMID:38123684); mouse Arpp19-null fibroblasts prematurely dephosphorylate CDK1 substrates during mitotic progression (deep research). An annotation at this level is acceptable alongside the more specific term. Supporting Evidence: PMID:21164014 We identified cyclic adenosine monophosphate-regulated phosphoprotein 19 (Arpp19) and Ξ±-Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry. file:human/ARPP19/ARPP19-deep-research-falcon.md Arpp19-null mouse embryonic fibroblasts had greatly reduced viability and premature dephosphorylation of key cyclin-B/CDK1 substrates during mitotic progression, consistent with insufficient PP2A-B55 inhibition. PMID:38123684 pS62-ARPP19 functions first as an inhibitor of PP2A:B55 but later becomes a substrate PMID:38123684 This dephosphorylation reactivates PP2A:B55 and enables progression through mitotic exit. |
| GO:0004864 protein phosphatase inhibitor activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT propagation of PP2A inhibitor activity across the endosulfine family (fly endos, yeast Igo1, pombe igo1, human ARPP19 itself). Reason: The endosulfine family is a Greatwall-phosphorylated PP2A-B55 inhibitor family from yeast to human, so the ancestral node placement is sound. Human ARPP19 has its own IDA for the term (PMID:28167675, PMID:38123684), which is why it appears among the descendant evidences; this is expected and marks direct experimental grounding on the target. Supporting Evidence: PMID:21164014 We identified cyclic adenosine monophosphate-regulated phosphoprotein 19 (Arpp19) and Ξ±-Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry. PMID:38123684 ARPP19 strictly requires phosphorylation by MASTL kinase to inhibit PP2A:B55 |
| GO:0004864 protein phosphatase inhibitor activity | IDA PMID:28167675 ARPP-16 Is a Striatal-Enriched Inhibitor of Protein Phosphat... | ACCEPT | Summary: The striatal ARPP-16 isoform of this gene binds the PP2A A subunit and, once phosphorylated on Ser46 (= Ser62 of ARPP-19) by MAST3, selectively inhibits B55alpha- and B56delta-containing PP2A heterotrimers in vitro. Reason: Direct in vitro phosphatase assays with purified components, plus in vivo support (conditional knockout raises dephosphorylation of PP2A substrates in striatum). ARPP-16 is an alternatively spliced product of ARPP19 and the inhibitory site is the same residue, so the activity belongs to this gene. The GO-CAM gocams/69729a3800000481 models this activity. Supporting Evidence: PMID:28167675 We find that ARPP-16 interacts directly with the scaffolding A subunit of the serine/threonine protein phosphatase, PP2A, and that phosphorylation of ARPP-16 at Ser46 by MAST3 kinase converts the protein into a selective inhibitor of B55Ξ±- and B56Ξ΄-containing heterotrimeric forms of PP2A. PMID:28167675 ARPP-16 is closely related to ARPP-19, an alternatively spliced variant that contains an additional 16 amino acids at the N terminus. |
| GO:0004864 protein phosphatase inhibitor activity | IDA PMID:38123684 Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19. | ACCEPT | Summary: Purified human MASTL-thiophosphorylated ARPP19 inhibits purified human PP2A:B55 in DiFMUP assays; unphosphorylated ARPP19 does not, and the C-terminal B55-binding segment is required for potent inhibition. Reason: Quantitative IC50 measurements with fully defined human components, backed by cryo-EM and NMR mapping of the inhibitory interface. This is the strongest direct evidence for the core activity. Supporting Evidence: PMID:38123684 ARPP19 strictly requires phosphorylation by MASTL kinase to inhibit PP2A:B55 PMID:38123684 the C-terminal deletion variants either do not inhibit (non-phosphorylated ARPP19 versus ARPP1919β75) or become a more than 50-fold weaker inhibitor (tpARPP19 versus tpARPP1919β75) |
| GO:0004864 protein phosphatase inhibitor activity | IMP PMID:38123684 Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19. | ACCEPT | Summary: Alanine-scanning and deletion mutants of ARPP19 lose PP2A:B55 binding and inhibition, mapping the activity to helices alpha2/alpha3, the pSer62 kink and the C terminus. Reason: Mutational evidence from the same structural study; mutant variants with reduced B55 binding (in HeLa pull-downs) and 38- to 50-fold weaker IC50 values establish which residues carry the inhibitory activity. Supporting Evidence: PMID:38123684 the C-terminal deletion variants either do not inhibit (non-phosphorylated ARPP19 versus ARPP1919β75) or become a more than 50-fold weaker inhibitor (tpARPP19 versus tpARPP1919β75) PMID:38123684 Consistent with their weaker affinities, the IC50 values of the 84AA85 and 88AA89 variants increased by 38- and 48-fold, respectively |
| GO:0005102 signaling receptor binding | IDA PMID:9653196 Human alpha-endosulfine, a possible regulator of sulfonylure... | REMOVE | Summary: The cited paper reports displacement of glibenclamide binding to the sulfonylurea receptor SUR1 by recombinant alpha-endosulfine (ENSA), not by ARPP19. Reason: The full text is cached. Every functional assay in this paper (glibenclamide displacement, KATP current inhibition, insulin secretion) used recombinant human alpha-endosulfine, which the authors state is encoded by a different gene from ARPP-19; the only ARPP-19 experiment is cloning a partial cDNA for sequence comparison. The paper is UniProt reference 1 for the ARPP-19 mRNA sequence, which is the likely origin of the mis-assignment; the same paper is correctly annotated to ENSA in GOA (GO:0005102, GO:0019870, GO:0050796). No later work reports SUR1 or KATP binding by ARPP19, and a later review of the family notes that there is no evidence ENSA is even extracellular. This is a mis-attribution to the paralog established from the full text, not an inference from the abstract. Supporting Evidence: PMID:9653196 We therefore cloned part of the human ARPP-19 cDNA (EMBL accession no. AJ223091 ), and compared its sequence to that of human Ξ±-endosulfine (Fig. 1 A ). PMID:9653196 A partial bovine Ξ±-endosulfine sequence displayed considerable homology with that of bovine ARPP-19 ( 14 β 16 ), although the two proteins appeared to be encoded by different genes ( 14 ). PMID:9653196 The recombinant protein displaces binding of the sulfonylurea [ 3 H]glibenclamide to Ξ² cell membranes, inhibits cloned K ATP channel currents, and stimulates insulin secretion. PMID:28167675 However, there is no evidence that ENSA is found extracellularly. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Single yeast two-hybrid pair (ARPP19-SPDYC, Speedy protein C) from the HuRI proteome-wide binary interactome screen. Reason: Generic protein binding carries no functional information; the screen is a high-throughput Y2H map with no ARPP19-specific follow-up, and no MF can be inferred from it. Removal does not assert that the interaction is false. Supporting Evidence: PMID:32296183 Specifically, yeast two-hybrid (Y2H) represents the only binary PPI assay that can be operated at sufficient throughput to systematically screen the human proteome for binary PPIs. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: ARPP19-APP pair from a neurodegenerative-disease-focused Y2H interactome map (abstract only in cache). Reason: Generic protein binding from a systematic Y2H screen; no functional consequence for ARPP19 is described and no informative MF can be assigned. Removal does not assert that the interaction is false (IntAct lists three supporting experiments). Supporting Evidence: PMID:32814053 connects βΌ5,000 human proteins via βΌ30,000 candidate interactions and is generated by systematic yeast two-hybrid interaction screening of βΌ500 ND-related proteins and integration of literature interactions |
| GO:0005515 protein binding | IPI PMID:38123684 Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19. | MODIFY | Summary: Direct binding of ARPP19 to PPP2R2A (B55alpha) within the PP2A:B55 holoenzyme, shown by cryo-EM, NMR and HeLa pull-downs. Reason: The interaction is real, direct and mechanistically characterized, so the generic term should be replaced by the informative one already carried by this gene, GO:0051721 protein phosphatase 2A binding, which is the binding component of the inhibitor activity (GO:0004864). Proposed replacements: protein phosphatase 2A binding Supporting Evidence: PMID:38123684 tpARPP19 binds PP2A:B55 using a tripartite mechanism: (1) residues 25β61 bind the top of B55 (B55 site 1); (2) tpS62 and helix Ξ±4 bind PP2Ac (B55 site 2); and (3) residues 86β112 bind B55 in a pocket (B55 site 3) nearly 50βΓ
away from site 1 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2168079 | KEEP AS NON CORE | Summary: Reactome places the MASTL-ARPP19 Ser62 phosphorylation reaction in the nucleoplasm. Reason: Plausible and consistent with the interphase/prophase nuclear localization of MASTL (accepted in the MASTL review) and with reports of ectopic Arpp19 in both cytoplasm and nucleus of fibroblasts, but it is a pathway-modelling placement rather than a localization experiment on ARPP19, and the protein is a small soluble IDP that is also cytoplasmic (UniProt, IBA). Retained as a non-core location. Supporting Evidence: Reactome:R-HSA-2168079 MASTL (GWL i.e. Greatwall kinase) phosphorylates ARPP19 on serine residue S62 (Gharbi-Ayachi et al. 2010). |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT propagation of cytoplasmic localization across the endosulfine family (rat Arpp19/Ensa, yeast Igo1). Reason: Consistent with UniProt (cytoplasm, by similarity), with the striatal localization of ARPP-16, and with the biology; PP2A-B55 is a cytoplasmic and nuclear phosphatase and after nuclear envelope breakdown all mitotic action is cytoplasmic. Supporting Evidence: PMID:28167675 We find that ARPP-16 interacts directly with the scaffolding A subunit of the serine/threonine protein phosphatase, PP2A, and that phosphorylation of ARPP-16 at Ser46 by MAST3 kinase converts the protein into a selective inhibitor of B55Ξ±- and B56Ξ΄-containing heterotrimeric forms of PP2A. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location keyword mapping (Cytoplasm, by similarity). Reason: Agrees with the IBA and with the known biology; no direct human localization study contradicts it. Supporting Evidence: PMID:28167675 We find that ARPP-16 interacts directly with the scaffolding A subunit of the serine/threonine protein phosphatase, PP2A, and that phosphorylation of ARPP-16 at Ser46 by MAST3 kinase converts the protein into a selective inhibitor of B55Ξ±- and B56Ξ΄-containing heterotrimeric forms of PP2A. |
| GO:0010923 negative regulation of phosphatase activity | IDA PMID:28167675 ARPP-16 Is a Striatal-Enriched Inhibitor of Protein Phosphat... | ACCEPT | Summary: MAST3-phosphorylated ARPP-16 suppresses PP2A activity toward striatal substrates; conditional knockout increases dephosphorylation of DARPP-32 Thr75, Akt Thr308 and ERK. Reason: This is the process term that directly corresponds to the inhibitor activity, and the one the UniProt GO-CAM curator chose for this activity (gocams/69729a3800000481). The more specific children (negative regulation of phosphoprotein phosphatase activity, negative regulation of protein dephosphorylation) are obsolete, so this is the correct level. Supporting Evidence: PMID:28167675 We find that ARPP-16 interacts directly with the scaffolding A subunit of the serine/threonine protein phosphatase, PP2A, and that phosphorylation of ARPP-16 at Ser46 by MAST3 kinase converts the protein into a selective inhibitor of B55Ξ±- and B56Ξ΄-containing heterotrimeric forms of PP2A. PMID:28167675 conditional knock-out of ARPP-16 in CaMKIIΞ±::cre/floxed ARPP-16/19 mice results in dephosphorylation of a subset of PP2A substrates including phospho-Thr75-DARPP-32, phospho-T308-Akt, and phospho-T202/Y204-ERK. |
| GO:0015459 potassium channel regulator activity | IDA PMID:9653196 Human alpha-endosulfine, a possible regulator of sulfonylure... | REMOVE | Summary: Inhibition of cloned Kir6.2/SUR1 KATP currents in this paper was measured with recombinant alpha-endosulfine (ENSA), not ARPP19. Reason: As for GO:0005102 from the same paper. The full text shows that the electrophysiology used recombinant human alpha-endosulfine, which the authors explicitly distinguish from ARPP-19 as the product of a different gene; ARPP-19 appears only in a sequence comparison. GOA already carries this evidence on ENSA (GO:0019870 potassium channel inhibitor activity, IDA). No independent evidence links ARPP19 to potassium channels. Supporting Evidence: PMID:9653196 We therefore cloned part of the human ARPP-19 cDNA (EMBL accession no. AJ223091 ), and compared its sequence to that of human Ξ±-endosulfine (Fig. 1 A ). PMID:9653196 A partial bovine Ξ±-endosulfine sequence displayed considerable homology with that of bovine ARPP-19 ( 14 β 16 ), although the two proteins appeared to be encoded by different genes ( 14 ). PMID:9653196 The recombinant protein displaces binding of the sulfonylurea [ 3 H]glibenclamide to Ξ² cell membranes, inhibits cloned K ATP channel currents, and stimulates insulin secretion. |
| GO:0019212 phosphatase inhibitor activity | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from Xenopus laevis Arpp19-A, the protein used in the original egg-extract work; parent of the experimentally supported GO:0004864. Reason: Correct and directly supported for the human protein; the Xenopus donor is the orthologue in which the function was first demonstrated, and human ARPP19 now has its own IDA for the more specific child term. An annotation at this parent level is acceptable. Supporting Evidence: PMID:21164014 We identified cyclic adenosine monophosphate-regulated phosphoprotein 19 (Arpp19) and Ξ±-Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry. PMID:38123684 ARPP19 strictly requires phosphorylation by MASTL kinase to inhibit PP2A:B55 |
| GO:0019888 protein phosphatase regulator activity | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from Xenopus Arpp19-A; parent of the experimentally supported GO:0004864. Reason: Correct, if general. ARPP19 is a bona fide PP2A-B55 regulator; the inhibitor child term is the informative one and is carried by IBA and IDA. Supporting Evidence: PMID:21164014 We identified cyclic adenosine monophosphate-regulated phosphoprotein 19 (Arpp19) and Ξ±-Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry. PMID:38123684 ARPP19 strictly requires phosphorylation by MASTL kinase to inhibit PP2A:B55 |
| GO:0045722 positive regulation of gluconeogenesis | IDA PMID:9653196 Human alpha-endosulfine, a possible regulator of sulfonylure... | REMOVE | Summary: The cited paper contains no gluconeogenesis experiment at all; it reports that recombinant alpha-endosulfine stimulates insulin secretion from MIN6 beta cells. Reason: The full text never mentions gluconeogenesis, and the protein assayed was ENSA, not ARPP19. Even for ENSA the observation (KATP closure and insulin secretion) is annotated in GOA as regulation of insulin secretion (GO:0050796), which if anything would suppress hepatic gluconeogenesis. There is no evidence in any later literature for a role of ARPP19 in gluconeogenesis; the annotation appears to be an erroneous transfer. Supporting Evidence: PMID:9653196 We therefore cloned part of the human ARPP-19 cDNA (EMBL accession no. AJ223091 ), and compared its sequence to that of human Ξ±-endosulfine (Fig. 1 A ). PMID:9653196 The recombinant protein displaces binding of the sulfonylurea [ 3 H]glibenclamide to Ξ² cell membranes, inhibits cloned K ATP channel currents, and stimulates insulin secretion. |
| GO:0046326 positive regulation of D-glucose import across plasma membrane | NAS PMID:9653196 Human alpha-endosulfine, a possible regulator of sulfonylure... | REMOVE | Summary: Author-statement annotation; the cited paper describes glucose-stimulated insulin secretion, not glucose import, and the protein studied was ENSA. Reason: The full text contains no statement about glucose uptake or import by any cell type, and no experiment with ARPP19. The NAS code indicates the term was not supported by an experiment even in the source; with the wrong gene as well, there is no basis to retain it. Supporting Evidence: PMID:9653196 We therefore cloned part of the human ARPP-19 cDNA (EMBL accession no. AJ223091 ), and compared its sequence to that of human Ξ±-endosulfine (Fig. 1 A ). PMID:9653196 The recombinant protein displaces binding of the sulfonylurea [ 3 H]glibenclamide to Ξ² cell membranes, inhibits cloned K ATP channel currents, and stimulates insulin secretion. |
| GO:0051721 protein phosphatase 2A binding | EXP PMID:38123684 Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19. | ACCEPT | Summary: DisProt-curated binding of the disordered ARPP19 to the PP2A:B55 holoenzyme (cryo-EM structure 8TTB, NMR). Reason: The binding is direct, structurally resolved and is the physical basis of the inhibitor activity; ARPP19 contacts both B55 and the catalytic subunit. This is an informative binding term, not a generic one. Supporting Evidence: PMID:38123684 tpARPP19 binds PP2A:B55 using a tripartite mechanism: (1) residues 25β61 bind the top of B55 (B55 site 1); (2) tpS62 and helix Ξ±4 bind PP2Ac (B55 site 2); and (3) residues 86β112 bind B55 in a pocket (B55 site 3) nearly 50βΓ
away from site 1 |
| GO:0051721 protein phosphatase 2A binding | IDA PMID:38123684 Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19. | ACCEPT | Summary: NMR titrations and pull-downs show ARPP19 (phosphorylated and unphosphorylated) binding PP2A:B55, with phosphorylation and the C terminus required for high affinity. Reason: Direct assay with purified human proteins and in HeLa cell extracts. Supporting Evidence: PMID:38123684 tpARPP19 binds PP2A:B55 using a tripartite mechanism: (1) residues 25β61 bind the top of B55 (B55 site 1); (2) tpS62 and helix Ξ±4 bind PP2Ac (B55 site 2); and (3) residues 86β112 bind B55 in a pocket (B55 site 3) nearly 50βΓ
away from site 1 PMID:38123684 YFPβARPP19 variants were transfected into HeLa cells, immunopurified and B55 binding was determined by western blot (nβ=β2). |
| GO:0051721 protein phosphatase 2A binding | IMP PMID:38123684 Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19. | ACCEPT | Summary: Alanine-scan mutants of ARPP19 helices alpha2/alpha3 and the pSer62 kink weaken B55 binding in HeLa pull-downs. Reason: Mutational mapping of the binding interface in cells; complements the structural IDA. Supporting Evidence: PMID:38123684 YFPβARPP19 variants were transfected into HeLa cells, immunopurified and B55 binding was determined by western blot (nβ=β2). PMID:38123684 pull-down experiments using YFPβARPP19 5-Ala variants, in which the kink and helix Ξ±4 residues are mutated to alanine (57AAAAA61, 62AAAAA66, 67AAAAA71 and 72AAAAA76), weaken B55 binding, albeit not to the same extent as 5-Ala variants of Ξ±2 or Ξ±3 |
| GO:0051721 protein phosphatase 2A binding | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from Xenopus Arpp19-A, which co-precipitates PP2A when phosphorylated by Greatwall. Reason: Now directly confirmed for the human protein (EXP/IDA/IMP above); the transfer is sound. Supporting Evidence: PMID:21164014 Conversely, in the absence of Gwl activity, Arpp19 and Ξ±-Endosulfine are dephosphorylated and lose their capacity to bind and inhibit PP2A. PMID:38123684 tpARPP19 binds PP2A:B55 using a tripartite mechanism: (1) residues 25β61 bind the top of B55 (B55 site 1); (2) tpS62 and helix Ξ±4 bind PP2Ac (B55 site 2); and (3) residues 86β112 bind B55 in a pocket (B55 site 3) nearly 50βΓ
away from site 1 |
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Download this section (compressed HTML)Q: Were the four GOA rows citing PMID:9653196 for ARPP19 (signaling receptor binding, potassium channel regulator activity, positive regulation of gluconeogenesis, positive regulation of D-glucose import) transferred from the alpha-endosulfine (ENSA) work because the paper is UniProt reference 1 for the ARPP-19 mRNA? If so they should be retired from P56211 and left on ENSA (O43768).
Suggested experts: UniProt GOA curators
Q: In human somatic cells, how is labour divided between ARPP19 and ENSA? Mouse genetics indicate ARPP19 is the non-redundant mitotic PP2A-B55 inhibitor while ENSA acts in S phase; is the same true in human cells, and does FAM122A initiate the inhibition that phospho-ARPP19 then takes over?
Suggested experts: Anna Castro, Thierry Lorca, Wolfgang Peti
Q: Does PKA phosphorylation of Ser104 have a physiological output in dividing human cells (as it does for prophase-I arrest in Xenopus oocytes and for MAST3 antagonism in striatal neurons), or is it restricted to non-dividing cells such as platelets and neurons?
Suggested experts: Angus C. Nairn
Experiment: Acute degron (dTAG/AID) depletion of endogenous ARPP19 versus ENSA in synchronized human cells, with live imaging of mitotic entry/exit timing and quantitative phosphoproteomics of CDK1 substrates; rescue with wild-type, S62A and S104A ARPP19 to separate the MASTL and PKA sites.
Hypothesis: ARPP19, not ENSA, is the physiological MASTL effector for PP2A-B55 inhibition at mitotic entry in human cells.
Type: degron genetics / phosphoproteomics
Experiment: Endogenous tagging of ARPP19 (CRISPR knock-in) with live imaging through the cell cycle, combined with a phospho-Ser62-specific antibody, to determine where and when the inhibitory form first appears relative to MASTL and PP2A-B55.
Hypothesis: Endogenous ARPP19 is nucleocytoplasmic in interphase and its MASTL-site phosphorylation begins in the nucleus before nuclear envelope breakdown.
Type: cell biology / imaging
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