ARPP19 (P56211) curation notes

2026-09-25 - initial review

Identity and inputs

• Human ARPP19, cAMP-regulated phosphoprotein 19, 112 aa, endosulfine family (PF04667),
  two isoforms: ARPP-19 (P56211-1) and the 16-residue-shorter, striatum-enriched ARPP-16
  (P56211-2). Paralog: ENSA (O43768).
• Inputs: UniProt record (entry v197), GOA tsv (23 rows), falcon deep research, cached
  publications for all six PMIDs and the Reactome reaction. Exemplar: genes/human/MASTL
  (COMPLETE). ENSA review was still INITIALIZED when this was written.
• Relevant repository objects: modules/g2_m_transition.yaml (endosulfine annoton, cites
  PMID:21164014) and GO-CAM gocams/69729a3800000481 (MAST3 regulates ARPP19; ARPP19
  activity typed GO:0004864, part_of GO:0010923, has_input PPP2R2A, negatively regulates
  the PP2A activity node).

Synthesized biology

• Core: MASTL/Greatwall phosphorylates Ser62 at mitotic entry; pSer62-ARPP19 binds and
  inhibits PP2A-B55 so CDK1 substrate phosphorylation persists; it is later slowly
  dephosphorylated by PP2A-B55, which times mitotic exit.
  PMID:21164014
  PMID:38123684 PMID:38123684
• Structure: cryo-EM 8TTB of PP2A:B55 with thiophosphorylated ARPP19; tripartite binding
  to the top of B55 (res 25-61), PP2Ac (pS62 + helix alpha4) and a distal B55 pocket
  (res 86-112). C-terminal deletion abolishes inhibition of the unphosphorylated protein
  and weakens the phosphorylated one >50-fold. PMID:38123684
• Endogenous relevance: in Xenopus egg extracts Arpp19, not ENSA, is the mitotic-entry
  inhibitor PMID:21164014. Deep research: mouse Arpp19
  KO is embryonic lethal; Arpp19-null MEFs prematurely dephosphorylate CDK1 substrates in
  mitosis and ENSA does not compensate (Hached et al. 2019, not cached).
• Neuronal arm: ARPP-16 in striatal MSNs is phosphorylated on Ser46 (= Ser62 of ARPP-19)
  by MAST3, giving basal inhibition of B55alpha/B56delta PP2A; PKA phosphorylation of
  Ser88 (= Ser104) is accompanied by Ser46 dephosphorylation, i.e. dopamine/cAMP relieves
  the inhibition. Conditional KO increases dephosphorylation of DARPP-32 Thr75, Akt
  Thr308, ERK. PMID:28167675
• PKA site Ser104 confirmed on human protein PMID:38123684. Xenopus oocyte
  prophase-I arrest via the PKA site is model-organism evidence (deep research).
• Localization: UniProt cytoplasm (by similarity); IBA cytoplasm; Reactome models the
  MASTL reaction in nucleoplasm. Deep research: ectopic Arpp19 in MEFs is both cytoplasmic
  and nuclear. No direct localization study of endogenous human ARPP19 through the cell
  cycle.
• The family authors themselves conclude the function is limited to PP2A control and
  that older ENSA "extracellular ligand" ideas are unsupported. PMID:28167675 PMID:28167675

Key curation decision: PMID:9653196 rows

Four GOA rows on ARPP19 cite Heron et al. 1998 (GO:0005102 IDA, GO:0015459 IDA,
GO:0045722 IDA, GO:0046326 NAS). The full text is cached. The paper clones and expresses
human alpha-endosulfine (ENSA) and performs every functional assay with that recombinant
protein; ARPP-19 appears only as a partial cDNA cloned for sequence comparison, explicitly
described as a different gene.
PMID:9653196
PMID:9653196
PMID:9653196

The paper never mentions gluconeogenesis or glucose import at all (grep of full text).
The same paper is correctly annotated to ENSA in GOA (GO:0005102, GO:0019870, GO:0050796,
GO:0007584). The likely origin of the ARPP19 rows is that this paper is UniProt reference
[1] for the ARPP-19 mRNA (AJ223091). All four rows -> REMOVE. This is not a case of
overruling a curator from an abstract: the full text is available and explicit.
Raised as a suggested question for GOA curators.

Other decisions

• GO:0000086 IMP and GO:0000278 IMP (PMID:21164014): ACCEPT both. Abstract-only in
  cache, but the function is established and reconstituted with human proteins.
  mitotic cell cycle is general but not redundant, because ARPP19 also acts as the
  PP2A-B55 "timer" for mitotic exit.
• GO:0004864 IBA/IDA/IDA/IMP: ACCEPT. IBA node PTN001309504 spans fly/yeast/pombe/human;
  human ARPP19 in its own WITH/FROM is the expected marker of direct evidence.
• GO:0010923 IDA: ACCEPT; obsolete children (GO:0032515, GO:0035308) verified on QuickGO,
  so this is the right level; matches the GO-CAM.
• GO:0051721 EXP/IDA/IMP/ISS: ACCEPT; informative binding term, structurally resolved.
• GO:0005515 IPI x3: PPP2R2A (PMID:38123684) -> MODIFY to GO:0051721; SPDYC (HuRI Y2H)
  and APP (ND interactome Y2H) -> REMOVE as uninformative, without asserting the
  interactions are false.
• GO:0019212 / GO:0019888 ISS from Xenopus Arpp19-A (Q6DEB4): ACCEPT (parents of 0004864).
• GO:0005654 TAS Reactome: KEEP_AS_NON_CORE (pathway placement, not localization data);
  MASTL review ACCEPTed the same row for the kinase, which is nuclear in interphase.
• GO:0005737 IBA/IEA: ACCEPT.
• No NEW terms. Considered regulation of mitotic cell cycle and meiosis terms; the
  meiotic arrest role is Xenopus-only and the existing G2/M + mitotic cell cycle terms
  cover the human evidence.

Validation

just validate human ARPP19 -> Valid, no warnings (after fixing a folded-scalar hyphen
and adding a deep-research citation). All supporting_text checked as verbatim substrings
(three quotes contain U+2009 thin spaces copied from the source).