PPP2CA Review Notes

Gene Identity

• Gene: PPP2CA (Protein Phosphatase 2A Catalytic subunit alpha)
• UniProt: P67775
• EC: 3.1.3.16
• Aliases: PP2A-alpha, RP-C (Replication protein C)

Core Function Summary

PPP2CA encodes the catalytic subunit alpha of PP2A, a major serine/threonine phosphatase. The PP2A holoenzyme is a heterotrimer: catalytic C subunit (PPP2CA or PPP2CB) + scaffolding A subunit (PPP2R1A or PPP2R1B) + variable regulatory B subunit (from B55, B56, PR72, or striatin families). Over 80 distinct holoenzymes exist, together accounting for ~50-70% of cellular Ser/Thr phosphatase activity [deep-research-falcon; PMID:33243860 "INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7"].

Key Complexes

1. Canonical PP2A holoenzyme (AC dimer + B subunit) - substrate specificity determined by B subunit
2. INTAC complex (Integrator + PP2A-AC) - dephosphorylates Pol II CTD at S2, S5, S7 to regulate transcription [PMID:33243860, PMID:34004147, PMID:37080207, PMID:38570683]
3. STRIPAK complex (PP2A + striatins + STRIP1 + MOB4 etc.) - regulates Hippo signaling [PMID:33633399, PMID:29063833]

Key Regulation

• Leu309 methylation by LCMT-1, reversed by PME-1, regulates B subunit binding [PMID:8206937; UniProt PTM]
• Tyr307/Thr304 phosphorylation inhibits activity [UniProt PTM]
• Endogenous inhibitors: CIP2A, SET, PABIR1/FAM122A, ARPP19 [PMID:27588481, PMID:38123684]

Localization

• Cytoplasm, nucleus, chromosome (centromere during prometaphase), spindle pole during mitosis [PMID:16541025; UniProt SUBCELLULAR LOCATION]
• Chromatin-associated via INTAC complex [PMID:33243860, PMID:34004147]
• Membrane raft localization reported for ADCY8 interaction PMID:16258073

Substrate Landscape (2024 data)

• Brewer et al. 2024 (iScience) used dTAG degradation: 6,280 phosphopeptides increased >1.5-fold after PPP2CA loss, 2,651 >2-fold. Enriched in spliceosome, cell cycle, ubiquitin-mediated proteolysis pathways [deep-research-falcon].

Key Substrates (from UniProt FUNCTION)

• SV40 large T antigen, p53/TP53 PMID:1848668
• AXIN1 PMID:9920888
• RAF1 at Ser-259 (activation) PMID:10801873
• PIM3 (promoting degradation) PMID:12473674
• p53 at Thr55 (DNA damage response) PMID:17245430
• MYC (promoting degradation via AMBRA1) PMID:25438055
• FOXO3 (stabilization via AMBRA1) PMID:30513302
• WEE1 (stabilization, G2/M checkpoint) PMID:33108758
• Pol II CTD S2, S5, S7 (as INTAC) [PMID:33243860, PMID:34004147]
• MST1/2 T-loop (as STRIPAK) PMID:33633399
• AKT1 at Ser-473 (By similarity)
• CRTC3 PMID:30611118

Protein tyrosine phosphatase claim

• PMID:15525651 reports PP2A has tyrosine phosphatase activity stimulated by Galpha12. This is an unusual claim for PP2A. The paper shows "approximately 300% increase in phosphotyrosine phosphatase activity" in vitro. This is atypical and should be noted.

Disease

• Houge-Janssens syndrome 3 (HJS3) - de novo mutations cause syndromic intellectual disability PMID:30595372

Annotations Review Strategy

• Accept core phosphatase function annotations (GO:0004722, GO:0006470)
• Accept INTAC, STRIPAK complex memberships
• Accept well-supported localizations (cytoplasm, nucleus, chromatin, centromere)
• Mark "protein binding" annotations as uninformative - prefer more specific terms
• Evaluate pleiotropic process annotations (Wnt, Hippo, EMT, etc.) as non-core or context-dependent
• Some IEA annotations may be too broad or specific