Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004722 protein serine/threonine phosphatase activity	IBA GO_REF:0000033	ACCEPT	Summary: PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural, and genetic evidence. Reason: This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372, PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0000278 mitotic cell cycle	IBA GO_REF:0000033	ACCEPT	Summary: PP2A is involved in mitotic cell cycle regulation. IBA annotation from phylogenetic analysis. Reason: PP2A has well-established roles in mitotic cell cycle including centromeric cohesin protection via SGO1/SGO2 (PMID:16541025, PMID:16580887), spindle checkpoint regulation, and G2/M checkpoint (PMID:33108758). The 2024 substrate mapping study showed PPP2CA degradation causes G2/M arrest. This IBA annotation is well-supported. Supporting Evidence: PMID:16541025 Shugoshin collaborates with protein phosphatase 2A to protect cohesin
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0000775 chromosome, centromeric region	IEA GO_REF:0000120	ACCEPT	Summary: PPP2CA localizes to centromeric regions during prometaphase, where it protects centromeric cohesin via shugoshin. Reason: UniProt explicitly states: 'In prometaphase cells, but not in anaphase cells, localizes at centromeres' (PMID:16541025). This is supported by the SGO1/SGO2 interaction and centromeric cohesin protection function. Supporting Evidence: PMID:16541025 Shugoshin collaborates with protein phosphatase 2A to protect cohesin
GO:0000922 spindle pole	IEA GO_REF:0000044	ACCEPT	Summary: PPP2CA localizes to spindle poles during mitosis. Reason: UniProt subcellular location states: 'During mitosis, also found at spindle poles' (PMID:16541025). This is consistent with PP2A roles in mitotic regulation.
GO:0004722 protein serine/threonine phosphatase activity	IEA GO_REF:0000120	ACCEPT	Summary: PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural, and genetic evidence. Reason: This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372, PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: PPP2CA localizes to the nucleus, including via its role in the INTAC complex. Reason: Nuclear localization is well-established by multiple studies. UniProt cites PMID:16541025, PMID:33243860, PMID:34004147, PMID:39032490. Nuclear function includes transcription regulation via INTAC complex.
GO:0005694 chromosome	IEA GO_REF:0000044	ACCEPT	Summary: PPP2CA associates with chromosomes, consistent with its centromeric localization and INTAC complex function on chromatin. Reason: UniProt lists Chromosome as a subcellular location (PMID:33243860, PMID:34004147). PP2A is recruited to chromatin via the Integrator complex and localizes to centromeres during mitosis (PMID:16541025).
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: PPP2CA is present in the cytoplasm. Reason: Well-established cytoplasmic localization supported by UniProt (PMID:16541025, PMID:39032490) and consistent with PP2A function in cytoplasmic signaling pathways.
GO:0006357 regulation of transcription by RNA polymerase II	IEA GO_REF:0000108	ACCEPT	Summary: PPP2CA regulates transcription by RNA Polymerase II through the INTAC complex, which dephosphorylates the Pol II CTD. Reason: Well-supported by INTAC complex studies. PPP2CA dephosphorylates Pol II CTD at Ser2, Ser5, and Ser7 (PMID:33243860, PMID:34004147), thereby regulating transcription elongation. This IEA annotation based on logical inference is correct.
GO:0016787 hydrolase activity	IEA GO_REF:0000002	ACCEPT	Summary: PPP2CA has hydrolase activity as a phosphoprotein phosphatase that hydrolyzes phospho-ester bonds on serine/threonine residues. Reason: This is a correct but very broad parent term. PPP2CA is a hydrolase (phosphoester hydrolysis). More specific terms (GO:0004722) are also annotated, but this IEA annotation from InterPro is not wrong.
GO:0090443 FAR/SIN/STRIPAK complex	IEA GO_REF:0000117	ACCEPT	Summary: PPP2CA is a component of the STRIPAK complex as the catalytic subunit. Reason: Cryo-EM structure of human STRIPAK at 3.2 A confirms PPP2CA (PP2AC) is a core component, directly interacting with PP2AA, STRN3, and STRIP1 (PMID:33633399). STRIPAK regulates Hippo signaling by dephosphorylating MST1/2. Supporting Evidence: PMID:33633399 STRIPAK is established as a noncanonical PP2A complex with four copies of regulatory STRN3 for enhanced signal integration
GO:0005515 protein binding	IPI PMID:11591705 Protein phosphatase 2A interacts with and directly dephospho...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:11839802 Integrin alpha 2 beta 1 promotes activation of protein phosp...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:12963337 Parallel purification of three catalytic subunits of the pro...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:1328865 Identification of binding sites on the regulatory A subunit ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:15467457 A dynamic equilibrium between CDKs and PP2A modulates phosph...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:15761952 Single-step Strep-tag purification for the isolation and ide...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:16044149 Activation of the protein kinase B pathway by the HPV-16 E7 ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:16085932 A novel, evolutionarily conserved protein phosphatase comple...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:16126728 Positive regulation of IkappaB kinase signaling by protein s...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:16129692 Distinct protein phosphatase 2A heterotrimers modulate growt...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:16239230 Positive regulation of Raf1-MEK1/2-ERK1/2 signaling by prote...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:16456541 B56-containing PP2A dephosphorylate ERK and their activity i...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:16541025 Shugoshin collaborates with protein phosphatase 2A to protec...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:16764867 Interaction of nucleoredoxin with protein phosphatase 2A.	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:17055435 Structure of protein phosphatase 2A core enzyme bound to tum...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:17274953 Methylation of the C-terminal leucine residue of the PP2A ca...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:17384681 Identification of a PP2A-interacting protein that functions ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:17529992 Structural and biochemical insights into the regulation of p...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:17540176 The tumor suppressor PP2A Abeta regulates the RalA GTPase.	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:18394995 Structural mechanism of demethylation and inactivation of pr...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:18715871 PP4R4/KIAA1622 forms a novel stable cytosolic complex with p...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:18716626 Heterochromatin links to centromeric protection by recruitin...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:18782753 A PP2A phosphatase high density interaction network identifi...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:18977201 Physical association of GPR54 C-terminal with protein phosph...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:19060904 An empirical framework for binary interactome mapping.	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:19156129 An integrated workflow for charting the human interaction pr...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:19293187 PME-1 protects extracellular signal-regulated kinase pathway...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:19915589 The chromosomal association of condensin II is regulated by ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:20927323 Protein phosphatase 2A negatively regulates eukaryotic initi...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:21460856 ATM-mediated phosphorylation activates the tumor-suppressive...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:21806989 Mechanism of inhibition of PP2A activity and abnormal hyperp...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:23892082 A positive role of mammalian Tip41-like protein, TIPRL, in t...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:24126060 Over expression of PPP2R2C inhibits human glioma cells growt...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:25531779 STRIPAK components determine mode of cancer cell migration a...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:26256536 The Mechanism of ATP-Dependent Allosteric Protection of Akt ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:26496610 A human interactome in three quantitative dimensions organiz...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:27880917 Phenotypic and Interaction Profiling of the Human Phosphatas...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:28330616 Systematic Analysis of Human Protein Phosphatase Interaction...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:32878885 IRF1 Promotes the Innate Immune Response to Viral Infection ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:33633399 Cryo-EM structure of the Hippo signaling integrator human ST...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:37761890 Novel Variants of PPP2R1A in Catalytic Subunit Binding Domai...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:38123684 Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19.	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:7592815 Identification of a new family of protein phosphatase 2A reg...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:8392071 Structure and expression of a 72-kDa regulatory subunit of p...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:8617797 Identification of a novel protein phosphatase 2A regulatory ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:9647778 Alpha 4 associates with protein phosphatases 2A, 4, and 6.	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0000159 protein phosphatase type 2A complex	IEA GO_REF:0000107	ACCEPT	Summary: PPP2CA is a component of the protein phosphatase type 2A complex. Reason: PPP2CA is the catalytic subunit of PP2A. This is the defining complex for this protein. Supported by crystal structure (PMID:17055435), holoenzyme structure (PMID:17174897), and extensive biochemical characterization. Supporting Evidence: PMID:17055435 Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins
GO:0005829 cytosol	IEA GO_REF:0000107	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0005886 plasma membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation suggesting PPP2CA localizes to plasma membrane. Reason: PP2A has been reported at cell membranes in some contexts. The deep research notes localization to 'cell membrane'. However, this is not a primary localization and likely reflects B-subunit-dependent targeting to specific membrane-associated complexes.
GO:0043029 T cell homeostasis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: PP2Acalpha is required for CD8+ T-cell homeostasis, supported by mouse conditional deletion studies. Reason: A 2024 study (Zhou et al., Eur J Immunol) showed conditional PP2Acalpha deletion in T cells causes defective CD8+ T-cell homeostasis. While biologically significant, this is a tissue-specific phenotype rather than a core molecular function. The ISS annotation is based on mouse ortholog data.
GO:0045202 synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation suggesting PPP2CA localizes to synapses. PP2A is abundant in neurons and regulates synaptic proteins. Reason: PP2A is the major phosphatase in neurons (>70% of neuronal phosphatase activity) and regulates tau phosphorylation and other synaptic proteins. Synaptic localization is plausible but represents tissue-specific function rather than core function.
GO:0050811 GABA receptor binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation suggesting PPP2CA binds GABA receptors. PP2A has been implicated in regulation of GABA receptor phosphorylation in neurons. Reason: PP2A is known to regulate GABA receptor phosphorylation state in neurons, which is consistent with the very high abundance of PP2A in neuronal tissue (>70% of neuronal phosphatases). However, this is one of many substrate interactions and not a core defining function of PPP2CA.
GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: PP2A negatively regulates PI3K/AKT signaling by dephosphorylating AKT1 at Ser-473. Reason: PP2A dephosphorylation of AKT1 is supported by UniProt ('Together with RACK1 adapter, mediates dephosphorylation of AKT1 at Ser-473') and by PMID:21806946 (IMP). The 2024 T-cell study also implicates mTORC1 and AKT as PP2A downstream nodes. However, AKT regulation is one of many signaling roles of PP2A.
GO:1900227 positive regulation of NLRP3 inflammasome complex assembly	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: PP2A catalyzes dephosphorylation of the pyrin domain of NLRP3, promoting NLRP3 inflammasome assembly (by similarity from mouse). Reason: UniProt states 'Catalyzes dephosphorylation of the pyrin domain of NLRP3, promoting assembly of the NLRP3 inflammasome (By similarity)'. This is based on mouse ortholog data and represents one of many substrate-specific effects. Not a core function.
GO:1904539 negative regulation of glycolytic process through fructose-6-phosphate	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation suggesting PPP2CA negatively regulates glycolysis through fructose-6-phosphate. Reason: This is a very specific metabolic process annotation from Ensembl Compara (IEA). While PP2A may regulate glycolytic enzymes via dephosphorylation, this is a downstream pleiotropic effect rather than a core function.
GO:0004721 phosphoprotein phosphatase activity	IDA PMID:30595372 De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A...	ACCEPT	Summary: PPP2CA contributes phosphoprotein phosphatase activity as part of the PP2A holoenzyme complex. Reason: PPP2CA provides the catalytic phosphatase activity within the PP2A complex. The contributes_to qualifier is appropriate since the holoenzyme is required for full substrate-directed activity. The more specific GO:0004722 is also annotated. Supporting Evidence: PMID:30595372 PP2A, PPP2CA, Cause Syndromic Intellectual Disability
GO:0008287 protein serine/threonine phosphatase complex	IDA PMID:28167675 ARPP-16 Is a Striatal-Enriched Inhibitor of Protein Phosphat...	ACCEPT	Summary: PPP2CA is part of a protein serine/threonine phosphatase complex. Reason: PPP2CA functions in the PP2A complex, which is a serine/threonine phosphatase complex. This is a general cellular component term that is correct. PMID:28167675 identifies ARPP-16 as a PP2A inhibitor in the context of a serine/threonine phosphatase complex.
GO:0005634 nucleus	NAS PMID:32647223 INTS10-INTS13-INTS14 form a functional module of Integrator ...	ACCEPT	Summary: PPP2CA localizes to the nucleus, including via its role in the INTAC complex. Reason: Nuclear localization is well-established by multiple studies. UniProt cites PMID:16541025, PMID:33243860, PMID:34004147, PMID:39032490. Nuclear function includes transcription regulation via INTAC complex.
GO:0016180 snRNA processing	NAS PMID:16239144 Integrator, a multiprotein mediator of small nuclear RNA pro...	KEEP AS NON CORE	Summary: PPP2CA is linked to snRNA processing through the Integrator complex, which is involved in snRNA 3' end processing. Reason: The Integrator complex mediates snRNA 3' end processing (PMID:16239144). PPP2CA is part of the INTAC complex (Integrator + PP2A), but the endonuclease rather than the phosphatase module is primarily responsible for snRNA cleavage. PPP2CA's role in snRNA processing is indirect via its association with Integrator.
GO:0034243 regulation of transcription elongation by RNA polymerase II	IDA PMID:38570683 Structural basis of Integrator-dependent RNA polymerase II t...	ACCEPT	Summary: PPP2CA regulates transcription elongation by RNA polymerase II through the INTAC complex. Reason: Within the INTAC complex, PPP2CA dephosphorylates Pol II CTD and SUPT5H/SPT5, thereby preventing transcriptional elongation (PMID:38570683, PMID:34004147). This is a well-established function of the INTAC complex.
GO:0035330 regulation of hippo signaling	NAS PMID:33633399 Cryo-EM structure of the Hippo signaling integrator human ST...	KEEP AS NON CORE	Summary: PPP2CA regulates Hippo signaling through its role in the STRIPAK complex. Reason: This is the parent term of GO:0035331 (negative regulation of hippo signaling). Since the more specific child term is already annotated, this broader term is redundant but not incorrect. Hippo regulation is one of many pathways modulated by PP2A.
GO:0097706 vascular endothelial cell response to oscillatory fluid shear stress	TAS Reactome:R-HSA-9860927	MARK AS OVER ANNOTATED	Summary: Reactome annotation linking PP2A to endothelial cell response to oscillatory shear stress. Reason: This is a highly specific process term from Reactome. While PP2A may participate in signaling downstream of PIEZO1/integrins, this level of specificity likely represents an over-annotation. PPP2CA is a general phosphatase, not specifically evolved for shear stress response.
GO:0004722 protein serine/threonine phosphatase activity	TAS Reactome:R-HSA-9865226	ACCEPT	Summary: PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural, and genetic evidence. Reason: This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372, PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0160240 RNA polymerase II transcription initiation surveillance	IDA PMID:33243860 Identification of Integrator-PP2A complex (INTAC), an RNA po...	ACCEPT	Summary: PPP2CA participates in RNA polymerase II transcription initiation surveillance as part of the INTAC complex. Reason: The INTAC complex drives premature transcription termination of unfavorably configured transcripts by dephosphorylating Pol II CTD and SUPT5H/SPT5. This represents a quality checkpoint during transcription elongation (PMID:33243860, PMID:34004147, PMID:37080207, PMID:38570683). UniProt describes PPP2CA as 'Key mediator of a quality checkpoint during transcription elongation as part of the Integrator-PP2A (INTAC) complex'.
GO:0160240 RNA polymerase II transcription initiation surveillance	IDA PMID:34004147 The PP2A-Integrator-CDK9 axis fine-tunes transcription and c...	ACCEPT	Summary: PPP2CA participates in RNA polymerase II transcription initiation surveillance as part of the INTAC complex. Reason: The INTAC complex drives premature transcription termination of unfavorably configured transcripts by dephosphorylating Pol II CTD and SUPT5H/SPT5. This represents a quality checkpoint during transcription elongation (PMID:33243860, PMID:34004147, PMID:37080207, PMID:38570683). UniProt describes PPP2CA as 'Key mediator of a quality checkpoint during transcription elongation as part of the Integrator-PP2A (INTAC) complex'.
GO:0160240 RNA polymerase II transcription initiation surveillance	IDA PMID:37080207 INTAC endonuclease and phosphatase modules differentially re...	ACCEPT	Summary: PPP2CA participates in RNA polymerase II transcription initiation surveillance as part of the INTAC complex. Reason: The INTAC complex drives premature transcription termination of unfavorably configured transcripts by dephosphorylating Pol II CTD and SUPT5H/SPT5. This represents a quality checkpoint during transcription elongation (PMID:33243860, PMID:34004147, PMID:37080207, PMID:38570683). UniProt describes PPP2CA as 'Key mediator of a quality checkpoint during transcription elongation as part of the Integrator-PP2A (INTAC) complex'.
GO:0160240 RNA polymerase II transcription initiation surveillance	IDA PMID:38570683 Structural basis of Integrator-dependent RNA polymerase II t...	ACCEPT	Summary: PPP2CA participates in RNA polymerase II transcription initiation surveillance as part of the INTAC complex. Reason: The INTAC complex drives premature transcription termination of unfavorably configured transcripts by dephosphorylating Pol II CTD and SUPT5H/SPT5. This represents a quality checkpoint during transcription elongation (PMID:33243860, PMID:34004147, PMID:37080207, PMID:38570683). UniProt describes PPP2CA as 'Key mediator of a quality checkpoint during transcription elongation as part of the Integrator-PP2A (INTAC) complex'.
GO:0160232 INTAC complex	IDA PMID:33243860 Identification of Integrator-PP2A complex (INTAC), an RNA po...	ACCEPT	Summary: PPP2CA is a component of the INTAC (Integrator-PP2A) complex. Reason: PPP2CA is the phosphatase component of the INTAC complex, confirmed by cryo-EM structures (PMID:33243860, PMID:34762484, PMID:36869814, PMID:38570683) and functional studies (PMID:34004147, PMID:37080207). UniProt confirms PPP2CA as 'Phosphatase component of the Integrator-PP2A (INTAC) complex'. Supporting Evidence: PMID:33243860 we identified a complex containing Integrator and protein phosphatase 2A core enzyme (PP2A-AC), termed INTAC
GO:0160232 INTAC complex	IDA PMID:34004147 The PP2A-Integrator-CDK9 axis fine-tunes transcription and c...	ACCEPT	Summary: PPP2CA is a component of the INTAC (Integrator-PP2A) complex. Reason: PPP2CA is the phosphatase component of the INTAC complex, confirmed by cryo-EM structures (PMID:33243860, PMID:34762484, PMID:36869814, PMID:38570683) and functional studies (PMID:34004147, PMID:37080207). UniProt confirms PPP2CA as 'Phosphatase component of the Integrator-PP2A (INTAC) complex'. Supporting Evidence: PMID:33243860 we identified a complex containing Integrator and protein phosphatase 2A core enzyme (PP2A-AC), termed INTAC
GO:0160232 INTAC complex	IDA PMID:34762484 Structural basis of Integrator-mediated transcription regula...	ACCEPT	Summary: PPP2CA is a component of the INTAC (Integrator-PP2A) complex. Reason: PPP2CA is the phosphatase component of the INTAC complex, confirmed by cryo-EM structures (PMID:33243860, PMID:34762484, PMID:36869814, PMID:38570683) and functional studies (PMID:34004147, PMID:37080207). UniProt confirms PPP2CA as 'Phosphatase component of the Integrator-PP2A (INTAC) complex'. Supporting Evidence: PMID:33243860 we identified a complex containing Integrator and protein phosphatase 2A core enzyme (PP2A-AC), termed INTAC
GO:0160232 INTAC complex	IDA PMID:36869814 Structural basis of INTAC-regulated transcription.	ACCEPT	Summary: PPP2CA is a component of the INTAC (Integrator-PP2A) complex. Reason: PPP2CA is the phosphatase component of the INTAC complex, confirmed by cryo-EM structures (PMID:33243860, PMID:34762484, PMID:36869814, PMID:38570683) and functional studies (PMID:34004147, PMID:37080207). UniProt confirms PPP2CA as 'Phosphatase component of the Integrator-PP2A (INTAC) complex'. Supporting Evidence: PMID:33243860 we identified a complex containing Integrator and protein phosphatase 2A core enzyme (PP2A-AC), termed INTAC
GO:0160232 INTAC complex	IDA PMID:37080207 INTAC endonuclease and phosphatase modules differentially re...	ACCEPT	Summary: PPP2CA is a component of the INTAC (Integrator-PP2A) complex. Reason: PPP2CA is the phosphatase component of the INTAC complex, confirmed by cryo-EM structures (PMID:33243860, PMID:34762484, PMID:36869814, PMID:38570683) and functional studies (PMID:34004147, PMID:37080207). UniProt confirms PPP2CA as 'Phosphatase component of the Integrator-PP2A (INTAC) complex'. Supporting Evidence: PMID:33243860 we identified a complex containing Integrator and protein phosphatase 2A core enzyme (PP2A-AC), termed INTAC
GO:0160232 INTAC complex	IDA PMID:38570683 Structural basis of Integrator-dependent RNA polymerase II t...	ACCEPT	Summary: PPP2CA is a component of the INTAC (Integrator-PP2A) complex. Reason: PPP2CA is the phosphatase component of the INTAC complex, confirmed by cryo-EM structures (PMID:33243860, PMID:34762484, PMID:36869814, PMID:38570683) and functional studies (PMID:34004147, PMID:37080207). UniProt confirms PPP2CA as 'Phosphatase component of the Integrator-PP2A (INTAC) complex'. Supporting Evidence: PMID:33243860 we identified a complex containing Integrator and protein phosphatase 2A core enzyme (PP2A-AC), termed INTAC
GO:0031113 regulation of microtubule polymerization	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PP2A regulates microtubule polymerization, consistent with its role as the major phosphatase for microtubule-associated proteins. Reason: UniProt states 'PP2A is the major phosphatase for microtubule-associated proteins (MAPs)' (PMID:22613722). MAP dephosphorylation affects microtubule dynamics. However, this is one of many PP2A functions and not the core defining function. ISS annotation from ortholog data.
GO:0090090 negative regulation of canonical Wnt signaling pathway	IMP PMID:20080667 Role of DAB2IP in modulating epithelial-to-mesenchymal trans...	KEEP AS NON CORE	Summary: PP2A negatively regulates canonical Wnt signaling. PMID:20080667 shows DAB2IP modulates PP2A-GSK3B interaction affecting Wnt/beta-catenin pathway. Reason: PP2A interacts with AXIN1 (PMID:9920888) and GSK3B (PMID:20080667) in the Wnt pathway context. However, Wnt signaling regulation is one of many pathways modulated by PP2A and is not a core function of PPP2CA itself.
GO:0000785 chromatin	IDA PMID:33243860 Identification of Integrator-PP2A complex (INTAC), an RNA po...	ACCEPT	Summary: PPP2CA associates with chromatin as part of the INTAC complex. Reason: PPP2CA is recruited to chromatin via its association with the Integrator complex (PMID:33243860, PMID:34004147). UniProt states: 'Recruited to chromatin and transcription pause-release checkpoint via its association with the Integrator complex'. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II
GO:0000785 chromatin	IDA PMID:34004147 The PP2A-Integrator-CDK9 axis fine-tunes transcription and c...	ACCEPT	Summary: PPP2CA associates with chromatin as part of the INTAC complex. Reason: PPP2CA is recruited to chromatin via its association with the Integrator complex (PMID:33243860, PMID:34004147). UniProt states: 'Recruited to chromatin and transcription pause-release checkpoint via its association with the Integrator complex'. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II
GO:0004722 protein serine/threonine phosphatase activity	IDA PMID:34004147 The PP2A-Integrator-CDK9 axis fine-tunes transcription and c...	ACCEPT	Summary: PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural, and genetic evidence. Reason: This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372, PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0005634 nucleus	IDA PMID:33243860 Identification of Integrator-PP2A complex (INTAC), an RNA po...	ACCEPT	Summary: PPP2CA localizes to the nucleus, including via its role in the INTAC complex. Reason: Nuclear localization is well-established by multiple studies. UniProt cites PMID:16541025, PMID:33243860, PMID:34004147, PMID:39032490. Nuclear function includes transcription regulation via INTAC complex.
GO:0005634 nucleus	IDA PMID:34004147 The PP2A-Integrator-CDK9 axis fine-tunes transcription and c...	ACCEPT	Summary: PPP2CA localizes to the nucleus, including via its role in the INTAC complex. Reason: Nuclear localization is well-established by multiple studies. UniProt cites PMID:16541025, PMID:33243860, PMID:34004147, PMID:39032490. Nuclear function includes transcription regulation via INTAC complex.
GO:0180006 RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity	IDA PMID:33243860 Identification of Integrator-PP2A complex (INTAC), an RNA po...	ACCEPT	Summary: PPP2CA has RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity as part of the INTAC complex. Reason: PMID:33243860 demonstrates that INTAC dephosphorylates Pol II CTD at Ser2 (as well as Ser5 and Ser7). This specific phosphatase activity is a core function within the INTAC complex. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0180006 RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity	IDA PMID:34004147 The PP2A-Integrator-CDK9 axis fine-tunes transcription and c...	ACCEPT	Summary: PPP2CA has RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity as part of the INTAC complex. Reason: PMID:33243860 demonstrates that INTAC dephosphorylates Pol II CTD at Ser2 (as well as Ser5 and Ser7). This specific phosphatase activity is a core function within the INTAC complex. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0180007 RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity	IDA PMID:33243860 Identification of Integrator-PP2A complex (INTAC), an RNA po...	ACCEPT	Summary: PPP2CA has RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity as part of the INTAC complex. Reason: PMID:33243860 demonstrates INTAC dephosphorylates Pol II CTD at Ser5. This specific phosphatase activity is well-supported. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0180007 RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity	IDA PMID:34004147 The PP2A-Integrator-CDK9 axis fine-tunes transcription and c...	ACCEPT	Summary: PPP2CA has RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity as part of the INTAC complex. Reason: PMID:33243860 demonstrates INTAC dephosphorylates Pol II CTD at Ser5. This specific phosphatase activity is well-supported. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0180008 RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity	IDA PMID:33243860 Identification of Integrator-PP2A complex (INTAC), an RNA po...	ACCEPT	Summary: PPP2CA has RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity as part of the INTAC complex. Reason: PMID:33243860 demonstrates INTAC dephosphorylates Pol II CTD at Ser7. This specific phosphatase activity is well-supported. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0180008 RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity	IDA PMID:34004147 The PP2A-Integrator-CDK9 axis fine-tunes transcription and c...	ACCEPT	Summary: PPP2CA has RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity as part of the INTAC complex. Reason: PMID:33243860 demonstrates INTAC dephosphorylates Pol II CTD at Ser7. This specific phosphatase activity is well-supported. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0005634 nucleus	IDA PMID:39032490 Cytoplasmic binding partners of the Integrator endonuclease ...	ACCEPT	Summary: PPP2CA localizes to the nucleus, including via its role in the INTAC complex. Reason: Nuclear localization is well-established by multiple studies. UniProt cites PMID:16541025, PMID:33243860, PMID:34004147, PMID:39032490. Nuclear function includes transcription regulation via INTAC complex.
GO:0005829 cytosol	IDA PMID:39032490 Cytoplasmic binding partners of the Integrator endonuclease ...	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0035331 negative regulation of hippo signaling	IDA PMID:33633399 Cryo-EM structure of the Hippo signaling integrator human ST...	KEEP AS NON CORE	Summary: PPP2CA, as part of the STRIPAK complex, negatively regulates Hippo signaling by dephosphorylating MST1/2 kinases. Reason: PP2A-STRIPAK dephosphorylates MST1/2 T-loop, restraining Hippo pathway activation (PMID:33633399, PMID:29063833). This is a well-characterized function of the STRIPAK complex but is one of many signaling pathways regulated by PP2A, not the core defining function. Supporting Evidence: PMID:33633399 STRIPAK is a key negative regulator of the Hippo pathway
GO:0090443 FAR/SIN/STRIPAK complex	IDA PMID:33633399 Cryo-EM structure of the Hippo signaling integrator human ST...	ACCEPT	Summary: PPP2CA is a component of the STRIPAK complex as the catalytic subunit. Reason: Cryo-EM structure of human STRIPAK at 3.2 A confirms PPP2CA (PP2AC) is a core component, directly interacting with PP2AA, STRN3, and STRIP1 (PMID:33633399). STRIPAK regulates Hippo signaling by dephosphorylating MST1/2. Supporting Evidence: PMID:33633399 STRIPAK is established as a noncanonical PP2A complex with four copies of regulatory STRN3 for enhanced signal integration
GO:0004722 protein serine/threonine phosphatase activity	IDA PMID:29063833 SAV1 promotes Hippo kinase activation through antagonizing t...	ACCEPT	Summary: PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural, and genetic evidence. Reason: This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372, PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0005737 cytoplasm	IDA PMID:29063833 SAV1 promotes Hippo kinase activation through antagonizing t...	ACCEPT	Summary: PPP2CA is present in the cytoplasm. Reason: Well-established cytoplasmic localization supported by UniProt (PMID:16541025, PMID:39032490) and consistent with PP2A function in cytoplasmic signaling pathways.
GO:0035331 negative regulation of hippo signaling	IDA PMID:29063833 SAV1 promotes Hippo kinase activation through antagonizing t...	KEEP AS NON CORE	Summary: PPP2CA, as part of the STRIPAK complex, negatively regulates Hippo signaling by dephosphorylating MST1/2 kinases. Reason: PP2A-STRIPAK dephosphorylates MST1/2 T-loop, restraining Hippo pathway activation (PMID:33633399, PMID:29063833). This is a well-characterized function of the STRIPAK complex but is one of many signaling pathways regulated by PP2A, not the core defining function. Supporting Evidence: PMID:33633399 STRIPAK is a key negative regulator of the Hippo pathway
GO:0090443 FAR/SIN/STRIPAK complex	IDA PMID:29063833 SAV1 promotes Hippo kinase activation through antagonizing t...	ACCEPT	Summary: PPP2CA is a component of the STRIPAK complex as the catalytic subunit. Reason: Cryo-EM structure of human STRIPAK at 3.2 A confirms PPP2CA (PP2AC) is a core component, directly interacting with PP2AA, STRN3, and STRIP1 (PMID:33633399). STRIPAK regulates Hippo signaling by dephosphorylating MST1/2. Supporting Evidence: PMID:33633399 STRIPAK is established as a noncanonical PP2A complex with four copies of regulatory STRN3 for enhanced signal integration
GO:0035556 intracellular signal transduction	NAS PMID:11007961 Type 2A protein phosphatase, the complex regulator of numero...	KEEP AS NON CORE	Summary: PPP2CA/PP2A is involved in intracellular signal transduction through dephosphorylation of multiple signaling proteins. Reason: While PP2A is a major regulator of signal transduction pathways (Wnt, Hippo, MAPK, mTOR, AKT), this term is very broad. The core function is protein dephosphorylation; signal transduction is a downstream consequence.
GO:0004722 protein serine/threonine phosphatase activity	TAS PMID:21131359 Nuclear tau, a key player in neuronal DNA protection.	ACCEPT	Summary: PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural, and genetic evidence. Reason: This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372, PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0043029 T cell homeostasis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PP2Acalpha is required for CD8+ T-cell homeostasis, supported by mouse conditional deletion studies. Reason: A 2024 study (Zhou et al., Eur J Immunol) showed conditional PP2Acalpha deletion in T cells causes defective CD8+ T-cell homeostasis. While biologically significant, this is a tissue-specific phenotype rather than a core molecular function. The ISS annotation is based on mouse ortholog data.
GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PP2A negatively regulates PI3K/AKT signaling by dephosphorylating AKT1 at Ser-473. Reason: PP2A dephosphorylation of AKT1 is supported by UniProt ('Together with RACK1 adapter, mediates dephosphorylation of AKT1 at Ser-473') and by PMID:21806946 (IMP). The 2024 T-cell study also implicates mTORC1 and AKT as PP2A downstream nodes. However, AKT regulation is one of many signaling roles of PP2A.
GO:1900227 positive regulation of NLRP3 inflammasome complex assembly	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: PP2A catalyzes dephosphorylation of the pyrin domain of NLRP3, promoting NLRP3 inflammasome assembly (by similarity from mouse). Reason: UniProt states 'Catalyzes dephosphorylation of the pyrin domain of NLRP3, promoting assembly of the NLRP3 inflammasome (By similarity)'. This is based on mouse ortholog data and represents one of many substrate-specific effects. Not a core function.
GO:0004725 protein tyrosine phosphatase activity	IDA PMID:15525651 Galpha12 directly interacts with PP2A: evidence FOR Galpha12...	MARK AS OVER ANNOTATED	Summary: PMID:15525651 reports that Galpha12 stimulates PP2A activity ~300%. The GO annotation claims protein tyrosine phosphatase activity, but the abstract discusses general PP2A stimulation and tau dephosphorylation (a Ser/Thr substrate). PP2A is canonically a Ser/Thr phosphatase. Reason: While PMID:15525651 reports in vitro phosphotyrosine phosphatase activity for PP2A, this is not the canonical or well-established function. PP2A is universally recognized as a Ser/Thr phosphatase (EC 3.1.3.16). The tyrosine phosphatase activity reported in this single study may represent a minor or artificial in vitro activity. The UniProt entry does not list tyrosine phosphatase activity. Supporting Evidence: PMID:15525651 approximately 300% stimulation of PP2A activity
GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IMP PMID:21806946 Neurotensin signaling activates microRNAs-21 and -155 and Ak...	KEEP AS NON CORE	Summary: PP2A negatively regulates PI3K/AKT signaling by dephosphorylating AKT1 at Ser-473. Reason: PP2A dephosphorylation of AKT1 is supported by UniProt ('Together with RACK1 adapter, mediates dephosphorylation of AKT1 at Ser-473') and by PMID:21806946 (IMP). The 2024 T-cell study also implicates mTORC1 and AKT as PP2A downstream nodes. However, AKT regulation is one of many signaling roles of PP2A.
GO:0004722 protein serine/threonine phosphatase activity	IDA PMID:25438055 AMBRA1 links autophagy to cell proliferation and tumorigenes...	ACCEPT	Summary: PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural, and genetic evidence. Reason: This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372, PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0004722 protein serine/threonine phosphatase activity	IDA PMID:30513302 AMBRA1 Controls Regulatory T-Cell Differentiation and Homeos...	ACCEPT	Summary: PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural, and genetic evidence. Reason: This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372, PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:2000045 regulation of G1/S transition of mitotic cell cycle	IDA PMID:25438055 AMBRA1 links autophagy to cell proliferation and tumorigenes...	KEEP AS NON CORE	Summary: PMID:25438055 shows PPP2CA/PP2A dephosphorylates MYC (via AMBRA1), promoting MYC degradation and thereby regulating G1/S transition. Reason: Cell cycle regulation is a major PP2A function, and G1/S transition regulation via MYC dephosphorylation is well-supported (PMID:25438055). However, this is one of many cell cycle roles and the broader mitotic cell cycle term is already accepted.
GO:0006470 protein dephosphorylation	IMP PMID:33108758 CHK1 Inhibitor Blocks Phosphorylation of FAM122A and Promote...	ACCEPT	Summary: PPP2CA catalyzes protein dephosphorylation as its core biological process. Reason: Protein dephosphorylation is the central biological process catalyzed by PPP2CA/PP2A. Supported by extensive evidence including substrate mapping (deep research: 6,280 phosphopeptides increased upon PPP2CA degradation), individual substrate studies (PMID:33108758 for WEE1, PMID:25438055 for MYC, PMID:30513302 for FOXO3), and the EC number 3.1.3.16.
GO:0005515 protein binding	IPI PMID:17974561 Tesk1 interacts with Spry2 to abrogate its inhibition of ERK...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0004722 protein serine/threonine phosphatase activity	IDA PMID:30595372 De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A...	ACCEPT	Summary: PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural, and genetic evidence. Reason: This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372, PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0005515 protein binding	IPI PMID:30595372 De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0004722 protein serine/threonine phosphatase activity	IDA PMID:30611118 Mitogenic Signals Stimulate the CREB Coactivator CRTC3 throu...	ACCEPT	Summary: PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural, and genetic evidence. Reason: This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372, PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0005515 protein binding	IPI PMID:30611118 Mitogenic Signals Stimulate the CREB Coactivator CRTC3 throu...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0048156 tau protein binding	NAS PMID:28386764 Roles of tau protein in health and disease.	KEEP AS NON CORE	Summary: PP2A is reported to dephosphorylate tau and to bind tau, relevant to neurodegeneration. Reason: PP2A is described as a major tau phosphatase (PMID:10640627, PMID:16262633, PMID:28386764). While tau dephosphorylation is biologically important, it is one of many PP2A substrates and not a core defining function. Tau binding is context-dependent and mediated by specific holoenzymes (B55 family).
GO:0005515 protein binding	IPI PMID:16258073 A direct interaction between the N terminus of adenylyl cycl...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0045121 membrane raft	IDA PMID:16258073 A direct interaction between the N terminus of adenylyl cycl...	KEEP AS NON CORE	Summary: PMID:16258073 reports PP2A catalytic subunit localizes to membrane rafts in the context of ADCY8 interaction. Reason: The ADCY8 interaction study (PMID:16258073) provides direct evidence for membrane raft localization. However, this is likely context-dependent rather than a primary localization site.
GO:0005515 protein binding	IPI PMID:27588481 FAM122A, a new endogenous inhibitor of protein phosphatase 2...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:28609714 MFHAS1 suppresses TLR4 signaling pathway via induction of PP...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0004721 phosphoprotein phosphatase activity	TAS PMID:28386764 Roles of tau protein in health and disease.	ACCEPT	Summary: General phosphoprotein phosphatase activity annotation for PPP2CA. Reason: This is a parent term of GO:0004722. Acceptable as a broader annotation. Supporting Evidence: PMID:30595372 PP2A, PPP2CA, Cause Syndromic Intellectual Disability
GO:0004722 protein serine/threonine phosphatase activity	TAS PMID:28386764 Roles of tau protein in health and disease.	ACCEPT	Summary: PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural, and genetic evidence. Reason: This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372, PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0010288 response to lead ion	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: PP2A activity is affected by lead exposure. PMID:22387731 reports lead-induced over-activation of PP2A in rat hippocampus. Reason: PMID:22387731 reports lead exposure affects PP1 and PP2A activity in rat brain. However, this describes an environmental toxicology effect rather than a biological function of PPP2CA. The protein responds to lead by being affected, but this is not a functional annotation of the gene product.
GO:0010288 response to lead ion	TAS PMID:22387731 Over activation of hippocampal serine/threonine protein phos...	MARK AS OVER ANNOTATED	Summary: PP2A activity is affected by lead exposure. PMID:22387731 reports lead-induced over-activation of PP2A in rat hippocampus. Reason: PMID:22387731 reports lead exposure affects PP1 and PP2A activity in rat brain. However, this describes an environmental toxicology effect rather than a biological function of PPP2CA. The protein responds to lead by being affected, but this is not a functional annotation of the gene product.
GO:0004722 protein serine/threonine phosphatase activity	ISS GO_REF:0000024	ACCEPT	Summary: PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural, and genetic evidence. Reason: This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372, PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0004722 protein serine/threonine phosphatase activity	TAS PMID:10640627 Regulation of phosphorylation of neuronal microtubule-associ...	ACCEPT	Summary: PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural, and genetic evidence. Reason: This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372, PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0004722 protein serine/threonine phosphatase activity	TAS PMID:16262633 Contributions of protein phosphatases PP1, PP2A, PP2B and PP...	ACCEPT	Summary: PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural, and genetic evidence. Reason: This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372, PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity. Supporting Evidence: PMID:33243860 the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7
GO:0046982 protein heterodimerization activity	IPI PMID:9847399 Binding specificity of protein phosphatase 2A core enzyme fo...	ACCEPT	Summary: PPP2CA forms a heterodimer with the A scaffold subunit (PPP2R1A) as the PP2A core enzyme. Reason: PPP2CA forms a core heterodimer with PPP2R1A (the A subunit). This is well-established structurally (PMID:17055435, PMID:38123684) and functionally. PMID:9847399 specifically addresses binding specificity of the PP2A core enzyme. Supporting Evidence: PMID:9847399 Binding specificity of protein phosphatase 2A core enzyme for regulatory B subunits and T antigens
GO:0070062 extracellular exosome	HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote...	KEEP AS NON CORE	Summary: HDA annotation from PMID:20458337 identifies PPP2CA in B-cell exosomes by mass spectrometry. Reason: High-throughput proteomics data. PPP2CA was detected in exosomes but this likely reflects its high cellular abundance (~1% of total protein) rather than a specific exosomal function.
GO:0005829 cytosol	TAS Reactome:R-HSA-1295599	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0005829 cytosol	TAS Reactome:R-HSA-1295609	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0005829 cytosol	TAS Reactome:R-HSA-1295613	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0005829 cytosol	TAS Reactome:R-HSA-1295622	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0005829 cytosol	TAS Reactome:R-HSA-1295632	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0005829 cytosol	TAS Reactome:R-HSA-1549564	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0005829 cytosol	TAS Reactome:R-HSA-2995388	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0005829 cytosol	TAS Reactome:R-HSA-927813	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0005829 cytosol	TAS Reactome:R-HSA-927830	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0005829 cytosol	TAS Reactome:R-HSA-927836	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0005829 cytosol	TAS Reactome:R-HSA-934559	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0005829 cytosol	TAS Reactome:R-HSA-9667965	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0005829 cytosol	TAS Reactome:R-HSA-9865226	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0005515 protein binding	IPI PMID:20080667 Role of DAB2IP in modulating epithelial-to-mesenchymal trans...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0010719 negative regulation of epithelial to mesenchymal transition	IMP PMID:20080667 Role of DAB2IP in modulating epithelial-to-mesenchymal trans...	KEEP AS NON CORE	Summary: PMID:20080667 implicates PP2A in negative regulation of epithelial-to-mesenchymal transition via DAB2IP-mediated modulation. Reason: This is a downstream consequence of PP2A-mediated signaling rather than a core function. The study (PMID:20080667) shows DAB2IP modulates PP2A activity affecting EMT, but this is a pleiotropic effect rather than a primary function.
GO:0000159 protein phosphatase type 2A complex	IDA PMID:17055435 Structure of protein phosphatase 2A core enzyme bound to tum...	ACCEPT	Summary: PPP2CA is a component of the protein phosphatase type 2A complex. Reason: PPP2CA is the catalytic subunit of PP2A. This is the defining complex for this protein. Supported by crystal structure (PMID:17055435), holoenzyme structure (PMID:17174897), and extensive biochemical characterization. Supporting Evidence: PMID:17055435 Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins
GO:0000159 protein phosphatase type 2A complex	IDA PMID:17174897 Structure of the protein phosphatase 2A holoenzyme.	ACCEPT	Summary: PPP2CA is a component of the protein phosphatase type 2A complex. Reason: PPP2CA is the catalytic subunit of PP2A. This is the defining complex for this protein. Supported by crystal structure (PMID:17055435), holoenzyme structure (PMID:17174897), and extensive biochemical characterization. Supporting Evidence: PMID:17055435 Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins
GO:0005515 protein binding	IPI PMID:17485487 Tripin/hSgo2 recruits MCAK to the inner centromere to correc...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:16580887 PP2A is required for centromeric localization of Sgo1 and pr...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0005515 protein binding	IPI PMID:17245430 A specific PP2A regulatory subunit, B56gamma, mediates DNA d...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction data. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins). More specific molecular function terms should be used. The interactions themselves are well-documented but this GO term adds no functional insight.
GO:0000159 protein phosphatase type 2A complex	TAS PMID:11007961 Type 2A protein phosphatase, the complex regulator of numero...	ACCEPT	Summary: PPP2CA is a component of the protein phosphatase type 2A complex. Reason: PPP2CA is the catalytic subunit of PP2A. This is the defining complex for this protein. Supported by crystal structure (PMID:17055435), holoenzyme structure (PMID:17174897), and extensive biochemical characterization. Supporting Evidence: PMID:17055435 Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins
GO:0005634 nucleus	NAS PMID:11007961 Type 2A protein phosphatase, the complex regulator of numero...	ACCEPT	Summary: PPP2CA localizes to the nucleus, including via its role in the INTAC complex. Reason: Nuclear localization is well-established by multiple studies. UniProt cites PMID:16541025, PMID:33243860, PMID:34004147, PMID:39032490. Nuclear function includes transcription regulation via INTAC complex.
GO:0005739 mitochondrion	NAS PMID:11007961 Type 2A protein phosphatase, the complex regulator of numero...	KEEP AS NON CORE	Summary: NAS annotation from PMID:11007961 suggests mitochondrial localization of PP2A. Reason: Some PP2A holoenzymes have been reported to associate with mitochondria, consistent with PP2A roles in apoptosis regulation. However, this is not a primary localization and the NAS evidence code indicates non-traceable author statement.
GO:0005829 cytosol	TAS PMID:11007961 Type 2A protein phosphatase, the complex regulator of numero...	ACCEPT	Summary: PPP2CA localizes to the cytosol, which is a well-established localization for PP2A. Reason: PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025, PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A localization includes cytoplasm.
GO:0006470 protein dephosphorylation	TAS PMID:2849764 The nucleotide sequence of the cDNA encoding the human lung ...	ACCEPT	Summary: PPP2CA catalyzes protein dephosphorylation as its core biological process. Reason: Protein dephosphorylation is the central biological process catalyzed by PPP2CA/PP2A. Supported by extensive evidence including substrate mapping (deep research: 6,280 phosphopeptides increased upon PPP2CA degradation), individual substrate studies (PMID:33108758 for WEE1, PMID:25438055 for MYC, PMID:30513302 for FOXO3), and the EC number 3.1.3.16.
GO:0015630 microtubule cytoskeleton	NAS PMID:11007961 Type 2A protein phosphatase, the complex regulator of numero...	KEEP AS NON CORE	Summary: PP2A associates with the microtubule cytoskeleton, consistent with its role as the major MAP phosphatase. Reason: PP2A is the major phosphatase for microtubule-associated proteins (PMID:22613722). The MID1-alpha4-PP2Ac complex is described as microtubule-localized. However, this is one of many localizations. NAS evidence from review (PMID:11007961).
GO:0016020 membrane	NAS PMID:11007961 Type 2A protein phosphatase, the complex regulator of numero...	KEEP AS NON CORE	Summary: NAS annotation from PMID:11007961 suggests membrane localization. Reason: Very broad localization term. PP2A can associate with membranes through B-subunit targeting, but this is not a primary localization. NAS evidence from a review article.
GO:0040008 regulation of growth	NAS PMID:11360189 Absence of PPP2R1A mutations in Wilms tumor.	KEEP AS NON CORE	Summary: PP2A regulates cell growth through its phosphatase activity on multiple substrates. Reason: PP2A regulates cell growth through dephosphorylation of numerous signaling proteins. This is a very broad term. The NAS annotation from PMID:11360189 (a study about PPP2R1A mutations in Wilms tumor) provides indirect support.
GO:0045595 regulation of cell differentiation	NAS PMID:11360189 Absence of PPP2R1A mutations in Wilms tumor.	KEEP AS NON CORE	Summary: PP2A has been implicated in regulation of cell differentiation. Reason: PP2A affects cell differentiation through its broad phosphatase activity. This NAS annotation from PMID:11360189 is very general and represents a pleiotropic effect rather than a core function.

Core Functions

PPP2CA is the catalytic subunit of PP2A, the major cellular Ser/Thr phosphatase. It dephosphorylates phosphoserine and phosphothreonine residues on a wide range of protein substrates. EC 3.1.3.16. PP2A holoenzymes account for ~50-70% of total cellular Ser/Thr phosphatase activity.

Molecular Function:

protein serine/threonine phosphatase activity

Supporting Evidence:

PMID:33243860
the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7

As part of the INTAC complex (Integrator + PP2A-AC), PPP2CA dephosphorylates Pol II CTD at Ser2 (and also Ser5 and Ser7), driving premature transcription termination of unfavorably configured transcripts. This represents a transcription quality checkpoint function.

Molecular Function:

RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity

Supporting Evidence:

PMID:33243860
the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10640627

Regulation of phosphorylation of neuronal microtubule-associated proteins MAP1b and MAP2 by protein phosphatase-2A and -2B in rat brain.

PMID:11007961

Type 2A protein phosphatase, the complex regulator of numerous signaling pathways.

PMID:11360189

Absence of PPP2R1A mutations in Wilms tumor.

PMID:11591705

Protein phosphatase 2A interacts with and directly dephosphorylates RelA.

PMID:11839802

Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2A and dephosphorylation of Akt and glycogen synthase kinase 3 beta.

PMID:12963337

Parallel purification of three catalytic subunits of the protein serine/threonine phosphatase 2A family (PP2A(C), PP4(C), and PP6(C)) and analysis of the interaction of PP2A(C) with alpha4 protein.

PMID:1328865

Identification of binding sites on the regulatory A subunit of protein phosphatase 2A for the catalytic C subunit and for tumor antigens of simian virus 40 and polyomavirus.

PMID:15467457

A dynamic equilibrium between CDKs and PP2A modulates phosphorylation of pRB, p107 and p130.

PMID:15525651

Galpha12 directly interacts with PP2A: evidence FOR Galpha12-stimulated PP2A phosphatase activity and dephosphorylation of microtubule-associated protein, tau.

PMID:15761952

Single-step Strep-tag purification for the isolation and identification of protein complexes from mammalian cells.

PMID:16044149

Activation of the protein kinase B pathway by the HPV-16 E7 oncoprotein occurs through a mechanism involving interaction with PP2A.

PMID:16085932

A novel, evolutionarily conserved protein phosphatase complex involved in cisplatin sensitivity.

PMID:16126728

Positive regulation of IkappaB kinase signaling by protein serine/threonine phosphatase 2A.

PMID:16129692

Distinct protein phosphatase 2A heterotrimers modulate growth factor signaling to extracellular signal-regulated kinases and Akt.

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network.

PMID:16239144

Integrator, a multiprotein mediator of small nuclear RNA processing, associates with the C-terminal repeat of RNA polymerase II.

PMID:16239230

Positive regulation of Raf1-MEK1/2-ERK1/2 signaling by protein serine/threonine phosphatase 2A holoenzymes.

PMID:16258073

A direct interaction between the N terminus of adenylyl cyclase AC8 and the catalytic subunit of protein phosphatase 2A.

PMID:16262633

Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation.

PMID:16456541

B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK.

PMID:16541025

Shugoshin collaborates with protein phosphatase 2A to protect cohesin.

PMID:16580887

PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation.

PMID:16764867

Interaction of nucleoredoxin with protein phosphatase 2A.

PMID:17055435

Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins.

PMID:17174897

Structure of the protein phosphatase 2A holoenzyme.

PMID:17245430

A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55.

PMID:17274953

Methylation of the C-terminal leucine residue of the PP2A catalytic subunit is unnecessary for the catalytic activity and the binding of regulatory subunit (PR55/B).

PMID:17384681

Identification of a PP2A-interacting protein that functions as a negative regulator of phosphatase activity in the ATM/ATR signaling pathway.

PMID:17485487

Tripin/hSgo2 recruits MCAK to the inner centromere to correct defective kinetochore attachments.

PMID:17529992

Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40.

PMID:17540176

The tumor suppressor PP2A Abeta regulates the RalA GTPase.

PMID:17974561

Tesk1 interacts with Spry2 to abrogate its inhibition of ERK phosphorylation downstream of receptor tyrosine kinase signaling.

PMID:18394995

Structural mechanism of demethylation and inactivation of protein phosphatase 2A.

PMID:18715871

PP4R4/KIAA1622 forms a novel stable cytosolic complex with phosphoprotein phosphatase 4.

PMID:18716626

Heterochromatin links to centromeric protection by recruiting shugoshin.

PMID:18782753

A PP2A phosphatase high density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein.

PMID:18977201

Physical association of GPR54 C-terminal with protein phosphatase 2A.

PMID:19060904

An empirical framework for binary interactome mapping.

PMID:19156129

An integrated workflow for charting the human interaction proteome: insights into the PP2A system.

PMID:19293187

PME-1 protects extracellular signal-regulated kinase pathway activity from protein phosphatase 2A-mediated inactivation in human malignant glioma.

PMID:19915589

The chromosomal association of condensin II is regulated by a noncatalytic function of PP2A.

PMID:20080667

Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis.

PMID:20458337

MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.

PMID:20927323

Protein phosphatase 2A negatively regulates eukaryotic initiation factor 4E phosphorylation and eIF4F assembly through direct dephosphorylation of Mnk and eIF4E.

PMID:21131359

Nuclear tau, a key player in neuronal DNA protection.

PMID:21460856

ATM-mediated phosphorylation activates the tumor-suppressive function of B56γ-PP2A.

PMID:21806946

Neurotensin signaling activates microRNAs-21 and -155 and Akt, promotes tumor growth in mice, and is increased in human colon tumors.

PMID:21806989

Mechanism of inhibition of PP2A activity and abnormal hyperphosphorylation of tau by I2(PP2A)/SET.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:22387731

Over activation of hippocampal serine/threonine protein phosphatases PP1 and PP2A is involved in lead-induced deficits in learning and memory in young rats.

PMID:23892082

A positive role of mammalian Tip41-like protein, TIPRL, in the amino-acid dependent mTORC1-signaling pathway through interaction with PP2A.

PMID:24126060

Over expression of PPP2R2C inhibits human glioma cells growth through the suppression of mTOR pathway.

PMID:25438055

AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation.

PMID:25531779

STRIPAK components determine mode of cancer cell migration and metastasis.

PMID:26256536

The Mechanism of ATP-Dependent Allosteric Protection of Akt Kinase Phosphorylation.

PMID:26496610

A human interactome in three quantitative dimensions organized by stoichiometries and abundances.

PMID:27588481

FAM122A, a new endogenous inhibitor of protein phosphatase 2A.

PMID:27880917

Phenotypic and Interaction Profiling of the Human Phosphatases Identifies Diverse Mitotic Regulators.

PMID:28167675

ARPP-16 Is a Striatal-Enriched Inhibitor of Protein Phosphatase 2A Regulated by Microtubule-Associated Serine/Threonine Kinase 3 (Mast 3 Kinase).

PMID:28330616

Systematic Analysis of Human Protein Phosphatase Interactions and Dynamics.

PMID:28386764

Roles of tau protein in health and disease.

PMID:2849764

The nucleotide sequence of the cDNA encoding the human lung protein phosphatase 2A alpha catalytic subunit.

PMID:28609714

MFHAS1 suppresses TLR4 signaling pathway via induction of PP2A C subunit cytoplasm translocation and inhibition of c-Jun dephosphorylation at Thr239.

PMID:29063833

SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK.

PMID:30513302

AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis.

PMID:30595372

De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders.

PMID:30611118

Mitogenic Signals Stimulate the CREB Coactivator CRTC3 through PP2A Recruitment.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32647223

INTS10-INTS13-INTS14 form a functional module of Integrator that binds nucleic acids and the cleavage module.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:32878885

IRF1 Promotes the Innate Immune Response to Viral Infection by Enhancing the Activation of IRF3.

PMID:33108758

CHK1 Inhibitor Blocks Phosphorylation of FAM122A and Promotes Replication Stress.

PMID:33243860

Identification of Integrator-PP2A complex (INTAC), an RNA polymerase II phosphatase.

PMID:33633399

Cryo-EM structure of the Hippo signaling integrator human STRIPAK.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:34004147

The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer.

PMID:34762484

Structural basis of Integrator-mediated transcription regulation.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:36869814

Structural basis of INTAC-regulated transcription.

PMID:37080207

INTAC endonuclease and phosphatase modules differentially regulate transcription by RNA polymerase II.

PMID:37761890

Novel Variants of PPP2R1A in Catalytic Subunit Binding Domain and Genotype-Phenotype Analysis in Neurodevelopmentally Delayed Patients.

PMID:38123684

Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19.

PMID:38570683

Structural basis of Integrator-dependent RNA polymerase II termination.

PMID:39032490

Cytoplasmic binding partners of the Integrator endonuclease INTS11 and its paralog CPSF73 are required for their nuclear function.

PMID:7592815

Identification of a new family of protein phosphatase 2A regulatory subunits.

PMID:8392071

Structure and expression of a 72-kDa regulatory subunit of protein phosphatase 2A. Evidence for different size forms produced by alternative splicing.

PMID:8617797

Identification of a novel protein phosphatase 2A regulatory subunit highly expressed in muscle.

PMID:9647778

Alpha 4 associates with protein phosphatases 2A, 4, and 6.

PMID:9847399

Binding specificity of protein phosphatase 2A core enzyme for regulatory B subunits and T antigens.

Reactome:R-HSA-1295599

SPRY2 translocates to the plasma membrane

Reactome:R-HSA-1295609

SRC phosphorylates SPRY2 on Y55 and Y227

Reactome:R-HSA-1295613

SPRY2 binds GRB2

Reactome:R-HSA-1295622

SPRY2 binds CBL

Reactome:R-HSA-1295632

PPA2A dephosphorylates SPRY2

Reactome:R-HSA-1549564

PPTN11 dephosphorylates SPRY2

Reactome:R-HSA-2995388

PP2A dephosphorylates BANF1

Reactome:R-HSA-927813

p-4S-UPF1 recruits SMG5, SMG7, SMG6, PNRC2, DCP1A, and PP2A

Reactome:R-HSA-927830

Decay of mRNA in SMG6:SMG5:SMG7:mRNA complex

Reactome:R-HSA-927836

SMG6 hydrolyzes mRNA with premature termination codon

Reactome:R-HSA-934559

SPRY2 is phosphorylated by phosphorylated MNK1

Reactome:R-HSA-9667965

ANKLE2 binds PP2A

Reactome:R-HSA-9860927

Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells

Reactome:R-HSA-9865226

PP2A dephosphorylates serine-127 of YAP1

Deep Research

Falcon

(PPP2CA-deep-research-falcon.md)

Research Report: PPP2CA (PP2A catalytic subunit α; UniProt P67775) — Functional Annotation (Human) Falcon Edison Scientific Literature 23 citations 2026-03-07T19:25:36.087422

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: PPP2CA (PP2A catalytic subunit α; UniProt P67775) — Functional Annotation (Human)

Executive summary

PPP2CA encodes the catalytic subunit α isoform (PP2Acα) of protein phosphatase 2A (PP2A), a ubiquitous and highly abundant Ser/Thr phosphatase whose biological specificity is primarily determined by assembly into heterotrimeric PP2A holoenzymes with scaffold (A) and regulatory (B) subunits. PP2A activity and holoenzyme composition are regulated by C-terminal post-translational modifications (notably Leu309 methylation and inhibitory tail phosphorylation such as Thr304/Tyr307) and by endogenous inhibitor proteins. Recent 2024 studies provide (i) a quantitative, proteome-scale atlas of putative PPP2CA substrates using acute targeted degradation in human cells and (ii) new genetic evidence for essential PP2Acα functions in CD8+ T-cell homeostasis and antibacterial immunity. PP2A catalytic inhibition is also being pursued clinically (LB-100), and 2024 mechanistic work links LB-100 to mRNA splicing perturbation and neoantigen generation, suggesting a plausible basis for synergy with immune checkpoint blockade.

1. Target verification and gene/protein identity

1.1 Verification against the provided UniProt entry

Peer-reviewed sources explicitly identify PPP2CA as encoding the PP2A catalytic subunit α (PP2Acα), and distinguish it from the β isoform encoded by PPP2CB (i.e., not an unrelated gene or non-human ortholog), matching the UniProt identity context you provided. (peris2023regulationandrole pages 2-4)

1.2 Core definition: what PPP2CA encodes

PP2A is described as a heterotrimeric Ser/Thr phosphatase, where the C subunit provides catalytic activity, the A subunit provides scaffolding, and a variable B subunit determines substrate specificity and localization. (peris2023regulationandrole pages 1-2)

2. Key concepts, definitions, and current understanding

2.1 What PP2A does: Ser/Thr dephosphorylation and scale of influence

PP2A holoenzymes are a dominant component of cellular Ser/Thr phosphatase activity: a cancer-focused PP2A-B56 review notes that >80 PP2A holoenzymes account for ~50–70% of total Ser/Thr phosphatase activity. (peris2023regulationandrole pages 1-2)

High-level estimates of abundance further emphasize its centrality: PP2A can constitute ~1% of cellular protein in some tissues, and one review notes >70% of neuronal phosphatases are PP2A. (sarais2025targetingpp2ain pages 1-3)

2.2 Holoenzyme architecture and how PPP2CA gains specificity

PP2A is generally considered a modular system:
- Core AC dimer (A scaffold + C catalytic) plus
- Regulatory B subunit to form the active A–B–C heterotrimer, with the B subunit largely dictating substrate selection and subcellular targeting. (peris2023regulationandrole pages 2-4, peris2023regulationandrole pages 1-2)

A 2025 synthesis (non-peer-reviewed in this corpus) provides useful numerical context consistent with broader PP2A literature: at least 26 B-subunit isoforms grouped into major families, yielding ~80 distinct holoenzyme compositions. (poyhtari2025targetingpp2athrougha pages 10-15, poyhtari2025targetingpp2athroughb pages 10-15)

2.3 Regulation by post-translational modifications (PTMs)

Leu309 C-terminal methylation

A central regulatory axis is C-terminal Leu309 methylation of PP2Acα:
- Methylation is catalyzed by LCMT-1 and reversed by PME-1, and it biases holoenzyme assembly/biogenesis. (peris2023regulationandrole pages 2-4)
- A 2024 structural/biochemical study quantified methylation levels: recombinant proteins purified from insect cells were ~6–8% methylated, while in vitro LCMT1 methylation increased methylation to ~30–40% by mass spectrometry. (wachter2024structuralcharacterizationof pages 2-4)
- In that same study, methylation did not measurably change phosphatase activity toward peptide substrates, suggesting methylation’s key role is in assembly/complex context rather than intrinsic catalytic chemistry. (wachter2024structuralcharacterizationof pages 2-4)

A structural image showing Leu309 positioned at the A–B–C interface is available from this study. (wachter2024structuralcharacterizationof media 4512be59)

C-terminal tail phosphorylation (Thr304/Tyr307)

C-terminal tail phosphorylation is also implicated in controlling holoenzyme binding/assembly:
- A 2023 review discusses Thr304/Tyr307 tail phosphorylation as regulatory, affecting B-subunit binding and other interactions, though mechanistic interpretation (especially for Tyr307) remains incompletely resolved in some contexts. (peris2023regulationandrole pages 2-4)
- A broader synthesis explicitly states that phosphorylation at Tyr307 inhibits Leu309 methylation and prevents binding of certain B subunits, functionally deactivating PP2A. (poyhtari2025targetingpp2athrougha pages 10-15, poyhtari2025targetingpp2athroughb pages 10-15)

2.4 Cellular localization

PP2A is not confined to one compartment: one review summarizes PP2A localization as including nucleus, cytoplasm, and cell membrane, with compartment-specific functions and B-subunit–dependent targeting. (sarais2025targetingpp2ain pages 1-3, sarais2025targetingpp2ain pages 12-14)

At a mechanistic level, regulatory subunits and accessory complexes can anchor PP2A components to specific structures; for example, a MID1–α4–PP2Ac complex is described as microtubule-localized, in which PP2Ac is sequestered in an inactive form unable to bind A/B subunits. (poyhtari2025targetingpp2athrougha pages 22-26)

3. Primary function: reaction and substrate specificity (functional annotation focus)

3.1 Reaction (functional definition)

PPP2CA encodes a catalytic Ser/Thr phosphatase subunit that removes phosphate groups from protein Ser/Thr residues via hydrolysis (dephosphorylation). A recent PPP2CA-focused substrate mapping paper defines phosphorylation as formation of a hydrolysable phospho-ester bond and phosphatase action as hydrolytic removal of this group. (brewer2024mappingthesubstrate pages 1-2)

3.2 Substrate specificity is holoenzyme-dependent and large-scale

Substrate recognition is heavily influenced by regulatory subunits (e.g., B56 family) that recognize targeting motifs and constrain enzyme access to substrates. (peris2023regulationandrole pages 13-13, peris2023regulationandrole pages 2-4)

2024: proteome-scale substrate landscape of PPP2CA

A major 2024 advance is acute depletion of endogenous PPP2CA in human cells to infer substrates:
- Using CRISPR knock-in of a degron tag (dTAG-PPP2CA) and PROTAC-mediated degradation, phosphoproteomics detected 39,103 phosphopeptides from 5,829 proteins. (brewer2024mappingthesubstrate pages 5-7)
- Upon PPP2CA degradation, 6,280 phosphopeptides (2,204 proteins) increased >1.5-fold, and 2,651 phosphopeptides (1,149 proteins) increased >2-fold, while only 16 phosphopeptides (11 proteins) decreased significantly—consistent with PPP2CA acting broadly as a phosphatase whose loss predominantly causes hyperphosphorylation. (brewer2024mappingthesubstrate pages 5-7)
- Total proteomics quantified 80,998 peptides mapping to 7,589 proteins, and PPP2CA was the only protein significantly decreased (>2-fold; p<0.05), supporting on-target degradation specificity. (brewer2024mappingthesubstrate pages 5-7)
- Bioinformatic enrichment connected putative substrates to spliceosome/RNA transport, cell cycle, and ubiquitin-mediated proteolysis. (brewer2024mappingthesubstrate pages 1-2)

These data support annotating PPP2CA as a global phosphorylation setpoint enzyme with context-specific substrate selection dependent on holoenzyme composition and pathway state.

4. Recent developments (prioritizing 2023–2024)

4.1 2024 structural characterization of methylation-independent assembly

A 2024 JBC study provides structural and biochemical evidence that enzymatically active PP2A A–B–C trimers can assemble and that AC dimers have little enzymatic activity compared with trimers, while also quantifying partial methylation and reporting an X-ray structure of an unmethylated Aα–B56ε–Cα complex. (wachter2024structuralcharacterizationof pages 2-4)

Structural evidence: The retrieved figure highlights Leu309 in the C-terminal tail wedged at the A–B–C interface, reinforcing a model where the C-terminal tail contributes to holoenzyme assembly geometry. (wachter2024structuralcharacterizationof media 4512be59)

4.2 2024 substrate mapping by acute PPP2CA degradation

The 2024 iScience study provides one of the clearest functional-annotation resources for PPP2CA by producing a large, quantifiable list of candidate substrates and pathway enrichments. (brewer2024mappingthesubstrate pages 1-2)

It also ties PPP2CA loss to cell-cycle control phenotypes: time-dependent phosphorylation increases and an increased G2/M fraction after 24 h degradation, followed by significant inhibition of proliferation after 48–72 h. (brewer2024mappingthesubstrate pages 11-13)

4.3 2024 immunology genetics: PPP2CA is required for CD8+ T-cell homeostasis

A 2024 European Journal of Immunology study used a conditional deletion model (Cd4CrePpp2caf/f) to show that PP2Acα is critically required for CD8+ T-cell homeostasis (secondary lymphoid organs and intestinal mucosa) and antibacterial responses (Listeria model), with proteomics/phosphoproteomics implicating mTORC1 and AKT signaling as downstream nodes. (zhou2024pp2acatalyticsubunit pages 1-3)

5. Pathways and biological processes (with emphasis on mechanistic specificity)

5.1 Cell cycle and proliferation

PPP2CA/PP2A is repeatedly characterized as central to cell-cycle control; acute PPP2CA degradation causes broad hyperphosphorylation and cell-cycle effects, including a significant shift toward G2/M. (brewer2024mappingthesubstrate pages 11-13)

5.2 RNA processing / splicing axis

Two independent 2024 efforts converge on splicing-related biology:
- PPP2CA degradation enriches putative substrates in spliceosome and RNA transport pathways. (brewer2024mappingthesubstrate pages 1-2)
- PP2A inhibition with LB-100 produces phosphorylation changes in splicing proteins and causes >1,000 exon skipping and intron retention events, linked to neoantigen generation and MHC-I presentation. (dias2024thephosphataseinhibitor pages 1-2)

5.3 mTOR/AKT signaling

In CD8+ T cells, PP2Acα-dependent pathways include mTORC1 and AKT as candidate targets/nodes by proteomics and phosphoproteomics. (zhou2024pp2acatalyticsubunit pages 1-3)

6. Current applications and real-world implementations

6.1 Pharmacological inhibition: LB-100

Mechanism and rationale

A 2024 EMBO Reports study describes LB-100 as a small-molecule inhibitor of PP2A and PP5 (PP2A/PP5), producing widespread phosphorylation changes affecting splicing factors and downstream immunogenic consequences (neoantigens). (dias2024thephosphataseinhibitor pages 1-2)

Clinical development (registry evidence)

LB-100 is being evaluated clinically primarily in oncology. ClinicalTrials.gov records provide concrete implementation details:

NCT01837667 (Phase 1; completed; n=29): LB-100 with docetaxel in solid tumors; primary endpoint safety/tolerability (AEs). (NCT01837667 chunk 1)
NCT03027388 (Phase 2; completed; n=7): recurrent glioblastoma; primary endpoint drug presence in tumor tissue; PK/PD and BBB penetration emphasis. (NCT03027388 chunk 1)
NCT03886662 (Phase 1b/2; recruiting; planned n=47): LB-100 monotherapy IV in low/intermediate-1 risk MDS; Phase 2 endpoint best overall response rate (IWG 2006). (NCT03886662 chunk 1)
NCT06012734 (recruiting): LB-100 + atezolizumab in metastatic colorectal cancer; assesses pharmacodynamic biomarkers with an on-treatment biopsy at cycle 3 day 3 (21-day cycles) and requires MSS phenotype. (NCT06012734 chunk 2)

A compact trial summary table is included below.

NCT ID	Title / Indication	Phase	Status	Enrollment	Key Endpoints / Notes	Sources
NCT03027388	Protein Phosphatase 2A Inhibitor in Recurrent Glioblastoma	Phase 2	Completed	7 (Actual)	Primary: Drug presence in tumor tissue. Notes: Evaluated BBB penetration and PK/PD in glioma tissue vs plasma.	(NCT03027388 chunk 2, NCT03027388 chunk 3, NCT03027388 chunk 1)
NCT03886662	LB-100 in Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS)	Phase 1b/2	Recruiting	47 (Est.)	Ph1b: Safety/Tolerability (AEs). Ph2: Best Overall Response Rate (IWG 2006).	(NCT03886662 chunk 1)
NCT01837667	LB-100 With Docetaxel in Solid Tumors	Phase 1	Completed	29 (Actual)	Primary: Safety/Tolerability (AEs). Notes: First-in-human dose escalation; preliminary activity in relapsed solid tumors.	(NCT01837667 chunk 1)
NCT06012734	LB-100 and Atezolizumab in Metastatic Colorectal Cancer	Not listed in text	Recruiting	Not listed in text	Outcome: Pharmacodynamic biomarkers of LB-100. Notes: Requires microsatellite stable (MSS) phenotype.	(NCT06012734 chunk 2)

Table: A summary of key clinical trials involving the PP2A inhibitor LB-100, detailing indications, study phases, recruitment status, and primary endpoints based on registry data.

Quantitative dose-escalation/trial outcomes (literature synthesis)

A 2023 translational synthesis summarizes an LB-100 Phase I dose escalation as including 29 patients, with MTD 2.33 mg/m², reported maximum plasma ~34.7 ng/mL, and one partial response (pancreatic cancer); it reports that 50% tolerated ≥2 cycles with stable disease up to 15 cycles in some patients. (murr2023activatingtranscriptionalelongation pages 29-33)

6.2 Pharmacological activation/stabilization: SMAPs (e.g., DT-061) and other activators

A 2025 review of tumor microenvironment roles describes PP2A activators including DT-061 (a SMAP), stating it stabilizes a PP2A-B56α heterotrimer and promotes dephosphorylation of oncogenic substrates such as c-MYC, with synergy described with MEK inhibition in KRAS-mutant models. (liu2025proteinserinethreoninephosphatases pages 14-15)

7. Expert opinions and interpretive analysis (authoritative sources)

7.1 PP2A as a modular signaling “hub” rather than a single enzyme

A consistent expert view in the PP2A literature is that “PP2A” comprises many distinct holoenzymes. A 2023 review emphasizes that regulatory B subunits determine substrate recognition and localization and that biogenesis is regulated by chaperones and C-terminal methylation, leading to “biased” holoenzyme assembly that can be therapeutically leveraged. (peris2023regulationandrole pages 13-13, peris2023regulationandrole pages 2-4)

7.2 Translational tension: PP2A as tumor suppressor vs PP2A inhibition as therapy

Multiple sources highlight context dependence: PP2A is often framed as tumor suppressive, motivating PP2A activation; nevertheless, PP2A inhibition (LB-100) shows therapeutic utility, especially in combinations (chemo/radiation/immunotherapy), plausibly by increasing replication stress, DNA repair defects, and immunogenicity (including splicing-derived neoantigens). (dias2024thephosphataseinhibitor pages 1-2, murr2023activatingtranscriptionalelongation pages 29-33)

8. Relevant statistics and recent quantitative data (selected)

Holoenzyme scale/activity: >80 PP2A holoenzymes contribute ~50–70% of cellular Ser/Thr phosphatase activity. (peris2023regulationandrole pages 1-2)
PPP2CA substrate mapping (2024): 39,103 phosphopeptides detected; 6,280 phosphopeptides (2,204 proteins) increased >1.5-fold after PPP2CA degradation; 2,651 increased >2-fold; only 16 decreased. (brewer2024mappingthesubstrate pages 5-7)
PP2A methylation stoichiometry (2024): baseline 6–8% methylated in recombinant preparations; increased to ~30–40% with in vitro LCMT1 methylation. (wachter2024structuralcharacterizationof pages 2-4)
LB-100 clinical trial enrollment (registry): Phase 1 solid tumor trial n=29 (NCT01837667); Phase 2 glioblastoma PK-in-tumor trial n=7 (NCT03027388); MDS trial planned n=47 (NCT03886662). (NCT01837667 chunk 1, NCT03027388 chunk 1, NCT03886662 chunk 1)

9. Evidence-backed structural support

The following figure provides structural support for the mechanistic claim that the PP2A catalytic subunit C-terminal tail (including Leu309) is embedded at the interface of the heterotrimer and is positioned to influence holoenzyme assembly. (wachter2024structuralcharacterizationof media 4512be59)

10. Consolidated functional-annotation table

Aspect	Evidence Summary	Key Sources
Identity & Enzyme Function	PPP2CA encodes the PP2A catalytic subunit alpha (PP2Acα), a major serine/threonine phosphatase accounting for ~1% of cellular protein and >70% of neuronal phosphatase activity. It dephosphorylates over 300 reported protein substrates.	(peris2023regulationandrole pages 13-13, poyhtari2025targetingpp2athrougha pages 10-15, sarais2025targetingpp2ain pages 1-3)
Holoenzyme Composition	Functions as a heterotrimer with a scaffold (A) and regulatory (B) subunit. Over 80 distinct holoenzymes exist via combinations with ~26 B-isoforms (families B55, B56, PR72, STRN), which dictate substrate specificity and localization.	(peris2023regulationandrole pages 13-13, poyhtari2025targetingpp2athrougha pages 10-15, poyhtari2025targetingpp2athroughb pages 10-15)
Regulation & PTMs	Activity is tightly controlled by C-terminal modifications: methylation at Leu309 (promotes B-subunit binding) and phosphorylation at Tyr307 (inhibits activity/methylation). Regulated by endogenous inhibitors like CIP2A, SET, and PME-1.	(peris2023regulationandrole pages 13-13, poyhtari2025targetingpp2athroughb pages 10-15, poyhtari2025targetingpp2athrougha pages 10-15, peris2023regulationandrole pages 2-4)
Substrate Landscape	A 2024 dTAG-based degradation study identified 2,204 putative PPP2CA substrates and >6,000 altered phosphopeptides, mapping a vast network involving cell cycle and spliceosome components.	(brewer2024mappingthesubstrate pages 1-2, brewer2024mappingthesubstrate pages 11-13)
Key 2023-2024 Findings	Recent studies established PPP2CA as critical for CD8+ T-cell homeostasis (2024) and structurally characterized methylation-independent holoenzyme assembly (2024). Acute degradation causes G2/M cell cycle arrest.	(wachter2024structuralcharacterizationof pages 2-4, brewer2024mappingthesubstrate pages 11-13, zhou2024pp2acatalyticsubunit pages 1-3)
Localization	Ubiquitous expression; subcellular localization (nucleus, cytoplasm, cytoskeleton) is strictly determined by the associated regulatory B-subunit (e.g., B55α targets microtubules).	(poyhtari2025targetingpp2athrougha pages 10-15, poyhtari2025targetingpp2athroughb pages 10-15, sarais2025targetingpp2ain pages 1-3)
Pathways	A "master regulator" of the cell cycle, DNA replication, apoptosis, and key signaling cascades including MAPK, Wnt/β-catenin, mTOR, and AKT.	(poyhtari2025targetingpp2athroughb pages 10-15, sarais2025targetingpp2ain pages 19-19, brewer2024mappingthesubstrate pages 1-2, zhou2024pp2acatalyticsubunit pages 1-3)
Therapeutic Modulation	Targeted by small molecule activators (SMAPs like DT-061) and inhibitors (LB-100). LB-100 is in multiple Phase 1/2 clinical trials for cancers (e.g., colorectal, glioblastoma) often in combination with immunotherapy or chemotherapy.	(poyhtari2025targetingpp2athroughb pages 10-15, sarais2025targetingpp2ain pages 1-3)

Table: This table consolidates key functional attributes of the PPP2CA gene product, including its enzymatic role, regulation, recent high-throughput substrate mapping results, and clinical relevance.

11. Limitations of this evidence set

The UniProt-provided EC number (EC 3.1.3.16) and detailed catalytic chemistry (metallo-dependent hydrolysis mechanism) were not explicitly captured in the extracted text snippets; the report therefore frames catalysis at the functional level (Ser/Thr dephosphorylation and holoenzyme-dependent specificity) rather than reproducing the full enzymatic mechanism description.
Not all retrieved clinical trials for LB-100 had chunks available in this run (e.g., some trials appeared in search results but were not provided as text chunks for extraction), so the clinical table is restricted to trials with explicit extracted evidence.

Key sources (2023–2024 prioritized)

Peris et al., 2023-09, BBA Reviews on Cancer: Regulation and role of PP2A-B56 holoenzymes in cancer. https://doi.org/10.1016/j.bbcan.2023.188953 (peris2023regulationandrole pages 2-4, peris2023regulationandrole pages 1-2)
Wachter et al., 2024-04, J Biol Chem: Structural characterization of methylation-independent PP2A assembly. https://doi.org/10.1016/j.jbc.2024.107268 (wachter2024structuralcharacterizationof pages 2-4, wachter2024structuralcharacterizationof media 4512be59)
Brewer et al., 2024-09, iScience: Mapping the substrate landscape of PPP2CA. https://doi.org/10.1016/j.isci.2024.109302 (brewer2024mappingthesubstrate pages 1-2, brewer2024mappingthesubstrate pages 5-7, brewer2024mappingthesubstrate pages 11-13)
Zhou et al., 2024-07, Eur J Immunol: PP2Acα required for CD8+ T-cell homeostasis. https://doi.org/10.1002/eji.202451080 (zhou2024pp2acatalyticsubunit pages 1-3)
Dias et al., 2024-04, EMBO Reports: LB-100 perturbs splicing and creates neoantigens. https://doi.org/10.1038/s44319-024-00128-3 (dias2024thephosphataseinhibitor pages 1-2, dias2024thephosphataseinhibitor pages 9-10)
ClinicalTrials.gov: NCT01837667 (2013), NCT03027388 (2019), NCT03886662 (2019), NCT06012734 (2024). (NCT01837667 chunk 1, NCT03027388 chunk 1, NCT03886662 chunk 1, NCT06012734 chunk 2)

References

(peris2023regulationandrole pages 2-4): Irene Peris, Silvia Romero-Murillo, Carmen Vicente, Goutham Narla, and Maria D. Odero. Regulation and role of the pp2a-b56 holoenzyme family in cancer. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1878:188953, Sep 2023. URL: https://doi.org/10.1016/j.bbcan.2023.188953, doi:10.1016/j.bbcan.2023.188953. This article has 21 citations and is from a peer-reviewed journal.
(peris2023regulationandrole pages 1-2): Irene Peris, Silvia Romero-Murillo, Carmen Vicente, Goutham Narla, and Maria D. Odero. Regulation and role of the pp2a-b56 holoenzyme family in cancer. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1878:188953, Sep 2023. URL: https://doi.org/10.1016/j.bbcan.2023.188953, doi:10.1016/j.bbcan.2023.188953. This article has 21 citations and is from a peer-reviewed journal.
(sarais2025targetingpp2ain pages 1-3): Fabio Sarais, Finja Krempien, Caroline Koehn, Lara Brewing, Carl Friedrich Classen, Michael Walter, and Olia Shokraie. Targeting pp2a in cancer: an underrated option. Journal of Experimental & Clinical Cancer Research, Oct 2025. URL: https://doi.org/10.1186/s13046-025-03560-y, doi:10.1186/s13046-025-03560-y. This article has 1 citations and is from a domain leading peer-reviewed journal.
(poyhtari2025targetingpp2athrougha pages 10-15): F Pöyhtäri. Targeting pp2a through mid1 and prep inhibitors. Unknown journal, 2025.
(poyhtari2025targetingpp2athroughb pages 10-15): F Pöyhtäri. Targeting pp2a through mid1 and prep inhibitors. Unknown journal, 2025.
(wachter2024structuralcharacterizationof pages 2-4): Franziska Wachter, Radosław P. Nowak, Scott Ficarro, J. Marto, and Eric S. Fischer. Structural characterization of methylation-independent pp2a assembly guides alphafold2multimer prediction of family-wide pp2a complexes. The Journal of Biological Chemistry, Apr 2024. URL: https://doi.org/10.1016/j.jbc.2024.107268, doi:10.1016/j.jbc.2024.107268. This article has 4 citations.
(wachter2024structuralcharacterizationof media 4512be59): Franziska Wachter, Radosław P. Nowak, Scott Ficarro, J. Marto, and Eric S. Fischer. Structural characterization of methylation-independent pp2a assembly guides alphafold2multimer prediction of family-wide pp2a complexes. The Journal of Biological Chemistry, Apr 2024. URL: https://doi.org/10.1016/j.jbc.2024.107268, doi:10.1016/j.jbc.2024.107268. This article has 4 citations.
(sarais2025targetingpp2ain pages 12-14): Fabio Sarais, Finja Krempien, Caroline Koehn, Lara Brewing, Carl Friedrich Classen, Michael Walter, and Olia Shokraie. Targeting pp2a in cancer: an underrated option. Journal of Experimental & Clinical Cancer Research, Oct 2025. URL: https://doi.org/10.1186/s13046-025-03560-y, doi:10.1186/s13046-025-03560-y. This article has 1 citations and is from a domain leading peer-reviewed journal.
(poyhtari2025targetingpp2athrougha pages 22-26): F Pöyhtäri. Targeting pp2a through mid1 and prep inhibitors. Unknown journal, 2025.
(brewer2024mappingthesubstrate pages 1-2): Abigail Brewer, Gajanan Sathe, Billie E. Pflug, Thomas J. Macartney, and Gopal P. Sapkota. Mapping the substrate landscape of protein phosphatase 2a catalytic subunit ppp2ca. iScience, Sep 2024. URL: https://doi.org/10.1016/j.isci.2024.109302, doi:10.1016/j.isci.2024.109302. This article has 17 citations and is from a peer-reviewed journal.
(peris2023regulationandrole pages 13-13): Irene Peris, Silvia Romero-Murillo, Carmen Vicente, Goutham Narla, and Maria D. Odero. Regulation and role of the pp2a-b56 holoenzyme family in cancer. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1878:188953, Sep 2023. URL: https://doi.org/10.1016/j.bbcan.2023.188953, doi:10.1016/j.bbcan.2023.188953. This article has 21 citations and is from a peer-reviewed journal.
(brewer2024mappingthesubstrate pages 5-7): Abigail Brewer, Gajanan Sathe, Billie E. Pflug, Thomas J. Macartney, and Gopal P. Sapkota. Mapping the substrate landscape of protein phosphatase 2a catalytic subunit ppp2ca. iScience, Sep 2024. URL: https://doi.org/10.1016/j.isci.2024.109302, doi:10.1016/j.isci.2024.109302. This article has 17 citations and is from a peer-reviewed journal.
(brewer2024mappingthesubstrate pages 11-13): Abigail Brewer, Gajanan Sathe, Billie E. Pflug, Thomas J. Macartney, and Gopal P. Sapkota. Mapping the substrate landscape of protein phosphatase 2a catalytic subunit ppp2ca. iScience, Sep 2024. URL: https://doi.org/10.1016/j.isci.2024.109302, doi:10.1016/j.isci.2024.109302. This article has 17 citations and is from a peer-reviewed journal.
(zhou2024pp2acatalyticsubunit pages 1-3): Xian Zhou, Meilu Li, Minji Ai, Yanfeng Li, Xingxing Zhu, Michael J. Hansen, Jun Zhong, Kenneth L. Johnson, Roman Zenka, Akhilesh Pandey, Larry R. Pease, and Hu Zeng. Pp2a catalytic subunit alpha is critically required for cd8+ t‐cell homeostasis and antibacterial responses. European Journal of Immunology, Jul 2024. URL: https://doi.org/10.1002/eji.202451080, doi:10.1002/eji.202451080. This article has 2 citations and is from a peer-reviewed journal.
(dias2024thephosphataseinhibitor pages 1-2): Matheus H Dias, Vladyslava Liudkovska, Jasmine Montenegro Navarro, Lisanne Giebel, Julien Champagne, Chrysa Papagianni, Onno B Bleijerveld, Arno Velds, Reuven Agami, René Bernards, and Maciej Cieśla. The phosphatase inhibitor lb-100 creates neoantigens in colon cancer cells through perturbation of mrna splicing. EMBO Reports, 25:2220-2238, Apr 2024. URL: https://doi.org/10.1038/s44319-024-00128-3, doi:10.1038/s44319-024-00128-3. This article has 17 citations and is from a highest quality peer-reviewed journal.
(NCT01837667 chunk 1): Phase I Study of LB-100 With Docetaxel in Solid Tumors. Lixte Biotechnology Holdings, Inc.. 2013. ClinicalTrials.gov Identifier: NCT01837667
(NCT03027388 chunk 1): Eric Burton. Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma. National Cancer Institute (NCI). 2019. ClinicalTrials.gov Identifier: NCT03027388
(NCT03886662 chunk 1): A Study of LB-100 in Patients With Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS). Lixte Biotechnology Holdings, Inc.. 2019. ClinicalTrials.gov Identifier: NCT03886662
(NCT06012734 chunk 2): LB-100 (PP2A Inhibitor) and Atezolizumab (PD-L1 Inhibitor) in Metastatic Colorectal Cancer Patients. The Netherlands Cancer Institute. 2024. ClinicalTrials.gov Identifier: NCT06012734
(NCT03027388 chunk 2): Eric Burton. Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma. National Cancer Institute (NCI). 2019. ClinicalTrials.gov Identifier: NCT03027388
(NCT03027388 chunk 3): Eric Burton. Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma. National Cancer Institute (NCI). 2019. ClinicalTrials.gov Identifier: NCT03027388
(murr2023activatingtranscriptionalelongation pages 29-33): JV Murr. Activating transcriptional elongation as a strategy to treat aggressive mesenchymal pancreatic ductal adenocarcinoma. Unknown journal, 2023.
(liu2025proteinserinethreoninephosphatases pages 14-15): Yiyang Liu, Feng Xia, Chang Zhu, Jia Song, Bufu Tang, Bixiang Zhang, and Zhao Huang. Protein serine/threonine phosphatases in tumor microenvironment: a vital player and a promising therapeutic target. Theranostics, 15:1164-1184, Jan 2025. URL: https://doi.org/10.7150/thno.104529, doi:10.7150/thno.104529. This article has 1 citations and is from a domain leading peer-reviewed journal.
(sarais2025targetingpp2ain pages 19-19): Fabio Sarais, Finja Krempien, Caroline Koehn, Lara Brewing, Carl Friedrich Classen, Michael Walter, and Olia Shokraie. Targeting pp2a in cancer: an underrated option. Journal of Experimental & Clinical Cancer Research, Oct 2025. URL: https://doi.org/10.1186/s13046-025-03560-y, doi:10.1186/s13046-025-03560-y. This article has 1 citations and is from a domain leading peer-reviewed journal.
(dias2024thephosphataseinhibitor pages 9-10): Matheus H Dias, Vladyslava Liudkovska, Jasmine Montenegro Navarro, Lisanne Giebel, Julien Champagne, Chrysa Papagianni, Onno B Bleijerveld, Arno Velds, Reuven Agami, René Bernards, and Maciej Cieśla. The phosphatase inhibitor lb-100 creates neoantigens in colon cancer cells through perturbation of mrna splicing. EMBO Reports, 25:2220-2238, Apr 2024. URL: https://doi.org/10.1038/s44319-024-00128-3, doi:10.1038/s44319-024-00128-3. This article has 17 citations and is from a highest quality peer-reviewed journal.

Citations

peris2023regulationandrole pages 2-4
peris2023regulationandrole pages 1-2
wachter2024structuralcharacterizationof pages 2-4
brewer2024mappingthesubstrate pages 1-2
brewer2024mappingthesubstrate pages 5-7
brewer2024mappingthesubstrate pages 11-13
dias2024thephosphataseinhibitor pages 1-2
murr2023activatingtranscriptionalelongation pages 29-33
liu2025proteinserinethreoninephosphatases pages 14-15
peris2023regulationandrole pages 13-13
dias2024thephosphataseinhibitor pages 9-10
https://doi.org/10.1016/j.bbcan.2023.188953
https://doi.org/10.1016/j.jbc.2024.107268
https://doi.org/10.1016/j.isci.2024.109302
https://doi.org/10.1002/eji.202451080
https://doi.org/10.1038/s44319-024-00128-3
https://doi.org/10.1016/j.bbcan.2023.188953,
https://doi.org/10.1186/s13046-025-03560-y,
https://doi.org/10.1016/j.jbc.2024.107268,
https://doi.org/10.1016/j.isci.2024.109302,
https://doi.org/10.1002/eji.202451080,
https://doi.org/10.1038/s44319-024-00128-3,
https://doi.org/10.7150/thno.104529,

📚 Additional Documentation

Notes

(PPP2CA-notes.md)

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

Canonical PP2A holoenzyme (AC dimer + B subunit) - substrate specificity determined by B subunit
INTAC complex (Integrator + PP2A-AC) - dephosphorylates Pol II CTD at S2, S5, S7 to regulate transcription [PMID:33243860, PMID:34004147, PMID:37080207, PMID:38570683]
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

📄 View Raw YAML

id: P67775
gene_symbol: PPP2CA
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: "NCBITaxon:9606"
  label: Homo sapiens
description: "PPP2CA encodes the catalytic subunit alpha isoform (PP2Acalpha) of protein phosphatase 2A\
  \ (PP2A), a major serine/threonine phosphatase (EC 3.1.3.16) that functions as a heterotrimer with a\
  \ scaffold A subunit and a variable regulatory B subunit. Over 80 distinct PP2A holoenzymes exist, together\
  \ accounting for approximately 50-70% of total cellular Ser/Thr phosphatase activity. Substrate specificity\
  \ is primarily determined by the regulatory B subunit. PPP2CA also functions in two non-canonical complexes:\
  \ the Integrator-PP2A (INTAC) complex, which dephosphorylates Pol II CTD at Ser2/5/7 to regulate transcription;\
  \ and the STRIPAK complex, which regulates Hippo signaling by dephosphorylating MST1/2. Activity is\
  \ regulated by C-terminal Leu309 methylation (by LCMT-1), tail phosphorylation (Tyr307/Thr304), and\
  \ endogenous inhibitors (PABIR1/FAM122A, ARPP19, CIP2A, SET). De novo mutations cause Houge-Janssens\
  \ syndrome 3 (syndromic intellectual disability)."
alternative_products:
- name: 1 (PP2Acalpha1)
  id: P67775-1
- name: 2 (PP2Acalpha2)
  id: P67775-2
  sequence_note: VSP_044320
existing_annotations:
- term:
    id: "GO:0004722"
    label: protein serine/threonine phosphatase activity
  evidence_type: IBA
  original_reference_id: "GO_REF:0000033"
  review:
    summary: "PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase\
      \ (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural,\
      \ and genetic evidence."
    action: ACCEPT
    reason: "This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine\
      \ residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372,\
      \ PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms\
      \ PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0000278"
    label: mitotic cell cycle
  evidence_type: IBA
  original_reference_id: "GO_REF:0000033"
  review:
    summary: "PP2A is involved in mitotic cell cycle regulation. IBA annotation from phylogenetic analysis."
    action: ACCEPT
    reason: "PP2A has well-established roles in mitotic cell cycle including centromeric cohesin protection\
      \ via SGO1/SGO2 (PMID:16541025, PMID:16580887), spindle checkpoint regulation, and G2/M checkpoint\
      \ (PMID:33108758). The 2024 substrate mapping study showed PPP2CA degradation causes G2/M arrest.\
      \ This IBA annotation is well-supported."
    supported_by:
    - reference_id: "PMID:16541025"
      supporting_text: Shugoshin collaborates with protein phosphatase 2A to protect cohesin
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: IBA
  original_reference_id: "GO_REF:0000033"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0000775"
    label: chromosome, centromeric region
  evidence_type: IEA
  original_reference_id: "GO_REF:0000120"
  review:
    summary: "PPP2CA localizes to centromeric regions during prometaphase, where it protects centromeric\
      \ cohesin via shugoshin."
    action: ACCEPT
    reason: "UniProt explicitly states: 'In prometaphase cells, but not in anaphase cells, localizes at\
      \ centromeres' (PMID:16541025). This is supported by the SGO1/SGO2 interaction and centromeric cohesin\
      \ protection function."
    supported_by:
    - reference_id: "PMID:16541025"
      supporting_text: Shugoshin collaborates with protein phosphatase 2A to protect cohesin
- term:
    id: "GO:0000922"
    label: spindle pole
  evidence_type: IEA
  original_reference_id: "GO_REF:0000044"
  review:
    summary: PPP2CA localizes to spindle poles during mitosis.
    action: ACCEPT
    reason: "UniProt subcellular location states: 'During mitosis, also found at spindle poles' (PMID:16541025).\
      \ This is consistent with PP2A roles in mitotic regulation."
- term:
    id: "GO:0004722"
    label: protein serine/threonine phosphatase activity
  evidence_type: IEA
  original_reference_id: "GO_REF:0000120"
  review:
    summary: "PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase\
      \ (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural,\
      \ and genetic evidence."
    action: ACCEPT
    reason: "This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine\
      \ residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372,\
      \ PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms\
      \ PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0005634"
    label: nucleus
  evidence_type: IEA
  original_reference_id: "GO_REF:0000044"
  review:
    summary: PPP2CA localizes to the nucleus, including via its role in the INTAC complex.
    action: ACCEPT
    reason: "Nuclear localization is well-established by multiple studies. UniProt cites PMID:16541025,\
      \ PMID:33243860, PMID:34004147, PMID:39032490. Nuclear function includes transcription regulation\
      \ via INTAC complex."
- term:
    id: "GO:0005694"
    label: chromosome
  evidence_type: IEA
  original_reference_id: "GO_REF:0000044"
  review:
    summary: "PPP2CA associates with chromosomes, consistent with its centromeric localization and INTAC\
      \ complex function on chromatin."
    action: ACCEPT
    reason: "UniProt lists Chromosome as a subcellular location (PMID:33243860, PMID:34004147). PP2A is\
      \ recruited to chromatin via the Integrator complex and localizes to centromeres during mitosis\
      \ (PMID:16541025)."
- term:
    id: "GO:0005737"
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: "GO_REF:0000120"
  review:
    summary: PPP2CA is present in the cytoplasm.
    action: ACCEPT
    reason: "Well-established cytoplasmic localization supported by UniProt (PMID:16541025, PMID:39032490)\
      \ and consistent with PP2A function in cytoplasmic signaling pathways."
- term:
    id: "GO:0006357"
    label: regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: "GO_REF:0000108"
  review:
    summary: "PPP2CA regulates transcription by RNA Polymerase II through the INTAC complex, which dephosphorylates\
      \ the Pol II CTD."
    action: ACCEPT
    reason: "Well-supported by INTAC complex studies. PPP2CA dephosphorylates Pol II CTD at Ser2, Ser5,\
      \ and Ser7 (PMID:33243860, PMID:34004147), thereby regulating transcription elongation. This IEA\
      \ annotation based on logical inference is correct."
- term:
    id: "GO:0016787"
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: "GO_REF:0000002"
  review:
    summary: "PPP2CA has hydrolase activity as a phosphoprotein phosphatase that hydrolyzes phospho-ester\
      \ bonds on serine/threonine residues."
    action: ACCEPT
    reason: "This is a correct but very broad parent term. PPP2CA is a hydrolase (phosphoester hydrolysis).\
      \ More specific terms (GO:0004722) are also annotated, but this IEA annotation from InterPro is\
      \ not wrong."
- term:
    id: "GO:0090443"
    label: FAR/SIN/STRIPAK complex
  evidence_type: IEA
  original_reference_id: "GO_REF:0000117"
  review:
    summary: PPP2CA is a component of the STRIPAK complex as the catalytic subunit.
    action: ACCEPT
    reason: "Cryo-EM structure of human STRIPAK at 3.2 A confirms PPP2CA (PP2AC) is a core component,\
      \ directly interacting with PP2AA, STRN3, and STRIP1 (PMID:33633399). STRIPAK regulates Hippo signaling\
      \ by dephosphorylating MST1/2."
    supported_by:
    - reference_id: "PMID:33633399"
      supporting_text: "STRIPAK is established as a noncanonical PP2A complex with four copies of regulatory\
        \ STRN3 for enhanced signal integration"
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:11591705"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:11839802"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:12963337"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:1328865"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:15467457"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:15761952"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:16044149"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:16085932"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:16126728"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:16129692"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:16189514"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:16239230"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:16456541"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:16541025"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:16764867"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:17055435"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:17274953"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:17384681"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:17529992"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:17540176"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:18394995"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:18715871"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:18716626"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:18782753"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:18977201"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:19060904"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:19156129"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:19293187"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:19915589"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:20927323"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:21460856"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:21806989"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:21988832"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:23892082"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:24126060"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:25531779"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:26256536"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:26496610"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:27880917"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:28330616"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:32296183"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:32814053"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:32878885"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:33633399"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:33961781"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:35271311"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:37761890"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:38123684"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:7592815"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:8392071"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:8617797"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:9647778"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0000159"
    label: protein phosphatase type 2A complex
  evidence_type: IEA
  original_reference_id: "GO_REF:0000107"
  review:
    summary: PPP2CA is a component of the protein phosphatase type 2A complex.
    action: ACCEPT
    reason: "PPP2CA is the catalytic subunit of PP2A. This is the defining complex for this protein. Supported\
      \ by crystal structure (PMID:17055435), holoenzyme structure (PMID:17174897), and extensive biochemical\
      \ characterization."
    supported_by:
    - reference_id: "PMID:17055435"
      supporting_text: Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: IEA
  original_reference_id: "GO_REF:0000107"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0005886"
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: "GO_REF:0000107"
  review:
    summary: IEA annotation suggesting PPP2CA localizes to plasma membrane.
    action: KEEP_AS_NON_CORE
    reason: "PP2A has been reported at cell membranes in some contexts. The deep research notes localization\
      \ to 'cell membrane'. However, this is not a primary localization and likely reflects B-subunit-dependent\
      \ targeting to specific membrane-associated complexes."
- term:
    id: "GO:0043029"
    label: T cell homeostasis
  evidence_type: IEA
  original_reference_id: "GO_REF:0000107"
  review:
    summary: "PP2Acalpha is required for CD8+ T-cell homeostasis, supported by mouse conditional deletion\
      \ studies."
    action: KEEP_AS_NON_CORE
    reason: "A 2024 study (Zhou et al., Eur J Immunol) showed conditional PP2Acalpha deletion in T cells\
      \ causes defective CD8+ T-cell homeostasis. While biologically significant, this is a tissue-specific\
      \ phenotype rather than a core molecular function. The ISS annotation is based on mouse ortholog\
      \ data."
- term:
    id: "GO:0045202"
    label: synapse
  evidence_type: IEA
  original_reference_id: "GO_REF:0000107"
  review:
    summary: "IEA annotation suggesting PPP2CA localizes to synapses. PP2A is abundant in neurons and\
      \ regulates synaptic proteins."
    action: KEEP_AS_NON_CORE
    reason: "PP2A is the major phosphatase in neurons (>70% of neuronal phosphatase activity) and regulates\
      \ tau phosphorylation and other synaptic proteins. Synaptic localization is plausible but represents\
      \ tissue-specific function rather than core function."
- term:
    id: "GO:0050811"
    label: GABA receptor binding
  evidence_type: IEA
  original_reference_id: "GO_REF:0000107"
  review:
    summary: "IEA annotation suggesting PPP2CA binds GABA receptors. PP2A has been implicated in regulation\
      \ of GABA receptor phosphorylation in neurons."
    action: KEEP_AS_NON_CORE
    reason: "PP2A is known to regulate GABA receptor phosphorylation state in neurons, which is consistent\
      \ with the very high abundance of PP2A in neuronal tissue (>70% of neuronal phosphatases). However,\
      \ this is one of many substrate interactions and not a core defining function of PPP2CA."
- term:
    id: "GO:0051898"
    label: "negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction"
  evidence_type: IEA
  original_reference_id: "GO_REF:0000107"
  review:
    summary: "PP2A negatively regulates PI3K/AKT signaling by dephosphorylating AKT1 at Ser-473."
    action: KEEP_AS_NON_CORE
    reason: "PP2A dephosphorylation of AKT1 is supported by UniProt ('Together with RACK1 adapter, mediates\
      \ dephosphorylation of AKT1 at Ser-473') and by PMID:21806946 (IMP). The 2024 T-cell study also\
      \ implicates mTORC1 and AKT as PP2A downstream nodes. However, AKT regulation is one of many signaling\
      \ roles of PP2A."
- term:
    id: "GO:1900227"
    label: positive regulation of NLRP3 inflammasome complex assembly
  evidence_type: IEA
  original_reference_id: "GO_REF:0000107"
  review:
    summary: "PP2A catalyzes dephosphorylation of the pyrin domain of NLRP3, promoting NLRP3 inflammasome\
      \ assembly (by similarity from mouse)."
    action: KEEP_AS_NON_CORE
    reason: "UniProt states 'Catalyzes dephosphorylation of the pyrin domain of NLRP3, promoting assembly\
      \ of the NLRP3 inflammasome (By similarity)'. This is based on mouse ortholog data and represents\
      \ one of many substrate-specific effects. Not a core function."
- term:
    id: "GO:1904539"
    label: negative regulation of glycolytic process through fructose-6-phosphate
  evidence_type: IEA
  original_reference_id: "GO_REF:0000107"
  review:
    summary: "IEA annotation suggesting PPP2CA negatively regulates glycolysis through fructose-6-phosphate."
    action: KEEP_AS_NON_CORE
    reason: "This is a very specific metabolic process annotation from Ensembl Compara (IEA). While PP2A\
      \ may regulate glycolytic enzymes via dephosphorylation, this is a downstream pleiotropic effect\
      \ rather than a core function."
- term:
    id: "GO:0004721"
    label: phosphoprotein phosphatase activity
  evidence_type: IDA
  original_reference_id: "PMID:30595372"
  qualifier: contributes_to
  review:
    summary: "PPP2CA contributes phosphoprotein phosphatase activity as part of the PP2A holoenzyme complex."
    action: ACCEPT
    reason: "PPP2CA provides the catalytic phosphatase activity within the PP2A complex. The contributes_to\
      \ qualifier is appropriate since the holoenzyme is required for full substrate-directed activity.\
      \ The more specific GO:0004722 is also annotated."
    supported_by:
    - reference_id: "PMID:30595372"
      supporting_text: PP2A, PPP2CA, Cause Syndromic Intellectual Disability
- term:
    id: "GO:0008287"
    label: protein serine/threonine phosphatase complex
  evidence_type: IDA
  original_reference_id: "PMID:28167675"
  review:
    summary: PPP2CA is part of a protein serine/threonine phosphatase complex.
    action: ACCEPT
    reason: "PPP2CA functions in the PP2A complex, which is a serine/threonine phosphatase complex. This\
      \ is a general cellular component term that is correct. PMID:28167675 identifies ARPP-16 as a PP2A\
      \ inhibitor in the context of a serine/threonine phosphatase complex."
- term:
    id: "GO:0005634"
    label: nucleus
  evidence_type: NAS
  original_reference_id: "PMID:32647223"
  review:
    summary: PPP2CA localizes to the nucleus, including via its role in the INTAC complex.
    action: ACCEPT
    reason: "Nuclear localization is well-established by multiple studies. UniProt cites PMID:16541025,\
      \ PMID:33243860, PMID:34004147, PMID:39032490. Nuclear function includes transcription regulation\
      \ via INTAC complex."
- term:
    id: "GO:0016180"
    label: snRNA processing
  evidence_type: NAS
  original_reference_id: "PMID:16239144"
  review:
    summary: "PPP2CA is linked to snRNA processing through the Integrator complex, which is involved in\
      \ snRNA 3' end processing."
    action: KEEP_AS_NON_CORE
    reason: "The Integrator complex mediates snRNA 3' end processing (PMID:16239144). PPP2CA is part of\
      \ the INTAC complex (Integrator + PP2A), but the endonuclease rather than the phosphatase module\
      \ is primarily responsible for snRNA cleavage. PPP2CA's role in snRNA processing is indirect via\
      \ its association with Integrator."
- term:
    id: "GO:0034243"
    label: regulation of transcription elongation by RNA polymerase II
  evidence_type: IDA
  original_reference_id: "PMID:38570683"
  review:
    summary: "PPP2CA regulates transcription elongation by RNA polymerase II through the INTAC complex."
    action: ACCEPT
    reason: "Within the INTAC complex, PPP2CA dephosphorylates Pol II CTD and SUPT5H/SPT5, thereby preventing\
      \ transcriptional elongation (PMID:38570683, PMID:34004147). This is a well-established function\
      \ of the INTAC complex."
- term:
    id: "GO:0035330"
    label: regulation of hippo signaling
  evidence_type: NAS
  original_reference_id: "PMID:33633399"
  review:
    summary: PPP2CA regulates Hippo signaling through its role in the STRIPAK complex.
    action: KEEP_AS_NON_CORE
    reason: "This is the parent term of GO:0035331 (negative regulation of hippo signaling). Since the\
      \ more specific child term is already annotated, this broader term is redundant but not incorrect.\
      \ Hippo regulation is one of many pathways modulated by PP2A."
- term:
    id: "GO:0097706"
    label: vascular endothelial cell response to oscillatory fluid shear stress
  evidence_type: TAS
  original_reference_id: "Reactome:R-HSA-9860927"
  review:
    summary: "Reactome annotation linking PP2A to endothelial cell response to oscillatory shear stress."
    action: MARK_AS_OVER_ANNOTATED
    reason: "This is a highly specific process term from Reactome. While PP2A may participate in signaling\
      \ downstream of PIEZO1/integrins, this level of specificity likely represents an over-annotation.\
      \ PPP2CA is a general phosphatase, not specifically evolved for shear stress response."
- term:
    id: "GO:0004722"
    label: protein serine/threonine phosphatase activity
  evidence_type: TAS
  original_reference_id: "Reactome:R-HSA-9865226"
  review:
    summary: "PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase\
      \ (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural,\
      \ and genetic evidence."
    action: ACCEPT
    reason: "This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine\
      \ residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372,\
      \ PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms\
      \ PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0160240"
    label: RNA polymerase II transcription initiation surveillance
  evidence_type: IDA
  original_reference_id: "PMID:33243860"
  review:
    summary: "PPP2CA participates in RNA polymerase II transcription initiation surveillance as part of\
      \ the INTAC complex."
    action: ACCEPT
    reason: "The INTAC complex drives premature transcription termination of unfavorably configured transcripts\
      \ by dephosphorylating Pol II CTD and SUPT5H/SPT5. This represents a quality checkpoint during transcription\
      \ elongation (PMID:33243860, PMID:34004147, PMID:37080207, PMID:38570683). UniProt describes PPP2CA\
      \ as 'Key mediator of a quality checkpoint during transcription elongation as part of the Integrator-PP2A\
      \ (INTAC) complex'."
- term:
    id: "GO:0160240"
    label: RNA polymerase II transcription initiation surveillance
  evidence_type: IDA
  original_reference_id: "PMID:34004147"
  review:
    summary: "PPP2CA participates in RNA polymerase II transcription initiation surveillance as part of\
      \ the INTAC complex."
    action: ACCEPT
    reason: "The INTAC complex drives premature transcription termination of unfavorably configured transcripts\
      \ by dephosphorylating Pol II CTD and SUPT5H/SPT5. This represents a quality checkpoint during transcription\
      \ elongation (PMID:33243860, PMID:34004147, PMID:37080207, PMID:38570683). UniProt describes PPP2CA\
      \ as 'Key mediator of a quality checkpoint during transcription elongation as part of the Integrator-PP2A\
      \ (INTAC) complex'."
- term:
    id: "GO:0160240"
    label: RNA polymerase II transcription initiation surveillance
  evidence_type: IDA
  original_reference_id: "PMID:37080207"
  review:
    summary: "PPP2CA participates in RNA polymerase II transcription initiation surveillance as part of\
      \ the INTAC complex."
    action: ACCEPT
    reason: "The INTAC complex drives premature transcription termination of unfavorably configured transcripts\
      \ by dephosphorylating Pol II CTD and SUPT5H/SPT5. This represents a quality checkpoint during transcription\
      \ elongation (PMID:33243860, PMID:34004147, PMID:37080207, PMID:38570683). UniProt describes PPP2CA\
      \ as 'Key mediator of a quality checkpoint during transcription elongation as part of the Integrator-PP2A\
      \ (INTAC) complex'."
- term:
    id: "GO:0160240"
    label: RNA polymerase II transcription initiation surveillance
  evidence_type: IDA
  original_reference_id: "PMID:38570683"
  review:
    summary: "PPP2CA participates in RNA polymerase II transcription initiation surveillance as part of\
      \ the INTAC complex."
    action: ACCEPT
    reason: "The INTAC complex drives premature transcription termination of unfavorably configured transcripts\
      \ by dephosphorylating Pol II CTD and SUPT5H/SPT5. This represents a quality checkpoint during transcription\
      \ elongation (PMID:33243860, PMID:34004147, PMID:37080207, PMID:38570683). UniProt describes PPP2CA\
      \ as 'Key mediator of a quality checkpoint during transcription elongation as part of the Integrator-PP2A\
      \ (INTAC) complex'."
- term:
    id: "GO:0160232"
    label: INTAC complex
  evidence_type: IDA
  original_reference_id: "PMID:33243860"
  review:
    summary: PPP2CA is a component of the INTAC (Integrator-PP2A) complex.
    action: ACCEPT
    reason: "PPP2CA is the phosphatase component of the INTAC complex, confirmed by cryo-EM structures\
      \ (PMID:33243860, PMID:34762484, PMID:36869814, PMID:38570683) and functional studies (PMID:34004147,\
      \ PMID:37080207). UniProt confirms PPP2CA as 'Phosphatase component of the Integrator-PP2A (INTAC)\
      \ complex'."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "we identified a complex containing Integrator and protein phosphatase 2A core\
        \ enzyme (PP2A-AC), termed INTAC"
- term:
    id: "GO:0160232"
    label: INTAC complex
  evidence_type: IDA
  original_reference_id: "PMID:34004147"
  review:
    summary: PPP2CA is a component of the INTAC (Integrator-PP2A) complex.
    action: ACCEPT
    reason: "PPP2CA is the phosphatase component of the INTAC complex, confirmed by cryo-EM structures\
      \ (PMID:33243860, PMID:34762484, PMID:36869814, PMID:38570683) and functional studies (PMID:34004147,\
      \ PMID:37080207). UniProt confirms PPP2CA as 'Phosphatase component of the Integrator-PP2A (INTAC)\
      \ complex'."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "we identified a complex containing Integrator and protein phosphatase 2A core\
        \ enzyme (PP2A-AC), termed INTAC"
- term:
    id: "GO:0160232"
    label: INTAC complex
  evidence_type: IDA
  original_reference_id: "PMID:34762484"
  review:
    summary: PPP2CA is a component of the INTAC (Integrator-PP2A) complex.
    action: ACCEPT
    reason: "PPP2CA is the phosphatase component of the INTAC complex, confirmed by cryo-EM structures\
      \ (PMID:33243860, PMID:34762484, PMID:36869814, PMID:38570683) and functional studies (PMID:34004147,\
      \ PMID:37080207). UniProt confirms PPP2CA as 'Phosphatase component of the Integrator-PP2A (INTAC)\
      \ complex'."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "we identified a complex containing Integrator and protein phosphatase 2A core\
        \ enzyme (PP2A-AC), termed INTAC"
- term:
    id: "GO:0160232"
    label: INTAC complex
  evidence_type: IDA
  original_reference_id: "PMID:36869814"
  review:
    summary: PPP2CA is a component of the INTAC (Integrator-PP2A) complex.
    action: ACCEPT
    reason: "PPP2CA is the phosphatase component of the INTAC complex, confirmed by cryo-EM structures\
      \ (PMID:33243860, PMID:34762484, PMID:36869814, PMID:38570683) and functional studies (PMID:34004147,\
      \ PMID:37080207). UniProt confirms PPP2CA as 'Phosphatase component of the Integrator-PP2A (INTAC)\
      \ complex'."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "we identified a complex containing Integrator and protein phosphatase 2A core\
        \ enzyme (PP2A-AC), termed INTAC"
- term:
    id: "GO:0160232"
    label: INTAC complex
  evidence_type: IDA
  original_reference_id: "PMID:37080207"
  review:
    summary: PPP2CA is a component of the INTAC (Integrator-PP2A) complex.
    action: ACCEPT
    reason: "PPP2CA is the phosphatase component of the INTAC complex, confirmed by cryo-EM structures\
      \ (PMID:33243860, PMID:34762484, PMID:36869814, PMID:38570683) and functional studies (PMID:34004147,\
      \ PMID:37080207). UniProt confirms PPP2CA as 'Phosphatase component of the Integrator-PP2A (INTAC)\
      \ complex'."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "we identified a complex containing Integrator and protein phosphatase 2A core\
        \ enzyme (PP2A-AC), termed INTAC"
- term:
    id: "GO:0160232"
    label: INTAC complex
  evidence_type: IDA
  original_reference_id: "PMID:38570683"
  review:
    summary: PPP2CA is a component of the INTAC (Integrator-PP2A) complex.
    action: ACCEPT
    reason: "PPP2CA is the phosphatase component of the INTAC complex, confirmed by cryo-EM structures\
      \ (PMID:33243860, PMID:34762484, PMID:36869814, PMID:38570683) and functional studies (PMID:34004147,\
      \ PMID:37080207). UniProt confirms PPP2CA as 'Phosphatase component of the Integrator-PP2A (INTAC)\
      \ complex'."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "we identified a complex containing Integrator and protein phosphatase 2A core\
        \ enzyme (PP2A-AC), termed INTAC"
- term:
    id: "GO:0031113"
    label: regulation of microtubule polymerization
  evidence_type: ISS
  original_reference_id: "GO_REF:0000024"
  review:
    summary: "PP2A regulates microtubule polymerization, consistent with its role as the major phosphatase\
      \ for microtubule-associated proteins."
    action: KEEP_AS_NON_CORE
    reason: "UniProt states 'PP2A is the major phosphatase for microtubule-associated proteins (MAPs)'\
      \ (PMID:22613722). MAP dephosphorylation affects microtubule dynamics. However, this is one of many\
      \ PP2A functions and not the core defining function. ISS annotation from ortholog data."
- term:
    id: "GO:0090090"
    label: negative regulation of canonical Wnt signaling pathway
  evidence_type: IMP
  original_reference_id: "PMID:20080667"
  review:
    summary: "PP2A negatively regulates canonical Wnt signaling. PMID:20080667 shows DAB2IP modulates\
      \ PP2A-GSK3B interaction affecting Wnt/beta-catenin pathway."
    action: KEEP_AS_NON_CORE
    reason: "PP2A interacts with AXIN1 (PMID:9920888) and GSK3B (PMID:20080667) in the Wnt pathway context.\
      \ However, Wnt signaling regulation is one of many pathways modulated by PP2A and is not a core\
      \ function of PPP2CA itself."
- term:
    id: "GO:0000785"
    label: chromatin
  evidence_type: IDA
  original_reference_id: "PMID:33243860"
  review:
    summary: PPP2CA associates with chromatin as part of the INTAC complex.
    action: ACCEPT
    reason: "PPP2CA is recruited to chromatin via its association with the Integrator complex (PMID:33243860,\
      \ PMID:34004147). UniProt states: 'Recruited to chromatin and transcription pause-release checkpoint\
      \ via its association with the Integrator complex'."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II"
- term:
    id: "GO:0000785"
    label: chromatin
  evidence_type: IDA
  original_reference_id: "PMID:34004147"
  review:
    summary: PPP2CA associates with chromatin as part of the INTAC complex.
    action: ACCEPT
    reason: "PPP2CA is recruited to chromatin via its association with the Integrator complex (PMID:33243860,\
      \ PMID:34004147). UniProt states: 'Recruited to chromatin and transcription pause-release checkpoint\
      \ via its association with the Integrator complex'."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II"
- term:
    id: "GO:0004722"
    label: protein serine/threonine phosphatase activity
  evidence_type: IDA
  original_reference_id: "PMID:34004147"
  review:
    summary: "PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase\
      \ (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural,\
      \ and genetic evidence."
    action: ACCEPT
    reason: "This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine\
      \ residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372,\
      \ PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms\
      \ PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0005634"
    label: nucleus
  evidence_type: IDA
  original_reference_id: "PMID:33243860"
  review:
    summary: PPP2CA localizes to the nucleus, including via its role in the INTAC complex.
    action: ACCEPT
    reason: "Nuclear localization is well-established by multiple studies. UniProt cites PMID:16541025,\
      \ PMID:33243860, PMID:34004147, PMID:39032490. Nuclear function includes transcription regulation\
      \ via INTAC complex."
- term:
    id: "GO:0005634"
    label: nucleus
  evidence_type: IDA
  original_reference_id: "PMID:34004147"
  review:
    summary: PPP2CA localizes to the nucleus, including via its role in the INTAC complex.
    action: ACCEPT
    reason: "Nuclear localization is well-established by multiple studies. UniProt cites PMID:16541025,\
      \ PMID:33243860, PMID:34004147, PMID:39032490. Nuclear function includes transcription regulation\
      \ via INTAC complex."
- term:
    id: "GO:0180006"
    label: RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity
  evidence_type: IDA
  original_reference_id: "PMID:33243860"
  review:
    summary: "PPP2CA has RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity as part of\
      \ the INTAC complex."
    action: ACCEPT
    reason: "PMID:33243860 demonstrates that INTAC dephosphorylates Pol II CTD at Ser2 (as well as Ser5\
      \ and Ser7). This specific phosphatase activity is a core function within the INTAC complex."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0180006"
    label: RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity
  evidence_type: IDA
  original_reference_id: "PMID:34004147"
  review:
    summary: "PPP2CA has RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity as part of\
      \ the INTAC complex."
    action: ACCEPT
    reason: "PMID:33243860 demonstrates that INTAC dephosphorylates Pol II CTD at Ser2 (as well as Ser5\
      \ and Ser7). This specific phosphatase activity is a core function within the INTAC complex."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0180007"
    label: RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity
  evidence_type: IDA
  original_reference_id: "PMID:33243860"
  review:
    summary: "PPP2CA has RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity as part of\
      \ the INTAC complex."
    action: ACCEPT
    reason: "PMID:33243860 demonstrates INTAC dephosphorylates Pol II CTD at Ser5. This specific phosphatase\
      \ activity is well-supported."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0180007"
    label: RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity
  evidence_type: IDA
  original_reference_id: "PMID:34004147"
  review:
    summary: "PPP2CA has RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity as part of\
      \ the INTAC complex."
    action: ACCEPT
    reason: "PMID:33243860 demonstrates INTAC dephosphorylates Pol II CTD at Ser5. This specific phosphatase\
      \ activity is well-supported."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0180008"
    label: RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity
  evidence_type: IDA
  original_reference_id: "PMID:33243860"
  review:
    summary: "PPP2CA has RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity as part of\
      \ the INTAC complex."
    action: ACCEPT
    reason: "PMID:33243860 demonstrates INTAC dephosphorylates Pol II CTD at Ser7. This specific phosphatase\
      \ activity is well-supported."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0180008"
    label: RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity
  evidence_type: IDA
  original_reference_id: "PMID:34004147"
  review:
    summary: "PPP2CA has RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity as part of\
      \ the INTAC complex."
    action: ACCEPT
    reason: "PMID:33243860 demonstrates INTAC dephosphorylates Pol II CTD at Ser7. This specific phosphatase\
      \ activity is well-supported."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0005634"
    label: nucleus
  evidence_type: IDA
  original_reference_id: "PMID:39032490"
  review:
    summary: PPP2CA localizes to the nucleus, including via its role in the INTAC complex.
    action: ACCEPT
    reason: "Nuclear localization is well-established by multiple studies. UniProt cites PMID:16541025,\
      \ PMID:33243860, PMID:34004147, PMID:39032490. Nuclear function includes transcription regulation\
      \ via INTAC complex."
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: IDA
  original_reference_id: "PMID:39032490"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0035331"
    label: negative regulation of hippo signaling
  evidence_type: IDA
  original_reference_id: "PMID:33633399"
  review:
    summary: "PPP2CA, as part of the STRIPAK complex, negatively regulates Hippo signaling by dephosphorylating\
      \ MST1/2 kinases."
    action: KEEP_AS_NON_CORE
    reason: "PP2A-STRIPAK dephosphorylates MST1/2 T-loop, restraining Hippo pathway activation (PMID:33633399,\
      \ PMID:29063833). This is a well-characterized function of the STRIPAK complex but is one of many\
      \ signaling pathways regulated by PP2A, not the core defining function."
    supported_by:
    - reference_id: "PMID:33633399"
      supporting_text: STRIPAK is a key negative regulator of the Hippo pathway
- term:
    id: "GO:0090443"
    label: FAR/SIN/STRIPAK complex
  evidence_type: IDA
  original_reference_id: "PMID:33633399"
  review:
    summary: PPP2CA is a component of the STRIPAK complex as the catalytic subunit.
    action: ACCEPT
    reason: "Cryo-EM structure of human STRIPAK at 3.2 A confirms PPP2CA (PP2AC) is a core component,\
      \ directly interacting with PP2AA, STRN3, and STRIP1 (PMID:33633399). STRIPAK regulates Hippo signaling\
      \ by dephosphorylating MST1/2."
    supported_by:
    - reference_id: "PMID:33633399"
      supporting_text: "STRIPAK is established as a noncanonical PP2A complex with four copies of regulatory\
        \ STRN3 for enhanced signal integration"
- term:
    id: "GO:0004722"
    label: protein serine/threonine phosphatase activity
  evidence_type: IDA
  original_reference_id: "PMID:29063833"
  qualifier: contributes_to
  review:
    summary: "PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase\
      \ (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural,\
      \ and genetic evidence."
    action: ACCEPT
    reason: "This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine\
      \ residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372,\
      \ PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms\
      \ PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0005737"
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: "PMID:29063833"
  review:
    summary: PPP2CA is present in the cytoplasm.
    action: ACCEPT
    reason: "Well-established cytoplasmic localization supported by UniProt (PMID:16541025, PMID:39032490)\
      \ and consistent with PP2A function in cytoplasmic signaling pathways."
- term:
    id: "GO:0035331"
    label: negative regulation of hippo signaling
  evidence_type: IDA
  original_reference_id: "PMID:29063833"
  review:
    summary: "PPP2CA, as part of the STRIPAK complex, negatively regulates Hippo signaling by dephosphorylating\
      \ MST1/2 kinases."
    action: KEEP_AS_NON_CORE
    reason: "PP2A-STRIPAK dephosphorylates MST1/2 T-loop, restraining Hippo pathway activation (PMID:33633399,\
      \ PMID:29063833). This is a well-characterized function of the STRIPAK complex but is one of many\
      \ signaling pathways regulated by PP2A, not the core defining function."
    supported_by:
    - reference_id: "PMID:33633399"
      supporting_text: STRIPAK is a key negative regulator of the Hippo pathway
- term:
    id: "GO:0090443"
    label: FAR/SIN/STRIPAK complex
  evidence_type: IDA
  original_reference_id: "PMID:29063833"
  review:
    summary: PPP2CA is a component of the STRIPAK complex as the catalytic subunit.
    action: ACCEPT
    reason: "Cryo-EM structure of human STRIPAK at 3.2 A confirms PPP2CA (PP2AC) is a core component,\
      \ directly interacting with PP2AA, STRN3, and STRIP1 (PMID:33633399). STRIPAK regulates Hippo signaling\
      \ by dephosphorylating MST1/2."
    supported_by:
    - reference_id: "PMID:33633399"
      supporting_text: "STRIPAK is established as a noncanonical PP2A complex with four copies of regulatory\
        \ STRN3 for enhanced signal integration"
- term:
    id: "GO:0035556"
    label: intracellular signal transduction
  evidence_type: NAS
  original_reference_id: "PMID:11007961"
  review:
    summary: "PPP2CA/PP2A is involved in intracellular signal transduction through dephosphorylation of\
      \ multiple signaling proteins."
    action: KEEP_AS_NON_CORE
    reason: "While PP2A is a major regulator of signal transduction pathways (Wnt, Hippo, MAPK, mTOR,\
      \ AKT), this term is very broad. The core function is protein dephosphorylation; signal transduction\
      \ is a downstream consequence."
- term:
    id: "GO:0004722"
    label: protein serine/threonine phosphatase activity
  evidence_type: TAS
  original_reference_id: "PMID:21131359"
  review:
    summary: "PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase\
      \ (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural,\
      \ and genetic evidence."
    action: ACCEPT
    reason: "This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine\
      \ residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372,\
      \ PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms\
      \ PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0043029"
    label: T cell homeostasis
  evidence_type: ISS
  original_reference_id: "GO_REF:0000024"
  review:
    summary: "PP2Acalpha is required for CD8+ T-cell homeostasis, supported by mouse conditional deletion\
      \ studies."
    action: KEEP_AS_NON_CORE
    reason: "A 2024 study (Zhou et al., Eur J Immunol) showed conditional PP2Acalpha deletion in T cells\
      \ causes defective CD8+ T-cell homeostasis. While biologically significant, this is a tissue-specific\
      \ phenotype rather than a core molecular function. The ISS annotation is based on mouse ortholog\
      \ data."
- term:
    id: "GO:0051898"
    label: "negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction"
  evidence_type: ISS
  original_reference_id: "GO_REF:0000024"
  review:
    summary: "PP2A negatively regulates PI3K/AKT signaling by dephosphorylating AKT1 at Ser-473."
    action: KEEP_AS_NON_CORE
    reason: "PP2A dephosphorylation of AKT1 is supported by UniProt ('Together with RACK1 adapter, mediates\
      \ dephosphorylation of AKT1 at Ser-473') and by PMID:21806946 (IMP). The 2024 T-cell study also\
      \ implicates mTORC1 and AKT as PP2A downstream nodes. However, AKT regulation is one of many signaling\
      \ roles of PP2A."
- term:
    id: "GO:1900227"
    label: positive regulation of NLRP3 inflammasome complex assembly
  evidence_type: ISS
  original_reference_id: "GO_REF:0000024"
  review:
    summary: "PP2A catalyzes dephosphorylation of the pyrin domain of NLRP3, promoting NLRP3 inflammasome\
      \ assembly (by similarity from mouse)."
    action: KEEP_AS_NON_CORE
    reason: "UniProt states 'Catalyzes dephosphorylation of the pyrin domain of NLRP3, promoting assembly\
      \ of the NLRP3 inflammasome (By similarity)'. This is based on mouse ortholog data and represents\
      \ one of many substrate-specific effects. Not a core function."
- term:
    id: "GO:0004725"
    label: protein tyrosine phosphatase activity
  evidence_type: IDA
  original_reference_id: "PMID:15525651"
  review:
    summary: "PMID:15525651 reports that Galpha12 stimulates PP2A activity ~300%. The GO annotation claims\
      \ protein tyrosine phosphatase activity, but the abstract discusses general PP2A stimulation and\
      \ tau dephosphorylation (a Ser/Thr substrate). PP2A is canonically a Ser/Thr phosphatase."
    action: MARK_AS_OVER_ANNOTATED
    reason: "While PMID:15525651 reports in vitro phosphotyrosine phosphatase activity for PP2A, this\
      \ is not the canonical or well-established function. PP2A is universally recognized as a Ser/Thr\
      \ phosphatase (EC 3.1.3.16). The tyrosine phosphatase activity reported in this single study may\
      \ represent a minor or artificial in vitro activity. The UniProt entry does not list tyrosine phosphatase\
      \ activity."
    supported_by:
    - reference_id: "PMID:15525651"
      supporting_text: approximately 300% stimulation of PP2A activity
- term:
    id: "GO:0051898"
    label: "negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction"
  evidence_type: IMP
  original_reference_id: "PMID:21806946"
  review:
    summary: "PP2A negatively regulates PI3K/AKT signaling by dephosphorylating AKT1 at Ser-473."
    action: KEEP_AS_NON_CORE
    reason: "PP2A dephosphorylation of AKT1 is supported by UniProt ('Together with RACK1 adapter, mediates\
      \ dephosphorylation of AKT1 at Ser-473') and by PMID:21806946 (IMP). The 2024 T-cell study also\
      \ implicates mTORC1 and AKT as PP2A downstream nodes. However, AKT regulation is one of many signaling\
      \ roles of PP2A."
- term:
    id: "GO:0004722"
    label: protein serine/threonine phosphatase activity
  evidence_type: IDA
  original_reference_id: "PMID:25438055"
  review:
    summary: "PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase\
      \ (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural,\
      \ and genetic evidence."
    action: ACCEPT
    reason: "This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine\
      \ residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372,\
      \ PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms\
      \ PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0004722"
    label: protein serine/threonine phosphatase activity
  evidence_type: IDA
  original_reference_id: "PMID:30513302"
  review:
    summary: "PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase\
      \ (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural,\
      \ and genetic evidence."
    action: ACCEPT
    reason: "This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine\
      \ residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372,\
      \ PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms\
      \ PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:2000045"
    label: regulation of G1/S transition of mitotic cell cycle
  evidence_type: IDA
  original_reference_id: "PMID:25438055"
  review:
    summary: "PMID:25438055 shows PPP2CA/PP2A dephosphorylates MYC (via AMBRA1), promoting MYC degradation\
      \ and thereby regulating G1/S transition."
    action: KEEP_AS_NON_CORE
    reason: "Cell cycle regulation is a major PP2A function, and G1/S transition regulation via MYC dephosphorylation\
      \ is well-supported (PMID:25438055). However, this is one of many cell cycle roles and the broader\
      \ mitotic cell cycle term is already accepted."
- term:
    id: "GO:0006470"
    label: protein dephosphorylation
  evidence_type: IMP
  original_reference_id: "PMID:33108758"
  review:
    summary: PPP2CA catalyzes protein dephosphorylation as its core biological process.
    action: ACCEPT
    reason: "Protein dephosphorylation is the central biological process catalyzed by PPP2CA/PP2A. Supported\
      \ by extensive evidence including substrate mapping (deep research: 6,280 phosphopeptides increased\
      \ upon PPP2CA degradation), individual substrate studies (PMID:33108758 for WEE1, PMID:25438055\
      \ for MYC, PMID:30513302 for FOXO3), and the EC number 3.1.3.16."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:17974561"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0004722"
    label: protein serine/threonine phosphatase activity
  evidence_type: IDA
  original_reference_id: "PMID:30595372"
  review:
    summary: "PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase\
      \ (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural,\
      \ and genetic evidence."
    action: ACCEPT
    reason: "This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine\
      \ residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372,\
      \ PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms\
      \ PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:30595372"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0004722"
    label: protein serine/threonine phosphatase activity
  evidence_type: IDA
  original_reference_id: "PMID:30611118"
  review:
    summary: "PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase\
      \ (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural,\
      \ and genetic evidence."
    action: ACCEPT
    reason: "This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine\
      \ residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372,\
      \ PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms\
      \ PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:30611118"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0048156"
    label: tau protein binding
  evidence_type: NAS
  original_reference_id: "PMID:28386764"
  review:
    summary: "PP2A is reported to dephosphorylate tau and to bind tau, relevant to neurodegeneration."
    action: KEEP_AS_NON_CORE
    reason: "PP2A is described as a major tau phosphatase (PMID:10640627, PMID:16262633, PMID:28386764).\
      \ While tau dephosphorylation is biologically important, it is one of many PP2A substrates and not\
      \ a core defining function. Tau binding is context-dependent and mediated by specific holoenzymes\
      \ (B55 family)."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:16258073"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0045121"
    label: membrane raft
  evidence_type: IDA
  original_reference_id: "PMID:16258073"
  review:
    summary: "PMID:16258073 reports PP2A catalytic subunit localizes to membrane rafts in the context\
      \ of ADCY8 interaction."
    action: KEEP_AS_NON_CORE
    reason: "The ADCY8 interaction study (PMID:16258073) provides direct evidence for membrane raft localization.\
      \ However, this is likely context-dependent rather than a primary localization site."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:27588481"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:28609714"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0004721"
    label: phosphoprotein phosphatase activity
  evidence_type: TAS
  original_reference_id: "PMID:28386764"
  review:
    summary: General phosphoprotein phosphatase activity annotation for PPP2CA.
    action: ACCEPT
    reason: "This is a parent term of GO:0004722. Acceptable as a broader annotation."
    supported_by:
    - reference_id: "PMID:30595372"
      supporting_text: PP2A, PPP2CA, Cause Syndromic Intellectual Disability
- term:
    id: "GO:0004722"
    label: protein serine/threonine phosphatase activity
  evidence_type: TAS
  original_reference_id: "PMID:28386764"
  review:
    summary: "PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase\
      \ (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural,\
      \ and genetic evidence."
    action: ACCEPT
    reason: "This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine\
      \ residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372,\
      \ PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms\
      \ PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0010288"
    label: response to lead ion
  evidence_type: ISS
  original_reference_id: "GO_REF:0000024"
  review:
    summary: "PP2A activity is affected by lead exposure. PMID:22387731 reports lead-induced over-activation\
      \ of PP2A in rat hippocampus."
    action: MARK_AS_OVER_ANNOTATED
    reason: "PMID:22387731 reports lead exposure affects PP1 and PP2A activity in rat brain. However,\
      \ this describes an environmental toxicology effect rather than a biological function of PPP2CA.\
      \ The protein responds to lead by being affected, but this is not a functional annotation of the\
      \ gene product."
- term:
    id: "GO:0010288"
    label: response to lead ion
  evidence_type: TAS
  original_reference_id: "PMID:22387731"
  review:
    summary: "PP2A activity is affected by lead exposure. PMID:22387731 reports lead-induced over-activation\
      \ of PP2A in rat hippocampus."
    action: MARK_AS_OVER_ANNOTATED
    reason: "PMID:22387731 reports lead exposure affects PP1 and PP2A activity in rat brain. However,\
      \ this describes an environmental toxicology effect rather than a biological function of PPP2CA.\
      \ The protein responds to lead by being affected, but this is not a functional annotation of the\
      \ gene product."
- term:
    id: "GO:0004722"
    label: protein serine/threonine phosphatase activity
  evidence_type: ISS
  original_reference_id: "GO_REF:0000024"
  review:
    summary: "PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase\
      \ (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural,\
      \ and genetic evidence."
    action: ACCEPT
    reason: "This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine\
      \ residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372,\
      \ PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms\
      \ PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0004722"
    label: protein serine/threonine phosphatase activity
  evidence_type: TAS
  original_reference_id: "PMID:10640627"
  review:
    summary: "PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase\
      \ (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural,\
      \ and genetic evidence."
    action: ACCEPT
    reason: "This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine\
      \ residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372,\
      \ PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms\
      \ PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0004722"
    label: protein serine/threonine phosphatase activity
  evidence_type: TAS
  original_reference_id: "PMID:16262633"
  review:
    summary: "PPP2CA is the catalytic subunit of PP2A, a well-established serine/threonine phosphatase\
      \ (EC 3.1.3.16). This is the core molecular function, supported by extensive biochemical, structural,\
      \ and genetic evidence."
    action: ACCEPT
    reason: "This is the primary molecular function of PPP2CA. PP2A dephosphorylates protein serine/threonine\
      \ residues. Confirmed by crystal structures (PMID:17055435), enzymatic assays (PMID:1848668, PMID:30595372,\
      \ PMID:30611118), and INTAC complex activity (PMID:33243860, PMID:34004147). The deep research confirms\
      \ PP2A accounts for ~50-70% of total Ser/Thr phosphatase activity."
    supported_by:
    - reference_id: "PMID:33243860"
      supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
        \ II at serine-2, -5, and -7"
- term:
    id: "GO:0046982"
    label: protein heterodimerization activity
  evidence_type: IPI
  original_reference_id: "PMID:9847399"
  review:
    summary: "PPP2CA forms a heterodimer with the A scaffold subunit (PPP2R1A) as the PP2A core enzyme."
    action: ACCEPT
    reason: "PPP2CA forms a core heterodimer with PPP2R1A (the A subunit). This is well-established structurally\
      \ (PMID:17055435, PMID:38123684) and functionally. PMID:9847399 specifically addresses binding specificity\
      \ of the PP2A core enzyme."
    supported_by:
    - reference_id: "PMID:9847399"
      supporting_text: "Binding specificity of protein phosphatase 2A core enzyme for regulatory B subunits\
        \ and T antigens"
- term:
    id: "GO:0070062"
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: "PMID:20458337"
  review:
    summary: "HDA annotation from PMID:20458337 identifies PPP2CA in B-cell exosomes by mass spectrometry."
    action: KEEP_AS_NON_CORE
    reason: "High-throughput proteomics data. PPP2CA was detected in exosomes but this likely reflects\
      \ its high cellular abundance (~1% of total protein) rather than a specific exosomal function."
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: TAS
  original_reference_id: "Reactome:R-HSA-1295599"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: TAS
  original_reference_id: "Reactome:R-HSA-1295609"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: TAS
  original_reference_id: "Reactome:R-HSA-1295613"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: TAS
  original_reference_id: "Reactome:R-HSA-1295622"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: TAS
  original_reference_id: "Reactome:R-HSA-1295632"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: TAS
  original_reference_id: "Reactome:R-HSA-1549564"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: TAS
  original_reference_id: "Reactome:R-HSA-2995388"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: TAS
  original_reference_id: "Reactome:R-HSA-927813"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: TAS
  original_reference_id: "Reactome:R-HSA-927830"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: TAS
  original_reference_id: "Reactome:R-HSA-927836"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: TAS
  original_reference_id: "Reactome:R-HSA-934559"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: TAS
  original_reference_id: "Reactome:R-HSA-9667965"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: TAS
  original_reference_id: "Reactome:R-HSA-9865226"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:20080667"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0010719"
    label: negative regulation of epithelial to mesenchymal transition
  evidence_type: IMP
  original_reference_id: "PMID:20080667"
  review:
    summary: "PMID:20080667 implicates PP2A in negative regulation of epithelial-to-mesenchymal transition\
      \ via DAB2IP-mediated modulation."
    action: KEEP_AS_NON_CORE
    reason: "This is a downstream consequence of PP2A-mediated signaling rather than a core function.\
      \ The study (PMID:20080667) shows DAB2IP modulates PP2A activity affecting EMT, but this is a pleiotropic\
      \ effect rather than a primary function."
- term:
    id: "GO:0000159"
    label: protein phosphatase type 2A complex
  evidence_type: IDA
  original_reference_id: "PMID:17055435"
  review:
    summary: PPP2CA is a component of the protein phosphatase type 2A complex.
    action: ACCEPT
    reason: "PPP2CA is the catalytic subunit of PP2A. This is the defining complex for this protein. Supported\
      \ by crystal structure (PMID:17055435), holoenzyme structure (PMID:17174897), and extensive biochemical\
      \ characterization."
    supported_by:
    - reference_id: "PMID:17055435"
      supporting_text: Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins
- term:
    id: "GO:0000159"
    label: protein phosphatase type 2A complex
  evidence_type: IDA
  original_reference_id: "PMID:17174897"
  review:
    summary: PPP2CA is a component of the protein phosphatase type 2A complex.
    action: ACCEPT
    reason: "PPP2CA is the catalytic subunit of PP2A. This is the defining complex for this protein. Supported\
      \ by crystal structure (PMID:17055435), holoenzyme structure (PMID:17174897), and extensive biochemical\
      \ characterization."
    supported_by:
    - reference_id: "PMID:17055435"
      supporting_text: Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:17485487"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:16580887"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0005515"
    label: protein binding
  evidence_type: IPI
  original_reference_id: "PMID:17245430"
  review:
    summary: "Generic protein binding annotation for PPP2CA based on experimental protein-protein interaction\
      \ data."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Per curation guidelines, protein binding (GO:0005515) is uninformative and does not describe\
      \ the actual function of PPP2CA. PPP2CA interacts with numerous proteins as part of its role as\
      \ a phosphatase catalytic subunit (A subunits, B subunits, substrates, regulators, viral oncoproteins).\
      \ More specific molecular function terms should be used. The interactions themselves are well-documented\
      \ but this GO term adds no functional insight."
- term:
    id: "GO:0000159"
    label: protein phosphatase type 2A complex
  evidence_type: TAS
  original_reference_id: "PMID:11007961"
  review:
    summary: PPP2CA is a component of the protein phosphatase type 2A complex.
    action: ACCEPT
    reason: "PPP2CA is the catalytic subunit of PP2A. This is the defining complex for this protein. Supported\
      \ by crystal structure (PMID:17055435), holoenzyme structure (PMID:17174897), and extensive biochemical\
      \ characterization."
    supported_by:
    - reference_id: "PMID:17055435"
      supporting_text: Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins
- term:
    id: "GO:0005634"
    label: nucleus
  evidence_type: NAS
  original_reference_id: "PMID:11007961"
  review:
    summary: PPP2CA localizes to the nucleus, including via its role in the INTAC complex.
    action: ACCEPT
    reason: "Nuclear localization is well-established by multiple studies. UniProt cites PMID:16541025,\
      \ PMID:33243860, PMID:34004147, PMID:39032490. Nuclear function includes transcription regulation\
      \ via INTAC complex."
- term:
    id: "GO:0005739"
    label: mitochondrion
  evidence_type: NAS
  original_reference_id: "PMID:11007961"
  review:
    summary: "NAS annotation from PMID:11007961 suggests mitochondrial localization of PP2A."
    action: KEEP_AS_NON_CORE
    reason: "Some PP2A holoenzymes have been reported to associate with mitochondria, consistent with\
      \ PP2A roles in apoptosis regulation. However, this is not a primary localization and the NAS evidence\
      \ code indicates non-traceable author statement."
- term:
    id: "GO:0005829"
    label: cytosol
  evidence_type: TAS
  original_reference_id: "PMID:11007961"
  review:
    summary: "PPP2CA localizes to the cytosol, which is a well-established localization for PP2A."
    action: ACCEPT
    reason: "PP2A is present in the cytosol as supported by UniProt subcellular location (PMID:16541025,\
      \ PMID:39032490), immunofluorescence, and fractionation studies. The deep research confirms PP2A\
      \ localization includes cytoplasm."
- term:
    id: "GO:0006470"
    label: protein dephosphorylation
  evidence_type: TAS
  original_reference_id: "PMID:2849764"
  review:
    summary: PPP2CA catalyzes protein dephosphorylation as its core biological process.
    action: ACCEPT
    reason: "Protein dephosphorylation is the central biological process catalyzed by PPP2CA/PP2A. Supported\
      \ by extensive evidence including substrate mapping (deep research: 6,280 phosphopeptides increased\
      \ upon PPP2CA degradation), individual substrate studies (PMID:33108758 for WEE1, PMID:25438055\
      \ for MYC, PMID:30513302 for FOXO3), and the EC number 3.1.3.16."
- term:
    id: "GO:0015630"
    label: microtubule cytoskeleton
  evidence_type: NAS
  original_reference_id: "PMID:11007961"
  review:
    summary: "PP2A associates with the microtubule cytoskeleton, consistent with its role as the major\
      \ MAP phosphatase."
    action: KEEP_AS_NON_CORE
    reason: "PP2A is the major phosphatase for microtubule-associated proteins (PMID:22613722). The MID1-alpha4-PP2Ac\
      \ complex is described as microtubule-localized. However, this is one of many localizations. NAS\
      \ evidence from review (PMID:11007961)."
- term:
    id: "GO:0016020"
    label: membrane
  evidence_type: NAS
  original_reference_id: "PMID:11007961"
  review:
    summary: "NAS annotation from PMID:11007961 suggests membrane localization."
    action: KEEP_AS_NON_CORE
    reason: "Very broad localization term. PP2A can associate with membranes through B-subunit targeting,\
      \ but this is not a primary localization. NAS evidence from a review article."
- term:
    id: "GO:0040008"
    label: regulation of growth
  evidence_type: NAS
  original_reference_id: "PMID:11360189"
  review:
    summary: "PP2A regulates cell growth through its phosphatase activity on multiple substrates."
    action: KEEP_AS_NON_CORE
    reason: "PP2A regulates cell growth through dephosphorylation of numerous signaling proteins. This\
      \ is a very broad term. The NAS annotation from PMID:11360189 (a study about PPP2R1A mutations in\
      \ Wilms tumor) provides indirect support."
- term:
    id: "GO:0045595"
    label: regulation of cell differentiation
  evidence_type: NAS
  original_reference_id: "PMID:11360189"
  review:
    summary: PP2A has been implicated in regulation of cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: "PP2A affects cell differentiation through its broad phosphatase activity. This NAS annotation\
      \ from PMID:11360189 is very general and represents a pleiotropic effect rather than a core function."
references:
- id: "GO_REF:0000002"
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: "GO_REF:0000024"
  title: "Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator\
    \ judgment of sequence similarity"
  findings: []
- id: "GO_REF:0000033"
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: "GO_REF:0000044"
  title: "Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping,\
    \ accompanied by conservative changes to GO terms applied by UniProt"
  findings: []
- id: "GO_REF:0000107"
  title: "Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl\
    \ Compara"
  findings: []
- id: "GO_REF:0000108"
  title: "Automatic assignment of GO terms using logical inference, based on on inter-ontology links"
  findings: []
- id: "GO_REF:0000117"
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: "GO_REF:0000120"
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: "PMID:10640627"
  title: "Regulation of phosphorylation of neuronal microtubule-associated proteins MAP1b and MAP2 by\
    \ protein phosphatase-2A and -2B in rat brain."
  findings: []
- id: "PMID:11007961"
  title: "Type 2A protein phosphatase, the complex regulator of numerous signaling pathways."
  findings: []
- id: "PMID:11360189"
  title: Absence of PPP2R1A mutations in Wilms tumor.
  findings: []
- id: "PMID:11591705"
  title: Protein phosphatase 2A interacts with and directly dephosphorylates RelA.
  findings: []
- id: "PMID:11839802"
  title: "Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2A and dephosphorylation\
    \ of Akt and glycogen synthase kinase 3 beta."
  findings: []
- id: "PMID:12963337"
  title: "Parallel purification of three catalytic subunits of the protein serine/threonine phosphatase\
    \ 2A family (PP2A(C), PP4(C), and PP6(C)) and analysis of the interaction of PP2A(C) with alpha4 protein."
  findings: []
- id: "PMID:1328865"
  title: "Identification of binding sites on the regulatory A subunit of protein phosphatase 2A for the\
    \ catalytic C subunit and for tumor antigens of simian virus 40 and polyomavirus."
  findings: []
- id: "PMID:15467457"
  title: "A dynamic equilibrium between CDKs and PP2A modulates phosphorylation of pRB, p107 and p130."
  findings: []
- id: "PMID:15525651"
  title: "Galpha12 directly interacts with PP2A: evidence FOR Galpha12-stimulated PP2A phosphatase activity\
    \ and dephosphorylation of microtubule-associated protein, tau."
  findings: []
- id: "PMID:15761952"
  title: "Single-step Strep-tag purification for the isolation and identification of protein complexes\
    \ from mammalian cells."
  findings: []
- id: "PMID:16044149"
  title: "Activation of the protein kinase B pathway by the HPV-16 E7 oncoprotein occurs through a mechanism\
    \ involving interaction with PP2A."
  findings: []
- id: "PMID:16085932"
  title: "A novel, evolutionarily conserved protein phosphatase complex involved in cisplatin sensitivity."
  findings: []
- id: "PMID:16126728"
  title: "Positive regulation of IkappaB kinase signaling by protein serine/threonine phosphatase 2A."
  findings: []
- id: "PMID:16129692"
  title: "Distinct protein phosphatase 2A heterotrimers modulate growth factor signaling to extracellular\
    \ signal-regulated kinases and Akt."
  findings: []
- id: "PMID:16189514"
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: "PMID:16239144"
  title: "Integrator, a multiprotein mediator of small nuclear RNA processing, associates with the C-terminal\
    \ repeat of RNA polymerase II."
  findings: []
- id: "PMID:16239230"
  title: "Positive regulation of Raf1-MEK1/2-ERK1/2 signaling by protein serine/threonine phosphatase\
    \ 2A holoenzymes."
  findings: []
- id: "PMID:16258073"
  title: "A direct interaction between the N terminus of adenylyl cyclase AC8 and the catalytic subunit\
    \ of protein phosphatase 2A."
  findings: []
- id: "PMID:16262633"
  title: "Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation."
  findings: []
- id: "PMID:16456541"
  title: "B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1\
    \ and ERK."
  findings: []
- id: "PMID:16541025"
  title: Shugoshin collaborates with protein phosphatase 2A to protect cohesin.
  findings: []
- id: "PMID:16580887"
  title: "PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation."
  findings: []
- id: "PMID:16764867"
  title: Interaction of nucleoredoxin with protein phosphatase 2A.
  findings: []
- id: "PMID:17055435"
  title: Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins.
  findings: []
- id: "PMID:17174897"
  title: Structure of the protein phosphatase 2A holoenzyme.
  findings: []
- id: "PMID:17245430"
  title: "A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation\
    \ of p53 at Thr55."
  findings: []
- id: "PMID:17274953"
  title: "Methylation of the C-terminal leucine residue of the PP2A catalytic subunit is unnecessary for\
    \ the catalytic activity and the binding of regulatory subunit (PR55/B)."
  findings: []
- id: "PMID:17384681"
  title: "Identification of a PP2A-interacting protein that functions as a negative regulator of phosphatase\
    \ activity in the ATM/ATR signaling pathway."
  findings: []
- id: "PMID:17485487"
  title: "Tripin/hSgo2 recruits MCAK to the inner centromere to correct defective kinetochore attachments."
  findings: []
- id: "PMID:17529992"
  title: "Structural and biochemical insights into the regulation of protein phosphatase 2A by small t\
    \ antigen of SV40."
  findings: []
- id: "PMID:17540176"
  title: The tumor suppressor PP2A Abeta regulates the RalA GTPase.
  findings: []
- id: "PMID:17974561"
  title: "Tesk1 interacts with Spry2 to abrogate its inhibition of ERK phosphorylation downstream of receptor\
    \ tyrosine kinase signaling."
  findings: []
- id: "PMID:18394995"
  title: "Structural mechanism of demethylation and inactivation of protein phosphatase 2A."
  findings: []
- id: "PMID:18715871"
  title: "PP4R4/KIAA1622 forms a novel stable cytosolic complex with phosphoprotein phosphatase 4."
  findings: []
- id: "PMID:18716626"
  title: Heterochromatin links to centromeric protection by recruiting shugoshin.
  findings: []
- id: "PMID:18782753"
  title: "A PP2A phosphatase high density interaction network identifies a novel striatin-interacting\
    \ phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein."
  findings: []
- id: "PMID:18977201"
  title: Physical association of GPR54 C-terminal with protein phosphatase 2A.
  findings: []
- id: "PMID:19060904"
  title: An empirical framework for binary interactome mapping.
  findings: []
- id: "PMID:19156129"
  title: "An integrated workflow for charting the human interaction proteome: insights into the PP2A system."
  findings: []
- id: "PMID:19293187"
  title: "PME-1 protects extracellular signal-regulated kinase pathway activity from protein phosphatase\
    \ 2A-mediated inactivation in human malignant glioma."
  findings: []
- id: "PMID:19915589"
  title: "The chromosomal association of condensin II is regulated by a noncatalytic function of PP2A."
  findings: []
- id: "PMID:20080667"
  title: "Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis."
  findings: []
- id: "PMID:20458337"
  title: "MHC class II-associated proteins in B-cell exosomes and potential functional implications for\
    \ exosome biogenesis."
  findings: []
- id: "PMID:20927323"
  title: "Protein phosphatase 2A negatively regulates eukaryotic initiation factor 4E phosphorylation\
    \ and eIF4F assembly through direct dephosphorylation of Mnk and eIF4E."
  findings: []
- id: "PMID:21131359"
  title: Nuclear tau, a key player in neuronal DNA protection.
  findings: []
- id: "PMID:21460856"
  title: "ATM-mediated phosphorylation activates the tumor-suppressive function of B56γ-PP2A."
  findings: []
- id: "PMID:21806946"
  title: "Neurotensin signaling activates microRNAs-21 and -155 and Akt, promotes tumor growth in mice,\
    \ and is increased in human colon tumors."
  findings: []
- id: "PMID:21806989"
  title: "Mechanism of inhibition of PP2A activity and abnormal hyperphosphorylation of tau by I2(PP2A)/SET."
  findings: []
- id: "PMID:21988832"
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
- id: "PMID:22387731"
  title: "Over activation of hippocampal serine/threonine protein phosphatases PP1 and PP2A is involved\
    \ in lead-induced deficits in learning and memory in young rats."
  findings: []
- id: "PMID:23892082"
  title: "A positive role of mammalian Tip41-like protein, TIPRL, in the amino-acid dependent mTORC1-signaling\
    \ pathway through interaction with PP2A."
  findings: []
- id: "PMID:24126060"
  title: "Over expression of PPP2R2C inhibits human glioma cells growth through the suppression of mTOR\
    \ pathway."
  findings: []
- id: "PMID:25438055"
  title: "AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation\
    \ and degradation."
  findings: []
- id: "PMID:25531779"
  title: STRIPAK components determine mode of cancer cell migration and metastasis.
  findings: []
- id: "PMID:26256536"
  title: "The Mechanism of ATP-Dependent Allosteric Protection of Akt Kinase Phosphorylation."
  findings: []
- id: "PMID:26496610"
  title: "A human interactome in three quantitative dimensions organized by stoichiometries and abundances."
  findings: []
- id: "PMID:27588481"
  title: FAM122A, a new endogenous inhibitor of protein phosphatase 2A.
  findings: []
- id: "PMID:27880917"
  title: "Phenotypic and Interaction Profiling of the Human Phosphatases Identifies Diverse Mitotic Regulators."
  findings: []
- id: "PMID:28167675"
  title: "ARPP-16 Is a Striatal-Enriched Inhibitor of Protein Phosphatase 2A Regulated by Microtubule-Associated\
    \ Serine/Threonine Kinase 3 (Mast 3 Kinase)."
  findings: []
- id: "PMID:28330616"
  title: Systematic Analysis of Human Protein Phosphatase Interactions and Dynamics.
  findings: []
- id: "PMID:28386764"
  title: Roles of tau protein in health and disease.
  findings: []
- id: "PMID:2849764"
  title: "The nucleotide sequence of the cDNA encoding the human lung protein phosphatase 2A alpha catalytic\
    \ subunit."
  findings: []
- id: "PMID:28609714"
  title: "MFHAS1 suppresses TLR4 signaling pathway via induction of PP2A C subunit cytoplasm translocation\
    \ and inhibition of c-Jun dephosphorylation at Thr239."
  findings: []
- id: "PMID:29063833"
  title: "SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK."
  findings: []
- id: "PMID:30513302"
  title: "AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3\
    \ Axis."
  findings: []
- id: "PMID:30595372"
  title: "De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual\
    \ Disability Resembling Other PP2A-Related Neurodevelopmental Disorders."
  findings: []
- id: "PMID:30611118"
  title: Mitogenic Signals Stimulate the CREB Coactivator CRTC3 through PP2A Recruitment.
  findings: []
- id: "PMID:32296183"
  title: A reference map of the human binary protein interactome.
  findings: []
- id: "PMID:32647223"
  title: "INTS10-INTS13-INTS14 form a functional module of Integrator that binds nucleic acids and the\
    \ cleavage module."
  findings: []
- id: "PMID:32814053"
  title: "Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread\
    \ Protein Aggregation in Affected Brains."
  findings: []
- id: "PMID:32878885"
  title: "IRF1 Promotes the Innate Immune Response to Viral Infection by Enhancing the Activation of IRF3."
  findings: []
- id: "PMID:33108758"
  title: "CHK1 Inhibitor Blocks Phosphorylation of FAM122A and Promotes Replication Stress."
  findings: []
- id: "PMID:33243860"
  title: "Identification of Integrator-PP2A complex (INTAC), an RNA polymerase II phosphatase."
  findings: []
- id: "PMID:33633399"
  title: Cryo-EM structure of the Hippo signaling integrator human STRIPAK.
  findings: []
- id: "PMID:33961781"
  title: "Dual proteome-scale networks reveal cell-specific remodeling of the human interactome."
  findings: []
- id: "PMID:34004147"
  title: "The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in\
    \ cancer."
  findings: []
- id: "PMID:34762484"
  title: Structural basis of Integrator-mediated transcription regulation.
  findings: []
- id: "PMID:35271311"
  title: "OpenCell: Endogenous tagging for the cartography of human cellular organization."
  findings: []
- id: "PMID:36869814"
  title: Structural basis of INTAC-regulated transcription.
  findings: []
- id: "PMID:37080207"
  title: "INTAC endonuclease and phosphatase modules differentially regulate transcription by RNA polymerase\
    \ II."
  findings: []
- id: "PMID:37761890"
  title: "Novel Variants of PPP2R1A in Catalytic Subunit Binding Domain and Genotype-Phenotype Analysis\
    \ in Neurodevelopmentally Delayed Patients."
  findings: []
- id: "PMID:38123684"
  title: "Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19."
  findings: []
- id: "PMID:38570683"
  title: Structural basis of Integrator-dependent RNA polymerase II termination.
  findings: []
- id: "PMID:39032490"
  title: "Cytoplasmic binding partners of the Integrator endonuclease INTS11 and its paralog CPSF73 are\
    \ required for their nuclear function."
  findings: []
- id: "PMID:7592815"
  title: Identification of a new family of protein phosphatase 2A regulatory subunits.
  findings: []
- id: "PMID:8392071"
  title: "Structure and expression of a 72-kDa regulatory subunit of protein phosphatase 2A. Evidence\
    \ for different size forms produced by alternative splicing."
  findings: []
- id: "PMID:8617797"
  title: "Identification of a novel protein phosphatase 2A regulatory subunit highly expressed in muscle."
  findings: []
- id: "PMID:9647778"
  title: Alpha 4 associates with protein phosphatases 2A, 4, and 6.
  findings: []
- id: "PMID:9847399"
  title: "Binding specificity of protein phosphatase 2A core enzyme for regulatory B subunits and T antigens."
  findings: []
- id: "Reactome:R-HSA-1295599"
  title: SPRY2 translocates to the plasma membrane
  findings: []
- id: "Reactome:R-HSA-1295609"
  title: SRC phosphorylates SPRY2 on Y55 and Y227
  findings: []
- id: "Reactome:R-HSA-1295613"
  title: SPRY2 binds GRB2
  findings: []
- id: "Reactome:R-HSA-1295622"
  title: SPRY2 binds CBL
  findings: []
- id: "Reactome:R-HSA-1295632"
  title: PPA2A dephosphorylates SPRY2
  findings: []
- id: "Reactome:R-HSA-1549564"
  title: PPTN11 dephosphorylates SPRY2
  findings: []
- id: "Reactome:R-HSA-2995388"
  title: PP2A dephosphorylates BANF1
  findings: []
- id: "Reactome:R-HSA-927813"
  title: p-4S-UPF1 recruits SMG5, SMG7, SMG6, PNRC2, DCP1A, and PP2A
  findings: []
- id: "Reactome:R-HSA-927830"
  title: "Decay of mRNA in SMG6:SMG5:SMG7:mRNA complex"
  findings: []
- id: "Reactome:R-HSA-927836"
  title: SMG6 hydrolyzes mRNA with premature termination codon
  findings: []
- id: "Reactome:R-HSA-934559"
  title: SPRY2 is phosphorylated by phosphorylated MNK1
  findings: []
- id: "Reactome:R-HSA-9667965"
  title: ANKLE2 binds PP2A
  findings: []
- id: "Reactome:R-HSA-9860927"
  title: "Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins\
    \ in endothelial cells"
  findings: []
- id: "Reactome:R-HSA-9865226"
  title: PP2A dephosphorylates serine-127 of YAP1
  findings: []
core_functions:
- molecular_function:
    id: "GO:0004722"
    label: protein serine/threonine phosphatase activity
  description: "PPP2CA is the catalytic subunit of PP2A, the major cellular Ser/Thr phosphatase. It dephosphorylates\
    \ phosphoserine and phosphothreonine residues on a wide range of protein substrates. EC 3.1.3.16.\
    \ PP2A holoenzymes account for ~50-70% of total cellular Ser/Thr phosphatase activity."
  supported_by:
  - reference_id: "PMID:33243860"
    supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
      \ II at serine-2, -5, and -7"
- molecular_function:
    id: "GO:0180006"
    label: RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity
  description: "As part of the INTAC complex (Integrator + PP2A-AC), PPP2CA dephosphorylates Pol II CTD\
    \ at Ser2 (and also Ser5 and Ser7), driving premature transcription termination of unfavorably configured\
    \ transcripts. This represents a transcription quality checkpoint function."
  supported_by:
  - reference_id: "PMID:33243860"
    supporting_text: "the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase\
      \ II at serine-2, -5, and -7"

PPP2CA

Gene Description

Existing Annotations Review

Core Functions

PPP2CA is the catalytic subunit of PP2A, the major cellular Ser/Thr phosphatase. It dephosphorylates phosphoserine and phosphothreonine residues on a wide range of protein substrates. EC 3.1.3.16. PP2A holoenzymes account for ~50-70% of total cellular Ser/Thr phosphatase activity.

As part of the INTAC complex (Integrator + PP2A-AC), PPP2CA dephosphorylates Pol II CTD at Ser2 (and also Ser5 and Ser7), driving premature transcription termination of unfavorably configured transcripts. This represents a transcription quality checkpoint function.

References

Deep Research

Falcon

Research Report: PPP2CA (PP2A catalytic subunit α; UniProt P67775) — Functional Annotation (Human)

Executive summary

1. Target verification and gene/protein identity

1.1 Verification against the provided UniProt entry

1.2 Core definition: what PPP2CA encodes

2. Key concepts, definitions, and current understanding

2.1 What PP2A does: Ser/Thr dephosphorylation and scale of influence

2.2 Holoenzyme architecture and how PPP2CA gains specificity

2.3 Regulation by post-translational modifications (PTMs)

Leu309 C-terminal methylation

C-terminal tail phosphorylation (Thr304/Tyr307)

2.4 Cellular localization

3. Primary function: reaction and substrate specificity (functional annotation focus)

3.1 Reaction (functional definition)

3.2 Substrate specificity is holoenzyme-dependent and large-scale

2024: proteome-scale substrate landscape of PPP2CA

4. Recent developments (prioritizing 2023–2024)

4.1 2024 structural characterization of methylation-independent assembly

4.2 2024 substrate mapping by acute PPP2CA degradation

4.3 2024 immunology genetics: PPP2CA is required for CD8+ T-cell homeostasis

5. Pathways and biological processes (with emphasis on mechanistic specificity)

5.1 Cell cycle and proliferation

5.2 RNA processing / splicing axis

5.3 mTOR/AKT signaling

6. Current applications and real-world implementations

6.1 Pharmacological inhibition: LB-100

Mechanism and rationale

Clinical development (registry evidence)

Quantitative dose-escalation/trial outcomes (literature synthesis)

6.2 Pharmacological activation/stabilization: SMAPs (e.g., DT-061) and other activators

7. Expert opinions and interpretive analysis (authoritative sources)

7.1 PP2A as a modular signaling “hub” rather than a single enzyme

7.2 Translational tension: PP2A as tumor suppressor vs PP2A inhibition as therapy

8. Relevant statistics and recent quantitative data (selected)

9. Evidence-backed structural support

10. Consolidated functional-annotation table

11. Limitations of this evidence set

Key sources (2023–2024 prioritized)

Citations

📚 Additional Documentation

Notes

PPP2CA Review Notes

Gene Identity

Core Function Summary

Key Complexes

Key Regulation

Localization

Substrate Landscape (2024 data)

Key Substrates (from UniProt FUNCTION)

Protein tyrosine phosphatase claim

Disease

Annotations Review Strategy

📄 View Raw YAML