id: P16298
gene_symbol: PPP3CB
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PPP3CB encodes the beta isoform of the catalytic subunit of calcineurin
  (protein phosphatase 2B, PP2B), a calcium-dependent, calmodulin-stimulated
  serine/threonine phosphatase. The enzyme functions as a heterodimer of a
  catalytic A subunit (PPP3CA, PPP3CB, or PPP3CC) and a regulatory
  Ca2+-binding B subunit (PPP3R1 or PPP3R2). PPP3CB is activated through a
  multi-level mechanism involving Ca2+/calmodulin binding that displaces
  autoinhibitory domains (AIS and AID) from the active site. Key substrates
  include NFAT transcription factors (driving T cell activation and immune
  signaling), TFEB (driving lysosomal biogenesis and autophagy), ELK1, and
  DARPP-32. PPP3CB was specifically identified as the key calcineurin isoform
  for TFEB dephosphorylation in response to lysosomal Ca2+ release. The
  enzyme has a unique proline-rich N-terminal domain that confers enhanced
  substrate binding affinity relative to other isoforms. Calcineurin is the
  target of the immunosuppressant drugs FK506 (tacrolimus) and cyclosporin A.
  Crystal structure available at 2.23 Angstroms (PDB:4OR9).
existing_annotations:
  # ============ IBA annotations (phylogenetic) ============
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ACCEPT. Calcineurin A beta localizes to the cytoplasm. Confirmed by
        IDA evidence in PMID:19154138 which demonstrated cytoplasmic
        subcellular distribution for all CaN isoforms.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:19154138
          supporting_text: >-
            this study demonstrates that all CaN isoforms display the same
            cytoplasmic subcellular distribution
  - term:
      id: GO:0005955
      label: calcineurin complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ACCEPT. PPP3CB forms the calcineurin heterodimer with regulatory
        subunit PPP3R1 (calcineurin B). Crystal structure of full-length
        PPP3CB in complex with PPP3R1 confirmed this (PMID:26794871).
      action: ACCEPT
      supported_by:
        - reference_id: PMID:26794871
          supporting_text: >-
            a heterodimer composed of a catalytic subunit A and an essential
            regulatory subunit B
  - term:
      id: GO:0097720
      label: calcineurin-mediated signaling
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ACCEPT. Calcineurin-mediated signaling is a core function of PPP3CB,
        including NFAT signaling and TFEB regulation. Supported by multiple
        experimental studies.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:25720963
          supporting_text: >-
            calcineurin plays a crucial role in the regulation of TFEB
            subcellular localization
        - reference_id: PMID:19154138
          supporting_text: >-
            Comparative kinetic analysis of the dephosphorylation of five
            specific CaN substrates provided evidence that the distinct
            isoforms of the catalytic subunit confer substrate specificities
  - term:
      id: GO:0033192
      label: calmodulin-dependent protein phosphatase activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ACCEPT. This is the core molecular function of PPP3CB. EC 3.1.3.16,
        confirmed by crystal structure and kinetic studies. Deep research
        confirms calcineurin is a calmodulin-dependent protein phosphatase
        (file:human/PPP3CB/PPP3CB-deep-research-falcon.md).
      action: ACCEPT
      additional_reference_ids:
        - file:human/PPP3CB/PPP3CB-deep-research-falcon.md
      supported_by:
        - reference_id: PMID:26794871
          supporting_text: >-
            The Ca(2+)/calmodulin-dependent protein phosphatase calcineurin
        - reference_id: PMID:19154138
          supporting_text: >-
            Ca(2+)-dependent serine/threonine protein phosphatase calcineurin
  - term:
      id: GO:0005516
      label: calmodulin binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ACCEPT. Calmodulin binding is essential for calcineurin activation.
        The calmodulin-binding domain has been structurally characterized
        (residues 401-415 of PPP3CB, PMID:26794871).
      action: ACCEPT
      supported_by:
        - reference_id: PMID:26794871
          supporting_text: >-
            The Ca(2+)/calmodulin-dependent protein phosphatase calcineurin

  # ============ IEA annotations (electronic) ============
  - term:
      id: GO:0004721
      label: phosphoprotein phosphatase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        ACCEPT. PPP3CB is a phosphoprotein phosphatase (EC 3.1.3.16). This
        is a correct parent term but more specific terms also apply
        (GO:0033192 calmodulin-dependent protein phosphatase activity).
      action: ACCEPT
  - term:
      id: GO:0004722
      label: protein serine/threonine phosphatase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        ACCEPT. PPP3CB is indeed a protein serine/threonine phosphatase.
        Consistent with its catalytic activity dephosphorylating Ser/Thr
        residues on substrates like NFAT, TFEB, ELK1, DARPP-32.
      action: ACCEPT
  - term:
      id: GO:0005516
      label: calmodulin binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        ACCEPT. Redundant with IBA annotation but correct. Calmodulin
        binding is experimentally verified.
      action: ACCEPT
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        ACCEPT. Cytoplasmic localization confirmed experimentally
        (PMID:19154138).
      action: ACCEPT
  - term:
      id: GO:0016787
      label: hydrolase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        ACCEPT. Phosphoprotein phosphatases are hydrolases. This is a
        correct but very general parent term. More specific terms also apply.
      action: ACCEPT
  - term:
      id: GO:0033173
      label: calcineurin-NFAT signaling cascade
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        ACCEPT. The calcineurin-NFAT signaling cascade is a core function,
        well supported by experimental evidence for PPP3CB
        (PMID:19154138, PMID:22688515).
      action: ACCEPT
  - term:
      id: GO:0033192
      label: calmodulin-dependent protein phosphatase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        ACCEPT. Core molecular function, redundant with IBA but correct.
      action: ACCEPT
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        ACCEPT. PPP3CB has a binuclear metal center with Fe3+ and Zn2+ at
        the active site, confirmed by crystal structure (PMID:8524402,
        PMID:26794871).
      action: ACCEPT
      supported_by:
        - reference_id: PMID:8524402
          supporting_text: >-
            the Zn/Fe-containing active site
  - term:
      id: GO:0097720
      label: calcineurin-mediated signaling
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        ACCEPT. Calcineurin-mediated signaling is a core function. Redundant
        with IBA but correct.
      action: ACCEPT

  # ============ IPI annotations (protein binding) ============
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21903422
    review:
      summary: >-
        MARK_AS_OVER_ANNOTATED. Generic protein binding is uninformative per
        curation guidelines. This is from a high-throughput innate immunity
        interaction network study. More specific binding terms would be
        preferred.
      action: MARK_AS_OVER_ANNOTATED
      supported_by:
        - reference_id: PMID:21903422
          supporting_text: >-
            Mapping a dynamic innate immunity protein interaction network
            regulating type I interferon production.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: >-
        MARK_AS_OVER_ANNOTATED. Generic protein binding from high-throughput
        interactome study. Uninformative per curation guidelines.
      action: MARK_AS_OVER_ANNOTATED
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: >-
            Dual proteome-scale networks reveal cell-specific remodeling of
            the human interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35914814
    review:
      summary: >-
        MARK_AS_OVER_ANNOTATED. Generic protein binding from Chr21
        protein-protein interaction study. Uninformative.
      action: MARK_AS_OVER_ANNOTATED
      supported_by:
        - reference_id: PMID:35914814
          supporting_text: >-
            Chr21 protein-protein interactions: enrichment in proteins
            involved in intellectual disability, autism, and late-onset
            Alzheimer's disease.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:40205054
    review:
      summary: >-
        MARK_AS_OVER_ANNOTATED. Generic protein binding from multimodal cell
        maps study. Uninformative.
      action: MARK_AS_OVER_ANNOTATED
      supported_by:
        - reference_id: PMID:40205054
          supporting_text: >-
            Multimodal cell maps as a foundation for structural and
            functional genomics.

  # ============ IEA from Ensembl Compara (GO_REF:0000107) ============
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        KEEP_AS_NON_CORE. Calcineurin can be localized to the plasma
        membrane via scaffolding proteins like AKAP79/150 (PMID:17640527),
        but this is not its primary localization. Cytoplasm is the primary
        location.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:17640527
          supporting_text: >-
            CaV1.2 interacts directly with AKAP79/150, which binds both PKA
            and the Ca2+/calmodulin-activated phosphatase calcineurin
  - term:
      id: GO:0017156
      label: calcium-ion regulated exocytosis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        KEEP_AS_NON_CORE. Plausible secondary function via calcineurin's
        role in calcium signaling. Supported by ortholog data.
      action: KEEP_AS_NON_CORE
  - term:
      id: GO:0023057
      label: negative regulation of signaling
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        KEEP_AS_NON_CORE. Calcineurin negatively regulates MAP3K14/NIK
        signaling via inhibition of nuclear translocation of RELA and RELB
        (UniProt, by similarity). Correct but very general term.
      action: KEEP_AS_NON_CORE
  - term:
      id: GO:0030018
      label: Z disc
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        KEEP_AS_NON_CORE. Plausible for skeletal/cardiac muscle context
        where calcineurin plays roles. Supported by tissue-enhanced
        expression in skeletal muscle (HPA).
      action: KEEP_AS_NON_CORE
  - term:
      id: GO:0030315
      label: T-tubule
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        KEEP_AS_NON_CORE. Plausible in muscle context. Calcineurin is
        involved in skeletal muscle fiber development and can localize to
        T-tubules via AKAP scaffolding.
      action: KEEP_AS_NON_CORE
  - term:
      id: GO:0035774
      label: positive regulation of insulin secretion involved in cellular
        response to glucose stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        KEEP_AS_NON_CORE. Calcineurin has been implicated in insulin
        secretion regulation through ortholog studies. Not a core function
        of PPP3CB.
      action: KEEP_AS_NON_CORE
  - term:
      id: GO:0048741
      label: skeletal muscle fiber development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        KEEP_AS_NON_CORE. UniProt states "May play a role in skeletal
        muscle fiber type specification (By similarity)". Supported by
        tissue-enhanced expression in skeletal muscle.
      action: KEEP_AS_NON_CORE
  - term:
      id: GO:0098978
      label: glutamatergic synapse
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        KEEP_AS_NON_CORE. Calcineurin plays roles at synapses but this
        localization is from ortholog data only.
      action: KEEP_AS_NON_CORE
  - term:
      id: GO:1900242
      label: regulation of synaptic vesicle endocytosis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        KEEP_AS_NON_CORE. Calcineurin has known roles in synaptic vesicle
        recycling via dephosphorylation of dynamin and other endocytic
        proteins. Ortholog-based annotation.
      action: KEEP_AS_NON_CORE

  # ============ IDA and NAS annotations ============
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        ACCEPT. Cytosol localization based on immunofluorescence data.
        Consistent with cytoplasmic localization confirmed by PMID:19154138.
      action: ACCEPT
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: NAS
    original_reference_id: PMID:22343722
    review:
      summary: >-
        ACCEPT. Calcineurin is present in the cytosol where it interacts
        with AKAP79 and regulates NFAT signaling (PMID:22343722).
      action: ACCEPT
      supported_by:
        - reference_id: PMID:22343722
          supporting_text: >-
            AKAP79 recruits the phosphatase calcineurin to L-type Ca(2+)
            channels and couples Ca(2+) influx to activation of calcineurin
            and of its substrate, the transcription factor NFAT.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: NAS
    original_reference_id: PMID:28126489
    review:
      summary: >-
        ACCEPT. Consistent with known cytosolic localization. This is a
        review paper discussing calcineurin's role in neuronal cytoskeleton
        regulation.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:28126489
          supporting_text: >-
            The protein serine/threonine phosphatases PP2A, PP1 and
            calcineurin: A triple threat in the regulation of the neuronal
            cytoskeleton.
  - term:
      id: GO:0070886
      label: positive regulation of calcineurin-NFAT signaling cascade
    evidence_type: NAS
    original_reference_id: PMID:22343722
    review:
      summary: >-
        ACCEPT. AKAP79 anchoring of calcineurin promotes NFAT signaling.
        This study showed that AKAP79 recruits calcineurin to L-type
        Ca2+ channels, coupling Ca2+ influx to calcineurin activation and
        NFAT signaling (PMID:22343722).
      action: ACCEPT
      supported_by:
        - reference_id: PMID:22343722
          supporting_text: >-
            an IAIIIT anchoring site in human AKAP79 binds the same surface
            of calcineurin as the PxIxIT recognition peptide of NFAT
  - term:
      id: GO:0070886
      label: positive regulation of calcineurin-NFAT signaling cascade
    evidence_type: NAS
    original_reference_id: PMID:8631904
    review:
      summary: >-
        ACCEPT. Calcineurin directly binds NFAT1, dephosphorylates it to
        enable nuclear translocation and transcriptional activation. This
        is a core function (PMID:8631904).
      action: ACCEPT
      supported_by:
        - reference_id: PMID:8631904
          supporting_text: >-
            a direct interaction between calcineurin and NFAT1 that is
            consistent with a direct enzyme-substrate relation between these
            two proteins
  - term:
      id: GO:1905665
      label: positive regulation of calcium ion import across plasma membrane
    evidence_type: NAS
    original_reference_id: PMID:17640527
    review:
      summary: >-
        KEEP_AS_NON_CORE. The study showed that AKAP79/150 anchoring of
        calcineurin controls neuronal L-type Ca2+ channel activity. CaN
        can both suppress (via PKA opposition) and promote channel activity
        depending on context. Not a core function of PPP3CB itself.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:17640527
          supporting_text: >-
            Cotargeting of PKA and CaN by AKAP79/150 confers bidirectional
            regulation of L-type current amplitude
  - term:
      id: GO:1905949
      label: negative regulation of calcium ion import across plasma membrane
    evidence_type: NAS
    original_reference_id: PMID:17640527
    review:
      summary: >-
        KEEP_AS_NON_CORE. Same study as above. CaN dominantly suppresses
        PKA enhancement of L-type Ca2+ channels. Context-dependent secondary
        function, not core.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:17640527
          supporting_text: >-
            anchored CaN dominantly suppresses PKA enhancement of the channel

  # ============ IDA annotations (experimental) ============
  - term:
      id: GO:0033192
      label: calmodulin-dependent protein phosphatase activity
    evidence_type: IDA
    original_reference_id: PMID:25720963
    review:
      summary: >-
        ACCEPT. Core molecular function. PPP3CB was specifically identified
        as the calcineurin isoform responsible for TFEB dephosphorylation.
        Phosphatase activity confirmed experimentally.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:25720963
          supporting_text: >-
            The most significant hit identified by the primary screening
            was the calcineurin catalytic subunit isoform beta (PPP3CB;
            Gene ID:5532)
  - term:
      id: GO:0033192
      label: calmodulin-dependent protein phosphatase activity
    evidence_type: IDA
    original_reference_id: PMID:32753672
    review:
      summary: >-
        ACCEPT. Core molecular function. IRGM promotes calcineurin
        (PPP3CB)-mediated TFEB dephosphorylation.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:32753672
          supporting_text: >-
            IRGM interacts with calcineurin PPP3CB... IRGM overexpression
            promoted dephosphorylation of another PPP3CB target, NFAT
  - term:
      id: GO:1900182
      label: positive regulation of protein localization to nucleus
    evidence_type: IDA
    original_reference_id: PMID:25720963
    review:
      summary: >-
        ACCEPT. PPP3CB dephosphorylates TFEB promoting its nuclear
        translocation. Direct experimental evidence with siRNA knockdown
        of PPP3CB specifically.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:25720963
          supporting_text: >-
            inhibition of PPP3CB suppressed starvation-induced nuclear
            translocation of TFEB
  - term:
      id: GO:1900182
      label: positive regulation of protein localization to nucleus
    evidence_type: IDA
    original_reference_id: PMID:32753672
    review:
      summary: >-
        ACCEPT. IRGM promotes PPP3CB-mediated TFEB nuclear translocation.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:32753672
          supporting_text: >-
            IRGM directly interacted with TFEB and promoted the nuclear
            translocation of TFEB
  - term:
      id: GO:1905673
      label: positive regulation of lysosome organization
    evidence_type: IDA
    original_reference_id: PMID:25720963
    review:
      summary: >-
        ACCEPT. PPP3CB-mediated TFEB activation drives lysosomal biogenesis.
        Constitutively active calcineurin induced TFEB target genes in a
        TFEB-dependent manner.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:25720963
          supporting_text: >-
            calcineurin overexpression and constitutive activation...
            induced the expression of TFEB transcriptional target genes
            in a TFEB-dependent manner
  - term:
      id: GO:1905673
      label: positive regulation of lysosome organization
    evidence_type: IDA
    original_reference_id: PMID:32753672
    review:
      summary: >-
        ACCEPT. IRGM-calcineurin-TFEB axis drives lysosomal biogenesis.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:32753672
          supporting_text: >-
            IRGM and its interactors mAtg8s close a loop between the
            autophagosomal pathway and the control of lysosomal biogenesis
            by TFEB

  # ============ IPI annotations (specific interactors) ============
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:34446558
    review:
      summary: >-
        MARK_AS_OVER_ANNOTATED. PPP3CB interacts with SPATA33 via PQIIIT
        motif. However, this study focused on testis-enriched sperm
        calcineurin (PPP3CC/PPP3R2), not PPP3CB specifically. The protein
        binding term is also too generic. A more specific term would be
        preferred but this interaction is not core for PPP3CB.
      action: MARK_AS_OVER_ANNOTATED
      supported_by:
        - reference_id: PMID:34446558
          supporting_text: >-
            SPATA33 interacts with sperm calcineurin via a PQIIIT sequence

  # ============ ISS annotations (sequence similarity) ============
  - term:
      id: GO:0023057
      label: negative regulation of signaling
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        KEEP_AS_NON_CORE. Calcineurin negatively regulates MAP3K14/NIK
        signaling. Supported by similarity to mouse ortholog. Secondary
        function.
      action: KEEP_AS_NON_CORE
  - term:
      id: GO:0048741
      label: skeletal muscle fiber development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        KEEP_AS_NON_CORE. UniProt states calcineurin may play a role in
        skeletal muscle fiber type specification (by similarity). Supported
        by tissue-enhanced expression in skeletal muscle. Not a core
        function.
      action: KEEP_AS_NON_CORE

  # ============ IMP annotation ============
  - term:
      id: GO:0097720
      label: calcineurin-mediated signaling
    evidence_type: IMP
    original_reference_id: PMID:11005320
    review:
      summary: >-
        ACCEPT. This study examined the immunophilin-binding domains of
        calcineurin A1 (PPP3CA) and A2 (PPP3CB). While primarily a
        genetics/polymorphism study, it confirms calcineurin's critical
        role in calcium-dependent T-cell activation via calcineurin-mediated
        signaling.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:11005320
          supporting_text: >-
            Calcineurin a calmodulin-dependent phosphatase plays a critical
            role in calcium-dependent activation of T-lymphocytes

  # ============ More IPI annotations ============
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26794871
    review:
      summary: >-
        MODIFY. This study demonstrated specific interactions of PPP3CB
        with PPP3R1/calcineurin B and calmodulin. More specific binding
        terms already exist (calmodulin binding, protein phosphatase 2B
        binding). The generic protein binding term is uninformative.
      action: MODIFY
      proposed_replacement_terms:
        - id: GO:0030346
          label: protein phosphatase 2B binding
  - term:
      id: GO:0005516
      label: calmodulin binding
    evidence_type: IDA
    original_reference_id: PMID:26794871
    review:
      summary: >-
        ACCEPT. Direct experimental demonstration of calmodulin binding.
        The calmodulin-binding domain (residues 401-415) was structurally
        characterized. Calmodulin binding leads to displacement of the
        AID from the active site.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:26794871
          supporting_text: >-
            biochemical studies demonstrate that calmodulin does not
            remove AID from the active site, but only regulates the
            orientation of AID with respect to the catalytic core
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:19154138
    review:
      summary: >-
        ACCEPT. Direct experimental evidence for cytoplasmic localization
        of PPP3CB.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:19154138
          supporting_text: >-
            all CaN isoforms display the same cytoplasmic subcellular
            distribution
  - term:
      id: GO:0005955
      label: calcineurin complex
    evidence_type: IDA
    original_reference_id: PMID:26794871
    review:
      summary: >-
        ACCEPT. Crystal structure of full-length PPP3CB in complex with
        PPP3R1, confirming calcineurin complex formation.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:26794871
          supporting_text: >-
            we report the crystal structure of full-length CN (beta isoform)
  - term:
      id: GO:0006470
      label: protein dephosphorylation
    evidence_type: IDA
    original_reference_id: PMID:19154138
    review:
      summary: >-
        ACCEPT. Core function. PPP3CB dephosphorylates NFATC1, ELK1, and
        DARPP-32 with characterized kinetics.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:19154138
          supporting_text: >-
            Comparative kinetic analysis of the dephosphorylation of five
            specific CaN substrates
  - term:
      id: GO:0006470
      label: protein dephosphorylation
    evidence_type: IDA
    original_reference_id: PMID:26794871
    review:
      summary: >-
        ACCEPT. Core function. Protein dephosphorylation confirmed by
        crystal structure and biochemical studies.
      action: ACCEPT
  - term:
      id: GO:0033173
      label: calcineurin-NFAT signaling cascade
    evidence_type: IDA
    original_reference_id: PMID:19154138
    review:
      summary: >-
        ACCEPT. Core function. PPP3CB dephosphorylates NFATC1 with
        Km=0.69 uM, driving NFAT nuclear translocation and
        transcriptional activation.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:19154138
          supporting_text: >-
            NFAT reporter gene activity measurements revealed even more
            pronounced substrate preferences of CaNA isoforms
  - term:
      id: GO:0033192
      label: calmodulin-dependent protein phosphatase activity
    evidence_type: IDA
    original_reference_id: PMID:19154138
    review:
      summary: >-
        ACCEPT. Core molecular function. PPP3CB's phosphatase activity
        requires calmodulin for full activation.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:19154138
          supporting_text: >-
            Ca(2+)-dependent serine/threonine protein phosphatase calcineurin
  - term:
      id: GO:0033192
      label: calmodulin-dependent protein phosphatase activity
    evidence_type: IDA
    original_reference_id: PMID:26794871
    review:
      summary: >-
        ACCEPT. Core molecular function confirmed by crystal structure
        and biochemical characterization of activation mechanism.
      action: ACCEPT

  # ============ More IPI/IDA annotations ============
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22688515
    review:
      summary: >-
        MODIFY. NHE1 directly binds calcineurin A via a PVITID sequence
        resembling the CaN-binding motif PxIxIT. This is a specific
        interaction, not just generic protein binding.
      action: MODIFY
      proposed_replacement_terms:
        - id: GO:0030346
          label: protein phosphatase 2B binding
      supported_by:
        - reference_id: PMID:22688515
          supporting_text: >-
            The calcineurin A (CaNA) subunit was identified as a novel
            binding partner of plasma membrane Na(+)/H(+) exchanger 1
            (NHE1)
  - term:
      id: GO:0005955
      label: calcineurin complex
    evidence_type: IDA
    original_reference_id: PMID:22688515
    review:
      summary: >-
        ACCEPT. Confirms calcineurin complex formation in the context of
        NHE1-mediated NFAT signaling in cardiomyocytes.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:22688515
          supporting_text: >-
            CaN is a Ca(2+)-dependent phosphatase involved in many cellular
            functions, including cardiac hypertrophy
  - term:
      id: GO:0033173
      label: calcineurin-NFAT signaling cascade
    evidence_type: IDA
    original_reference_id: PMID:22688515
    review:
      summary: >-
        ACCEPT. NHE1 activates calcineurin-NFAT signaling in
        cardiomyocytes, leading to hypertrophic gene expression.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:22688515
          supporting_text: >-
            NHE1 stimulated hypertrophic gene expression and the NFAT
            pathway, which were inhibited by a CaN inhibitor, FK506
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:22688515
    review:
      summary: >-
        KEEP_AS_NON_CORE. In the context of NHE1-calcineurin-NFAT
        signaling in cardiomyocytes, calcineurin activation leads to NFAT
        nuclear translocation and transcriptional activation of hypertrophic
        genes. This is a downstream consequence of NFAT dephosphorylation,
        not a direct function of PPP3CB.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:22688515
          supporting_text: >-
            Overexpression of NHE1 promoted serum-induced CaN/nuclear
            factor of activated T cells (NFAT) signaling... enhancement
            of NFAT promoter activity and nuclear translocation

  # ============ TAS Reactome annotations ============
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2730867
    review:
      summary: >-
        KEEP_AS_NON_CORE. Calcineurin translocates to the nucleus with
        NFAT (Reactome: Translocation of CaN:CaM:NFAT to nucleus).
        Not the primary localization.
      action: KEEP_AS_NON_CORE
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4551465
    review:
      summary: >-
        KEEP_AS_NON_CORE. Same as above - calcineurin accompanies NFAT
        to nucleus (Reactome: Translocation of NFATC1:CaN:CaM to nucleus).
      action: KEEP_AS_NON_CORE
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2025890
    review:
      summary: >-
        ACCEPT. Reactome: Calcineurin binds NFATC1,2,3. Cytosolic
        localization consistent with experimental data.
      action: ACCEPT
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2730849
    review:
      summary: >-
        ACCEPT. Reactome: Calcineurin binds and dephosphorylates NFAT.
      action: ACCEPT
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2730867
    review:
      summary: >-
        ACCEPT. Reactome: Translocation of CaN:CaM:NFAT to nucleus.
        Cytosol is the starting location.
      action: ACCEPT
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2730872
    review:
      summary: >-
        ACCEPT. Reactome: Activation of Calcineurin. Occurs in cytosol.
      action: ACCEPT
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4551451
    review:
      summary: >-
        ACCEPT. Reactome: Calcineurin binds and dephosphorylates NFAT1
        in response to WNT/Ca2+ signaling.
      action: ACCEPT
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4551465
    review:
      summary: >-
        ACCEPT. Reactome: Translocation of NFATC1:CaN:CaM to nucleus.
      action: ACCEPT

  # ============ ISS plasma membrane ============
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        KEEP_AS_NON_CORE. Calcineurin can localize to plasma membrane
        via AKAP79/150 scaffolding (PMID:17640527). Not primary
        localization.
      action: KEEP_AS_NON_CORE

  # ============ IDA calmodulin binding (PMID:11005320) ============
  - term:
      id: GO:0005516
      label: calmodulin binding
    evidence_type: IDA
    original_reference_id: PMID:11005320
    review:
      summary: >-
        ACCEPT. The immunophilin-binding domain region (aa 281-414)
        overlaps with the calmodulin binding domain. The study confirms
        conservation of this functional region.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:11005320
          supporting_text: >-
            The region of CNA that interacts with Calcineurin B, calmodulin,
            and immunosuppressive drugs bound to their receptors--the
            immunophilins--has been identified to amino acids 281-414
  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: IDA
    original_reference_id: PMID:11005320
    review:
      summary: >-
        KEEP_AS_NON_CORE. Calcineurin binds immunophilins (FKBP12, cyclophilin)
        when complexed with FK506 or cyclosporin A. This is a pharmacologically
        relevant interaction but somewhat generic as a GO term.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:11005320
          supporting_text: >-
            the major target for the inhibitory actions of the
            immunosuppressive drugs Tacrolimus (FK506) and Cyclosporin A
  - term:
      id: GO:0042110
      label: T cell activation
    evidence_type: TAS
    original_reference_id: PMID:11005320
    review:
      summary: >-
        ACCEPT. Calcineurin plays a critical role in calcium-dependent
        T cell activation via NFAT signaling. This is well established
        and is the basis for immunosuppressant therapy.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:11005320
          supporting_text: >-
            Calcineurin a calmodulin-dependent phosphatase plays a critical
            role in calcium-dependent activation of T-lymphocytes
  - term:
      id: GO:0046983
      label: protein dimerization activity
    evidence_type: IPI
    original_reference_id: PMID:11005320
    review:
      summary: >-
        ACCEPT. Calcineurin forms a heterodimer of catalytic A subunit and
        regulatory B subunit. The A-B dimerization is essential for
        calcineurin function.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:11005320
          supporting_text: >-
            Calcineurin is a dimeric protein consisting of distinct A
            (catalytic) and B (regulatory) subunits

  # ============ IDA calmodulin binding (PMID:2556704) ============
  - term:
      id: GO:0005516
      label: calmodulin binding
    evidence_type: IDA
    original_reference_id: PMID:2556704
    review:
      summary: >-
        ACCEPT. Original cloning paper identified calmodulin binding.
        The polyproline structural domain was proposed to have a role
        in calmodulin activation.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:2556704
          supporting_text: >-
            A role in the calmodulin activation of calcineurin is proposed
            for this novel structural element

  # ============ Protein phosphorylation MISANNOTATION ============
  - term:
      id: GO:0006468
      label: protein phosphorylation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CRITICAL MISANNOTATION: PPP3CB is a PHOSPHATASE (EC 3.1.3.16),
        NOT a kinase. PPP3CB dephosphorylates substrates including NFAT,
        TFEB, ELK1, and DARPP-32. Annotating a phosphatase to "protein
        phosphorylation" is the opposite of its function. The ISS transfer
        from mouse ortholog is erroneous.
      action: REMOVE

  # ============ ISS protein dephosphorylation ============
  - term:
      id: GO:0006470
      label: protein dephosphorylation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ACCEPT. Protein dephosphorylation is a core function, well
        supported by experimental data.
      action: ACCEPT

  # ============ TAS dephosphorylation (PMID:2556704) ============
  - term:
      id: GO:0016311
      label: dephosphorylation
    evidence_type: TAS
    original_reference_id: PMID:2556704
    review:
      summary: >-
        ACCEPT. PPP3CB is a calmodulin-regulated protein phosphatase.
        Dephosphorylation is its core catalytic function. The original
        cloning paper identified it as a protein phosphatase.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:2556704
          supporting_text: >-
            calcineurin, a calmodulin-regulated protein phosphatase

  # ============ ISS calcium-ion regulated exocytosis ============
  - term:
      id: GO:0017156
      label: calcium-ion regulated exocytosis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        KEEP_AS_NON_CORE. Plausible secondary function based on ortholog
        data. Calcineurin is involved in calcium-dependent vesicle
        trafficking.
      action: KEEP_AS_NON_CORE

  # ============ IDA protein phosphatase 2B binding ============
  - term:
      id: GO:0030346
      label: protein phosphatase 2B binding
    evidence_type: IDA
    original_reference_id: PMID:2556704
    review:
      summary: >-
        ACCEPT. PPP3CB self-associates as part of the calcineurin complex,
        and the original cloning study demonstrated interactions between
        calcineurin subunits.
      action: ACCEPT

  # ============ ISS/TAS calmodulin-dependent phosphatase activity ============
  - term:
      id: GO:0033192
      label: calmodulin-dependent protein phosphatase activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ACCEPT. Core molecular function. Confirmed by multiple experimental
        studies.
      action: ACCEPT
  - term:
      id: GO:0033192
      label: calmodulin-dependent protein phosphatase activity
    evidence_type: TAS
    original_reference_id: PMID:2556704
    review:
      summary: >-
        ACCEPT. Original cloning paper identified calcineurin as a
        calmodulin-regulated protein phosphatase.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:2556704
          supporting_text: >-
            calcineurin, a calmodulin-regulated protein phosphatase

  # ============ ISS insulin secretion ============
  - term:
      id: GO:0035774
      label: positive regulation of insulin secretion involved in cellular
        response to glucose stimulus
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        KEEP_AS_NON_CORE. Based on ortholog data. Calcineurin has been
        implicated in insulin secretion but this is not a core function
        of PPP3CB.
      action: KEEP_AS_NON_CORE
  - term:
      id: GO:0050796
      label: regulation of insulin secretion
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        KEEP_AS_NON_CORE. Parent term of above. Based on ortholog data.
      action: KEEP_AS_NON_CORE

  # ============ NAS annotations from PMID:8978785 (mapping paper) ============
  - term:
      id: GO:0007165
      label: signal transduction
    evidence_type: NAS
    original_reference_id: PMID:8978785
    review:
      summary: >-
        MARK_AS_OVER_ANNOTATED. This is from a chromosomal mapping paper
        that merely located PPP3CB on chromosome 10q21-q22. The paper
        briefly mentions calcineurin's role in signal transduction but
        provides no experimental evidence. The term is also very generic.
      action: MARK_AS_OVER_ANNOTATED
      supported_by:
        - reference_id: PMID:8978785
          supporting_text: >-
            Calcineurin (also called protein phosphatase-2B) is a
            calmodulin-regulated protein phosphatase which plays an
            important role in signal transduction
  - term:
      id: GO:0042098
      label: T cell proliferation
    evidence_type: NAS
    original_reference_id: PMID:8978785
    review:
      summary: >-
        MARK_AS_OVER_ANNOTATED. The mapping paper only briefly mentions
        calcineurin's role in T lymphocytes in the introduction.
        No experimental evidence for T cell proliferation is presented.
        T cell activation (GO:0042110) is better supported.
      action: MARK_AS_OVER_ANNOTATED
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: NAS
    original_reference_id: PMID:8978785
    review:
      summary: >-
        MARK_AS_OVER_ANNOTATED. From the chromosomal mapping paper.
        While calcineurin activates transcription factors (NFAT, TFEB),
        this is an indirect downstream effect. The paper provides no
        direct experimental evidence.
      action: MARK_AS_OVER_ANNOTATED

  # ============ TAS annotations from PMID:21531385 (schizophrenia GWAS) ============
  - term:
      id: GO:0007612
      label: learning
    evidence_type: TAS
    original_reference_id: PMID:21531385
    review:
      summary: >-
        MARK_AS_OVER_ANNOTATED. From a GWAS study associating PPP3CB
        locus at 10q22 with schizophrenia with attention/executive function
        deficits. The paper found reduced PPP3CB mRNA expression in
        schizophrenia patients but provides no direct evidence that PPP3CB
        is involved in learning. This is a genetic association, not
        functional evidence.
      action: MARK_AS_OVER_ANNOTATED
      supported_by:
        - reference_id: PMID:21531385
          supporting_text: >-
            there was significantly lower expression of ANXA7, PPP3CB,
            and DNAJC9
  - term:
      id: GO:0007613
      label: memory
    evidence_type: TAS
    original_reference_id: PMID:21531385
    review:
      summary: >-
        MARK_AS_OVER_ANNOTATED. Same GWAS study. No direct functional
        evidence for PPP3CB involvement in memory. Genetic association only.
      action: MARK_AS_OVER_ANNOTATED
  - term:
      id: GO:0048167
      label: regulation of synaptic plasticity
    evidence_type: TAS
    original_reference_id: PMID:21531385
    review:
      summary: >-
        MARK_AS_OVER_ANNOTATED. From GWAS study. While calcineurin has
        known roles in synaptic plasticity (from mouse studies), this
        paper provides no direct evidence for PPP3CB. The annotation is
        based on genetic association with schizophrenia.
      action: MARK_AS_OVER_ANNOTATED
  - term:
      id: GO:0048675
      label: axon extension
    evidence_type: TAS
    original_reference_id: PMID:21531385
    review:
      summary: >-
        MARK_AS_OVER_ANNOTATED. From GWAS study. No direct evidence for
        PPP3CB involvement in axon extension. Genetic association only.
      action: MARK_AS_OVER_ANNOTATED

  # ============ NAS protein Ser/Thr phosphatase (PMID:8392375) ============
  - term:
      id: GO:0004722
      label: protein serine/threonine phosphatase activity
    evidence_type: NAS
    original_reference_id: PMID:8392375
    review:
      summary: >-
        ACCEPT. The paper reports molecular cloning of full-length cDNA
        of the catalytic subunit of calmodulin-dependent protein
        phosphatase. Core molecular function.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:8392375
          supporting_text: >-
            Molecular cloning of a full-length cDNA encoding the catalytic
            subunit of human calmodulin-dependent protein phosphatase
            (calcineurin A alpha).

  # ============ IDA calcium ion binding (PMID:8524402) ============
  - term:
      id: GO:0005509
      label: calcium ion binding
    evidence_type: IDA
    original_reference_id: PMID:8524402
    review:
      summary: >-
        ACCEPT. Crystal structure of calcineurin revealed metal binding
        sites. The catalytic site contains Fe and Zn, and calcineurin B
        regulatory subunit binds Ca2+. The catalytic subunit itself has
        metal binding sites at the active site. Note that calcium binding
        per se is primarily a function of the regulatory B subunit, but
        the overall heterodimer is calcium-responsive.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:8524402
          supporting_text: >-
            the Zn/Fe-containing active site. The metal-site geometry and
            active-site water structure suggest a catalytic mechanism
  - term:
      id: GO:0005516
      label: calmodulin binding
    evidence_type: NAS
    original_reference_id: PMID:8524402
    review:
      summary: >-
        ACCEPT. Crystal structure paper confirms calmodulin binding
        capability of calcineurin.
      action: ACCEPT
  - term:
      id: GO:0005955
      label: calcineurin complex
    evidence_type: IDA
    original_reference_id: PMID:8524402
    review:
      summary: >-
        ACCEPT. Crystal structure of the calcineurin complex (CaN A + CaN B)
        and FKBP12-FK506-calcineurin complex determined.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:8524402
          supporting_text: >-
            the crystal structures of full-length human CaN at 2.1 A
            resolution and of the complex of human CaN with FKBP12-FK506
            at 3.5 A resolution

  # ============ NEW suggested annotations ============
  - term:
      id: GO:0010508
      label: positive regulation of autophagy
    evidence_type: IDA
    original_reference_id: PMID:25720963
    review:
      summary: >-
        NEW. PPP3CB dephosphorylates TFEB, a master regulator of autophagy
        genes. Lysosomal Ca2+ release through MCOLN1 activates calcineurin,
        which dephosphorylates TFEB promoting nuclear translocation and
        autophagy gene expression. This was directly demonstrated with
        PPP3CB-specific siRNA.
      action: NEW
      supported_by:
        - reference_id: PMID:25720963
          supporting_text: >-
            calcineurin activity was not only necessary but sufficient to
            induce TFEB nuclear translocation

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:0000043
    title: >-
      Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
    findings: []
  - id: GO_REF:0000044
    title: >-
      Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000052
    title: >-
      Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: >-
      Automatic transfer of experimentally verified manual GO annotation
      data to orthologs using Ensembl Compara
    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:2556704
    title: >-
      Cloning of human calcineurin A: evidence for two isozymes and
      identification of a polyproline structural domain.
    findings:
      - statement: >-
          First cloning of human calcineurin A beta (PPP3CB). Identified
          two isozymes from alternative splicing with a unique polyproline
          N-terminal domain proposed to play a role in calmodulin activation.
        supporting_text: >-
          calcineurin A consists of at least two isozymes that may result
          from alternative splicing events... A role in the calmodulin
          activation of calcineurin is proposed for this novel structural
          element
  - id: PMID:8392375
    title: >-
      Molecular cloning of a full-length cDNA encoding the catalytic subunit
      of human calmodulin-dependent protein phosphatase (calcineurin A alpha).
    findings:
      - statement: >-
          Full-length cDNA cloning of calcineurin A alpha. Confirms
          calcineurin as a calmodulin-dependent protein Ser/Thr phosphatase.
        supporting_text: >-
          Molecular cloning of a full-length cDNA encoding the catalytic
          subunit of human calmodulin-dependent protein phosphatase
          (calcineurin A alpha).
  - id: PMID:8524402
    title: >-
      Crystal structures of human calcineurin and the human
      FKBP12-FK506-calcineurin complex.
    findings:
      - statement: >-
          First crystal structures of human calcineurin at 2.1 A and
          FKBP12-FK506-calcineurin complex at 3.5 A. Revealed autoinhibitory
          element at Zn/Fe active site and catalytic mechanism.
        supporting_text: >-
          an auto-inhibitory element binds at the Zn/Fe-containing active
          site. The metal-site geometry and active-site water structure
          suggest a catalytic mechanism involving nucleophilic attack on
          the substrate phosphate by a metal-activated water molecule
  - id: PMID:8631904
    title: >-
      Calcineurin binds the transcription factor NFAT1 and reversibly
      regulates its activity.
    findings:
      - statement: >-
          Demonstrated direct enzyme-substrate interaction between
          calcineurin and NFAT1. NFAT activation is exquisitely sensitive
          to calcineurin activity level.
        supporting_text: >-
          a direct interaction between calcineurin and NFAT1 that is
          consistent with a direct enzyme-substrate relation between these
          two proteins
  - id: PMID:8978785
    title: >-
      Calcineurin A alpha (PPP3CA), calcineurin A beta (PPP3CB) and
      calcineurin B (PPP3R1) are located on human chromosomes 4, 10q21-->q22
      and 2p16-->p15 respectively.
    findings:
      - statement: >-
          Chromosomal localization study. PPP3CB mapped to 10q21-q22.
          Not a functional study.
        supporting_text: >-
          calcineurin A beta (PPP3CB, previous gene symbol CALNB) is
          present on 10q21-->q22
  - id: PMID:11005320
    title: >-
      Genetic conservation of the immunophilin-binding domains of human
      calcineurin A1 and A2.
    findings:
      - statement: >-
          Immunophilin-binding domains (aa 281-414) of PPP3CA and PPP3CB
          are highly conserved with no polymorphisms detected.
        supporting_text: >-
          Single-strand conformational polymorphism (SSCP) analysis of
          cDNAs derived from the coding region for amino acids 281-414
          of CNA1 and CNA2 in 32 healthy Caucasians did not detect
          polymorphic variations within these genes
  - id: PMID:17640527
    title: >-
      AKAP79/150 anchoring of calcineurin controls neuronal L-type Ca2+
      channel activity and nuclear signaling.
    findings:
      - statement: >-
          AKAP79/150 scaffolds calcineurin with PKA and L-type Ca2+ channels,
          enabling bidirectional regulation. Anchored CaN dominantly suppresses
          PKA enhancement of the channel.
        supporting_text: >-
          Cotargeting of PKA and CaN by AKAP79/150 confers bidirectional
          regulation of L-type current amplitude... anchored CaN dominantly
          suppresses PKA enhancement of the channel
  - id: PMID:19154138
    title: >-
      The proline-rich N-terminal sequence of calcineurin Abeta determines
      substrate binding.
    findings:
      - statement: >-
          CaN beta has the lowest Km for all protein substrates, indicating
          highest substrate affinity. The proline-rich N-terminal sequence
          is involved in substrate recognition.
        supporting_text: >-
          CaN beta exhibits for all tested protein substrates the lowest
          K(m) values... the proline-rich sequence of CaN beta is involved
          in substrate recognition
  - id: PMID:21531385
    title: >-
      ANXA7, PPP3CB, DNAJC9, and ZMYND17 genes at chromosome 10q22
      associated with the subgroup of schizophrenia with deficits in
      attention and executive function.
    findings:
      - statement: >-
          GWAS association of PPP3CB locus with schizophrenia subgroup.
          Reduced PPP3CB mRNA expression found. Genetic association, not
          direct functional evidence.
        supporting_text: >-
          there was significantly lower expression of ANXA7, PPP3CB,
          and DNAJC9
  - id: PMID:21903422
    title: >-
      Mapping a dynamic innate immunity protein interaction network
      regulating type I interferon production.
    findings:
      - statement: >-
          High-throughput interaction mapping. PPP3CB identified as a
          node in the innate immunity interactome.
        supporting_text: >-
          Fifty-eight baits were associated with 260 interacting proteins
          forming a human innate immunity interactome for type I interferon
  - id: PMID:22343722
    title: >-
      Balanced interactions of calcineurin with AKAP79 regulate
      Ca2+-calcineurin-NFAT signaling.
    findings:
      - statement: >-
          AKAP79 anchoring site (IAIIIT) binds the same calcineurin
          surface as the PxIxIT recognition peptide of NFAT. Demonstrates
          balanced competition between scaffold and substrate.
        supporting_text: >-
          an IAIIIT anchoring site in human AKAP79 binds the same surface
          of calcineurin as the PxIxIT recognition peptide of NFAT,
          albeit more strongly
  - id: PMID:22688515
    title: >-
      Na(+)/H(+) exchanger 1 directly binds to calcineurin A and activates
      downstream NFAT signaling, leading to cardiomyocyte hypertrophy.
    findings:
      - statement: >-
          NHE1 directly binds calcineurin A via PVITID motif and promotes
          CaN/NFAT signaling via increased intracellular pH in
          cardiomyocytes.
        supporting_text: >-
          Direct binding of CaN to the (715)PVITID(720) sequence of NHE1,
          which resembles the consensus CaN-binding motif (PXIXIT)
  - id: PMID:25720963
    title: >-
      Lysosomal calcium signalling regulates autophagy through calcineurin
      and TFEB.
    findings:
      - statement: >-
          PPP3CB identified as the key calcineurin isoform for TFEB
          dephosphorylation. Lysosomal Ca2+ release through MCOLN1
          activates calcineurin, which dephosphorylates TFEB promoting
          nuclear translocation and autophagy/lysosomal biogenesis.
        supporting_text: >-
          The most significant hit identified by the primary screening
          was the calcineurin catalytic subunit isoform beta (PPP3CB;
          Gene ID:5532)
  - id: PMID:26794871
    title: >-
      Cooperative autoinhibition and multi-level activation mechanisms of
      calcineurin.
    findings:
      - statement: >-
          Crystal structure of full-length PPP3CB at 2.23 A. Revealed
          novel autoinhibitory segment (AIS) in addition to AID. Challenges
          current activation model.
        supporting_text: >-
          revealed a novel autoinhibitory segment (AIS) in addition to
          the well-known autoinhibitory domain (AID). The AIS nestles in
          a hydrophobic intersubunit groove, which overlaps the recognition
          site for substrates
  - id: PMID:28126489
    title: >-
      The protein serine/threonine phosphatases PP2A, PP1 and calcineurin:
      A triple threat in the regulation of the neuronal cytoskeleton.
    findings:
      - statement: >-
          Review discussing calcineurin's role in regulating neuronal
          cytoskeletal dynamics through dephosphorylation of cytoskeletal
          proteins.
        supporting_text: >-
          the assembly/disassembly and stability of these cytoskeletal
          networks is crucially modulated by protein phosphorylation and
          dephosphorylation events
  - id: PMID:32753672
    title: >-
      Mammalian Atg8 proteins and the autophagy factor IRGM control mTOR
      and TFEB at a regulatory node critical for responses to pathogens.
    findings:
      - statement: >-
          IRGM directly interacts with calcineurin PPP3CB, promoting its
          association with TFEB and TFEB dephosphorylation. IRGM-dependent
          TFEB activation occurs during pathogen infection.
        supporting_text: >-
          FLAG-IRGM co-IPed with GFP-PPP3CB... A direct interaction
          between IRGM and PPP3CB was established in GST pull-downs...
          GFP-IRGM expression augmented whereas IRGM KD reduced
          association of TFEB with PPP3CB
  - id: PMID:33961781
    title: >-
      Dual proteome-scale networks reveal cell-specific remodeling of the
      human interactome.
    findings:
      - statement: >-
          High-throughput interactome study. PPP3CB identified as an
          interactor in proteome-scale networks.
        supporting_text: >-
          Dual proteome-scale networks reveal cell-specific remodeling of
          the human interactome
  - id: PMID:34446558
    title: >-
      SPATA33 localizes calcineurin to the mitochondria and regulates sperm
      motility in mice.
    findings:
      - statement: >-
          SPATA33 interacts with calcineurin via PQIIIT motif. Primarily
          relevant to sperm calcineurin (PPP3CC/PPP3R2), not PPP3CB.
        supporting_text: >-
          SPATA33 interacts with sperm calcineurin via a PQIIIT sequence
  - id: PMID:35914814
    title: >-
      Chr21 protein-protein interactions: enrichment in proteins involved
      in intellectual disability, autism, and late-onset Alzheimer's disease.
    findings:
      - statement: >-
          High-throughput Chr21 protein interaction study. PPP3CB
          identified as an interactor.
        supporting_text: >-
          Chr21 protein-protein interactions: enrichment in proteins
          involved in intellectual disability, autism, and late-onset
          Alzheimer's disease
  - id: PMID:40205054
    title: >-
      Multimodal cell maps as a foundation for structural and functional
      genomics.
    findings:
      - statement: >-
          Large-scale cell mapping study. PPP3CB identified in multimodal
          interaction datasets.
        supporting_text: >-
          Multimodal cell maps as a foundation for structural and
          functional genomics
  - id: Reactome:R-HSA-2025890
    title: Calcineurin binds NFATC1,2,3
    findings:
      - statement: >-
          Calcineurin heterodimer binds NFAT family members in the cytosol.
        supporting_text: >-
          B lymphocytes contain the R1 regulatory subunit (PPP3R1) and
          the beta catalytic subunit (PPP3CB)
  - id: Reactome:R-HSA-2730849
    title: Calcineurin binds and dephosphorylates NFAT
    findings:
      - statement: >-
          Calcineurin dephosphorylates NFAT, enabling nuclear translocation.
        supporting_text: >-
          these serine residues are dephosphorylated by calcineurin, that
          thought to cause exposure of nuclear localization signal sequences
          triggering translocation of the dephosphorylated NFAT-CaN complex
          to the nucleus
  - id: Reactome:R-HSA-2730867
    title: Translocation of CaN:CaM:NFAT to nucleus
    findings:
      - statement: >-
          Calcineurin:calmodulin:NFAT complex translocates to the nucleus.
        supporting_text: >-
          Dephosphorylated NFAT-calcineurin (CaN) complex translocates to
          nucleus, where it activates transcription of several cytokine
          genes
  - id: Reactome:R-HSA-2730872
    title: Activation of Calcineurin
    findings:
      - statement: >-
          Ca2+/calmodulin activates calcineurin in the cytosol.
        supporting_text: >-
          Active CaM binds to CaN regulatory domain (RD) and this causes
          release of the AID and activation of the phosphatase
  - id: Reactome:R-HSA-4551451
    title: >-
      Calcineurin binds and dephosphorylates NFAT1 in response to WNT/Ca2+
      signaling
    findings:
      - statement: >-
          Calcineurin-NFAT signaling downstream of Wnt/Ca2+ pathway.
        supporting_text: >-
          Calcineurin binds and dephosphorylates NFAT1 in response to
          WNT/Ca2+ signaling
  - id: Reactome:R-HSA-4551465
    title: Translocation of NFATC1:CaN:CaM to nucleus
    findings:
      - statement: >-
          NFATC1:calcineurin:calmodulin complex translocates to the nucleus.
        supporting_text: >-
          Dephosphorylated NFAT-calcineurin (CaN) complex translocates to
          nucleus, where it activates transcription

core_functions:
  - molecular_function:
      id: GO:0033192
      label: calmodulin-dependent protein phosphatase activity
    description: >-
      PPP3CB is a calmodulin-dependent serine/threonine phosphatase
      (EC 3.1.3.16). It requires Ca2+/calmodulin for full activation via
      displacement of autoinhibitory domains (AIS and AID). The beta isoform
      has the highest substrate binding affinity due to its unique
      proline-rich N-terminal domain.
    directly_involved_in:
      - id: GO:0033173
        label: calcineurin-NFAT signaling cascade
      - id: GO:0006470
        label: protein dephosphorylation
      - id: GO:0010508
        label: positive regulation of autophagy
    supported_by:
      - reference_id: PMID:19154138
        supporting_text: >-
          CaN beta exhibits for all tested protein substrates the lowest
          K(m) values
      - reference_id: PMID:26794871
        supporting_text: >-
          we report the crystal structure of full-length CN (beta isoform)