PPP3CB encodes calcineurin A beta (CnA-beta), one of three catalytic subunits of calcineurin (protein phosphatase 2B, PP2B), the Ca2+/calmodulin-dependent serine/threonine protein phosphatase of the PPP family. The catalytic subunit binds an Fe/Zn binuclear metal centre and forms an obligate heterodimer with the Ca2+-binding regulatory subunit calcineurin B (PPP3R1, or PPP3R2 in testis); Ca2+ binding to calcineurin B and Ca2+/calmodulin binding to the catalytic subunit relieve autoinhibition by an autoinhibitory segment and the C-terminal autoinhibitory domain. A proline-rich N-terminal extension unique to the beta isoform contributes to substrate recognition and gives CnA-beta the lowest Km of the isoforms toward tested protein substrates. Calcineurin docks substrates and regulators through PxIxIT and LxVP short linear motifs. Its best-characterized substrates are the NFAT transcription factors, whose dephosphorylation drives their nuclear import in Ca2+-dependent signaling, including T cell receptor signaling, and the lysosomal/autophagy transcription factor TFEB, which PPP3CB dephosphorylates in response to lysosomal Ca2+ release through MCOLN1. PPP3CB is largely cytosolic and can be recruited to membranes by anchoring proteins such as AKAP5 and, after lysosomal damage, by a galectin-3-SMURF1 complex. Calcineurin is the target of the immunosuppressants cyclosporin A and tacrolimus (FK506), which act as complexes with cyclophilin and FKBP12.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | 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. Supporting Evidence: PMID:19154138 this study demonstrates that all CaN isoforms display the same cytoplasmic subcellular distribution |
| GO:0005955 calcineurin complex | IBA GO_REF:0000033 | ACCEPT | 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). Supporting Evidence: PMID:26794871 a heterodimer composed of a catalytic subunit A and an essential regulatory subunit B |
| GO:0097720 calcineurin-mediated signaling | IBA GO_REF:0000033 | ACCEPT | Summary: ACCEPT. Calcineurin-mediated signaling is a core function of PPP3CB, including NFAT signaling and TFEB regulation. Supported by multiple experimental studies. Supporting Evidence: PMID:25720963 calcineurin plays a crucial role in the regulation of TFEB subcellular localization PMID:19154138 Comparative kinetic analysis of the dephosphorylation of five specific CaN substrates provided evidence that the distinct isoforms of the catalytic subunit confer substrate specificities |
| GO:0033192 calmodulin-dependent protein phosphatase activity | IBA GO_REF:0000033 | ACCEPT | 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). Supporting Evidence: PMID:26794871 The Ca(2+)/calmodulin-dependent protein phosphatase calcineurin PMID:19154138 Ca(2+)-dependent serine/threonine protein phosphatase calcineurin |
| GO:0005516 calmodulin binding | IBA GO_REF:0000033 | ACCEPT | Summary: ACCEPT. Calmodulin binding is essential for calcineurin activation. The calmodulin-binding domain has been structurally characterized (residues 401-415 of PPP3CB, PMID:26794871). Supporting Evidence: PMID:26794871 The Ca(2+)/calmodulin-dependent protein phosphatase calcineurin |
| GO:0004721 phosphoprotein phosphatase activity | IEA GO_REF:0000043 | ACCEPT | 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). |
| GO:0004722 protein serine/threonine phosphatase activity | IEA GO_REF:0000120 | ACCEPT | 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. |
| GO:0005516 calmodulin binding | IEA GO_REF:0000043 | ACCEPT | Summary: ACCEPT. Redundant with IBA annotation but correct. Calmodulin binding is experimentally verified. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: ACCEPT. Cytoplasmic localization confirmed experimentally (PMID:19154138). |
| GO:0016787 hydrolase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Correct but very general parent of protein serine/threonine phosphatase activity; the specific term GO:0033192 is the core MF. |
| GO:0033173 calcineurin-NFAT signaling cascade | IEA GO_REF:0000117 | ACCEPT | Summary: ACCEPT. The calcineurin-NFAT signaling cascade is a core function, well supported by experimental evidence for PPP3CB (PMID:19154138, PMID:22688515). |
| GO:0033192 calmodulin-dependent protein phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: ACCEPT. Core molecular function, redundant with IBA but correct. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: ACCEPT. PPP3CB has a binuclear metal center with Fe3+ and Zn2+ at the active site, confirmed by crystal structure (PMID:8524402, PMID:26794871). Supporting Evidence: PMID:8524402 the Zn/Fe-containing active site |
| GO:0097720 calcineurin-mediated signaling | IEA GO_REF:0000002 | ACCEPT | Summary: ACCEPT. Calcineurin-mediated signaling is a core function. Redundant with IBA but correct. |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: IRF2 interaction from a high-throughput innate-immunity interaction network (PMID:21903422). Removal of the uninformative protein binding term does not mean the interaction is false; the cited paper reports the interaction without evidence for a specific molecular activity of PPP3CB in it, and no informative MF term follows from it. Supporting Evidence: PMID:21903422 Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Interaction with RCAN1 (calcipressin-1, P53805) from a proteome-scale interaction screen. RCAN1 is a well-known endogenous calcineurin regulator that docks on the catalytic subunit, so the interaction is credible, but it is RCAN1 that carries the informative activity (calcineurin inhibitor/phosphatase regulator activity); there is no informative MF term for PPP3CB being bound. Removal of the uninformative protein binding term does not mean the interaction is false; the cited paper reports the interaction without evidence for a specific molecular activity of PPP3CB in it, and no informative MF term follows from it. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:35914814 Chr21 protein-protein interactions: enrichment in proteins i... | REMOVE | Summary: Interaction with RCAN1 (calcipressin-1, P53805) from a proteome-scale interaction screen. RCAN1 is a well-known endogenous calcineurin regulator that docks on the catalytic subunit, so the interaction is credible, but it is RCAN1 that carries the informative activity (calcineurin inhibitor/phosphatase regulator activity); there is no informative MF term for PPP3CB being bound. Removal of the uninformative protein binding term does not mean the interaction is false; the cited paper reports the interaction without evidence for a specific molecular activity of PPP3CB in it, and no informative MF term follows from it. Supporting Evidence: PMID:35914814 Chr21 protein-protein interactions: enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer's disease. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: Interaction with RCAN1 (calcipressin-1, P53805) from a proteome-scale interaction screen. RCAN1 is a well-known endogenous calcineurin regulator that docks on the catalytic subunit, so the interaction is credible, but it is RCAN1 that carries the informative activity (calcineurin inhibitor/phosphatase regulator activity); there is no informative MF term for PPP3CB being bound. Removal of the uninformative protein binding term does not mean the interaction is false; the cited paper reports the interaction without evidence for a specific molecular activity of PPP3CB in it, and no informative MF term follows from it. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics. |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. Supporting Evidence: PMID:17640527 CaV1.2 interacts directly with AKAP79/150, which binds both PKA and the Ca2+/calmodulin-activated phosphatase calcineurin |
| GO:0017156 calcium-ion regulated exocytosis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE. Plausible secondary function via calcineurin's role in calcium signaling. Supported by ortholog data. |
| GO:0023057 negative regulation of signaling | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. |
| GO:0030018 Z disc | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE. Plausible for skeletal/cardiac muscle context where calcineurin plays roles. Supported by tissue-enhanced expression in skeletal muscle (HPA). |
| GO:0030315 T-tubule | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. |
| GO:0035774 positive regulation of insulin secretion involved in cellular response to glucose stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE. Calcineurin has been implicated in insulin secretion regulation through ortholog studies. Not a core function of PPP3CB. |
| GO:0048741 skeletal muscle fiber development | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE. Calcineurin plays roles at synapses but this localization is from ortholog data only. |
| GO:1900242 regulation of synaptic vesicle endocytosis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE. Calcineurin has known roles in synaptic vesicle recycling via dephosphorylation of dynamin and other endocytic proteins. Ortholog-based annotation. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: ACCEPT. Cytosol localization based on immunofluorescence data. Consistent with cytoplasmic localization confirmed by PMID:19154138. |
| GO:0005829 cytosol | NAS PMID:22343722 Balanced interactions of calcineurin with AKAP79 regulate Ca... | ACCEPT | Summary: ACCEPT. Calcineurin is present in the cytosol where it interacts with AKAP79 and regulates NFAT signaling (PMID:22343722). Supporting Evidence: PMID:22343722 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. |
| GO:0005829 cytosol | NAS PMID:28126489 The protein serine/threonine phosphatases PP2A, PP1 and calc... | ACCEPT | Summary: ACCEPT. Consistent with known cytosolic localization. This is a review paper discussing calcineurin's role in neuronal cytoskeleton regulation. Supporting Evidence: PMID:28126489 The protein serine/threonine phosphatases PP2A, PP1 and calcineurin: A triple threat in the regulation of the neuronal cytoskeleton. |
| GO:0070886 positive regulation of calcineurin-NFAT signaling cascade | NAS PMID:22343722 Balanced interactions of calcineurin with AKAP79 regulate Ca... | MODIFY | Summary: Calcineurin does not regulate the calcineurin-NFAT cascade from outside; its NFAT phosphatase activity is the central step of the cascade. A positive-regulation term on the enzyme itself is a mis-framing; the appropriate term is calcineurin-NFAT signaling cascade (GO:0033173), which is also supported by IDA rows (PMID:19154138, PMID:22688515). Regulators of the cascade such as AKAP5 or NHE1 are the proper bearers of the regulation term. Proposed replacements: calcineurin-NFAT signaling cascade Supporting Evidence: PMID:22343722 an IAIIIT anchoring site in human AKAP79 binds the same surface of calcineurin as the PxIxIT recognition peptide of NFAT |
| GO:0070886 positive regulation of calcineurin-NFAT signaling cascade | NAS PMID:8631904 Calcineurin binds the transcription factor NFAT1 and reversi... | MODIFY | Summary: Calcineurin does not regulate the calcineurin-NFAT cascade from outside; its NFAT phosphatase activity is the central step of the cascade. A positive-regulation term on the enzyme itself is a mis-framing; the appropriate term is calcineurin-NFAT signaling cascade (GO:0033173), which is also supported by IDA rows (PMID:19154138, PMID:22688515). Regulators of the cascade such as AKAP5 or NHE1 are the proper bearers of the regulation term. Proposed replacements: calcineurin-NFAT signaling cascade Supporting Evidence: PMID:8631904 We also demonstrate a direct interaction between calcineurin and NFAT1 that is consistent with a direct enzyme-substrate relation between these two proteins |
| GO:1905665 positive regulation of calcium ion import across plasma membrane | NAS PMID:17640527 AKAP79/150 anchoring of calcineurin controls neuronal L-type... | KEEP AS NON CORE | 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. Supporting Evidence: PMID:17640527 Cotargeting of PKA and CaN by AKAP79/150 confers bidirectional regulation of L-type current amplitude |
| GO:1905949 negative regulation of calcium ion import across plasma membrane | NAS PMID:17640527 AKAP79/150 anchoring of calcineurin controls neuronal L-type... | KEEP AS NON CORE | 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. Supporting Evidence: PMID:17640527 anchored CaN dominantly suppresses PKA enhancement of the channel |
| GO:0033192 calmodulin-dependent protein phosphatase activity | IDA PMID:25720963 Lysosomal calcium signalling regulates autophagy through cal... | ACCEPT | Summary: ACCEPT. Core molecular function. PPP3CB was specifically identified as the calcineurin isoform responsible for TFEB dephosphorylation. Phosphatase activity confirmed experimentally. Supporting Evidence: PMID:25720963 The most significant hit identified by the primary screening was the calcineurin catalytic subunit isoform beta (PPP3CB; Gene ID:5532) |
| GO:0033192 calmodulin-dependent protein phosphatase activity | IDA PMID:32753672 Mammalian Atg8 proteins and the autophagy factor IRGM contro... | ACCEPT | Summary: ACCEPT. Core molecular function. IRGM promotes calcineurin (PPP3CB)-mediated TFEB dephosphorylation. Supporting Evidence: PMID:32753672 IRGM interacts with calcineurin PPP3CB... IRGM overexpression promoted dephosphorylation of another PPP3CB target, NFAT |
| GO:1900182 positive regulation of protein localization to nucleus | IDA PMID:25720963 Lysosomal calcium signalling regulates autophagy through cal... | ACCEPT | Summary: ACCEPT. PPP3CB dephosphorylates TFEB promoting its nuclear translocation. Direct experimental evidence with siRNA knockdown of PPP3CB specifically. Supporting Evidence: PMID:25720963 inhibition of PPP3CB suppressed starvation-induced nuclear translocation of TFEB |
| GO:1900182 positive regulation of protein localization to nucleus | IDA PMID:32753672 Mammalian Atg8 proteins and the autophagy factor IRGM contro... | ACCEPT | Summary: ACCEPT. IRGM promotes PPP3CB-mediated TFEB nuclear translocation. Supporting Evidence: PMID:32753672 IRGM directly interacted with TFEB and promoted the nuclear translocation of TFEB |
| GO:1905673 positive regulation of lysosome organization | IDA PMID:25720963 Lysosomal calcium signalling regulates autophagy through cal... | ACCEPT | Summary: ACCEPT. PPP3CB-mediated TFEB activation drives lysosomal biogenesis. Constitutively active calcineurin induced TFEB target genes in a TFEB-dependent manner. Supporting Evidence: PMID:25720963 calcineurin overexpression and constitutive activation... induced the expression of TFEB transcriptional target genes in a TFEB-dependent manner |
| GO:1905673 positive regulation of lysosome organization | IDA PMID:32753672 Mammalian Atg8 proteins and the autophagy factor IRGM contro... | ACCEPT | Summary: ACCEPT. IRGM-calcineurin-TFEB axis drives lysosomal biogenesis. Supporting Evidence: PMID:32753672 IRGM and its interactors mAtg8s close a loop between the autophagosomal pathway and the control of lysosomal biogenesis by TFEB |
| GO:0005515 protein binding | IPI PMID:34446558 SPATA33 localizes calcineurin to the mitochondria and regula... | REMOVE | Summary: SPATA33 binds calcineurin through a PQIIIT (PxIxIT-type) motif; the study concerns sperm calcineurin (mainly PPP3CC/PPP3R2) in mouse. As for other PxIxIT partners, the informative activity belongs to the docking partner, not to PPP3CB. Removal of the uninformative protein binding term does not mean the interaction is false; the cited paper reports the interaction without evidence for a specific molecular activity of PPP3CB in it, and no informative MF term follows from it. Supporting Evidence: PMID:34446558 SPATA33 interacts with sperm calcineurin via a PQIIIT sequence |
| GO:0023057 negative regulation of signaling | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE. Calcineurin negatively regulates MAP3K14/NIK signaling. Supported by similarity to mouse ortholog. Secondary function. |
| GO:0048741 skeletal muscle fiber development | ISS GO_REF:0000024 | KEEP AS NON CORE | 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. |
| GO:0097720 calcineurin-mediated signaling | IMP PMID:11005320 Genetic conservation of the immunophilin-binding domains of ... | ACCEPT | 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. Supporting Evidence: PMID:11005320 Calcineurin a calmodulin-dependent phosphatase plays a critical role in calcium-dependent activation of T-lymphocytes |
| GO:0005515 protein binding | IPI PMID:26794871 Cooperative autoinhibition and multi-level activation mechan... | REMOVE | Summary: Interaction with calcineurin B (PPP3R1, P63098) in the crystal structure of full-length CnA-beta/CnB. This is the obligate intra-complex A-B interaction and is already captured by the calcineurin complex annotation (GO:0005955, IDA from the same paper). The earlier proposal to replace it with GO:0030346 'protein phosphatase 2B binding' was withdrawn: that term describes a partner binding to calcineurin, and applying it to a calcineurin subunit is self-referential. Supporting Evidence: PMID:26794871 a heterodimer composed of a catalytic subunit A and an essential regulatory subunit B |
| GO:0005516 calmodulin binding | IDA PMID:26794871 Cooperative autoinhibition and multi-level activation mechan... | ACCEPT | 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. Supporting Evidence: PMID:26794871 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 |
| GO:0005737 cytoplasm | IDA PMID:19154138 The proline-rich N-terminal sequence of calcineurin Abeta de... | ACCEPT | Summary: ACCEPT. Direct experimental evidence for cytoplasmic localization of PPP3CB. Supporting Evidence: PMID:19154138 all CaN isoforms display the same cytoplasmic subcellular distribution |
| GO:0005955 calcineurin complex | IDA PMID:26794871 Cooperative autoinhibition and multi-level activation mechan... | ACCEPT | Summary: ACCEPT. Crystal structure of full-length PPP3CB in complex with PPP3R1, confirming calcineurin complex formation. Supporting Evidence: PMID:26794871 we report the crystal structure of full-length CN (beta isoform) |
| GO:0006470 protein dephosphorylation | IDA PMID:19154138 The proline-rich N-terminal sequence of calcineurin Abeta de... | ACCEPT | Summary: ACCEPT. Core function. PPP3CB dephosphorylates NFATC1, ELK1, and DARPP-32 with characterized kinetics. Supporting Evidence: PMID:19154138 Comparative kinetic analysis of the dephosphorylation of five specific CaN substrates |
| GO:0006470 protein dephosphorylation | IDA PMID:26794871 Cooperative autoinhibition and multi-level activation mechan... | ACCEPT | Summary: ACCEPT. Core function. Protein dephosphorylation confirmed by crystal structure and biochemical studies. |
| GO:0033173 calcineurin-NFAT signaling cascade | IDA PMID:19154138 The proline-rich N-terminal sequence of calcineurin Abeta de... | ACCEPT | Summary: ACCEPT. Core function. PPP3CB dephosphorylates NFATC1 with Km=0.69 uM, driving NFAT nuclear translocation and transcriptional activation. Supporting Evidence: PMID:19154138 NFAT reporter gene activity measurements revealed even more pronounced substrate preferences of CaNA isoforms |
| GO:0033192 calmodulin-dependent protein phosphatase activity | IDA PMID:19154138 The proline-rich N-terminal sequence of calcineurin Abeta de... | ACCEPT | Summary: ACCEPT. Core molecular function. PPP3CB's phosphatase activity requires calmodulin for full activation. Supporting Evidence: PMID:19154138 Ca(2+)-dependent serine/threonine protein phosphatase calcineurin file:human/PPP3CB/PPP3CB-deep-research-falcon.md a **Ca2+/calmodulin-dependent serine/threonine protein phosphatase** that functions as a **heterodimer** |
| GO:0033192 calmodulin-dependent protein phosphatase activity | IDA PMID:26794871 Cooperative autoinhibition and multi-level activation mechan... | ACCEPT | Summary: ACCEPT. Core molecular function confirmed by crystal structure and biochemical characterization of activation mechanism. |
| GO:0005515 protein binding | IPI PMID:22688515 Na(+)/H(+) exchanger 1 directly binds to calcineurin A and a... | REMOVE | Summary: NHE1 (SLC9A1) binds calcineurin A directly through a PVITID (PxIxIT-like) sequence. The docking motif and the informative activity are on NHE1; from the PPP3CB side the row records only that it is bound, and GO:0030346 'protein phosphatase 2B binding' (proposed earlier) would describe NHE1, not PPP3CB. The downstream NFAT signaling consequence is already captured by the calcineurin-NFAT signaling cascade IDA row from the same paper. Removal of the uninformative protein binding term does not mean the interaction is false; the cited paper reports the interaction without evidence for a specific molecular activity of PPP3CB in it, and no informative MF term follows from it. Supporting Evidence: PMID:22688515 The calcineurin A (CaNA) subunit was identified as a novel binding partner of plasma membrane Na(+)/H(+) exchanger 1 (NHE1) |
| GO:0005955 calcineurin complex | IDA PMID:22688515 Na(+)/H(+) exchanger 1 directly binds to calcineurin A and a... | ACCEPT | Summary: ACCEPT. Confirms calcineurin complex formation in the context of NHE1-mediated NFAT signaling in cardiomyocytes. Supporting Evidence: PMID:22688515 CaN is a Ca(2+)-dependent phosphatase involved in many cellular functions, including cardiac hypertrophy |
| GO:0033173 calcineurin-NFAT signaling cascade | IDA PMID:22688515 Na(+)/H(+) exchanger 1 directly binds to calcineurin A and a... | ACCEPT | Summary: ACCEPT. NHE1 activates calcineurin-NFAT signaling in cardiomyocytes, leading to hypertrophic gene expression. Supporting Evidence: PMID:22688515 NHE1 stimulated hypertrophic gene expression and the NFAT pathway, which were inhibited by a CaN inhibitor, FK506 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:22688515 Na(+)/H(+) exchanger 1 directly binds to calcineurin A and a... | KEEP AS NON CORE | 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. Supporting Evidence: PMID:22688515 Overexpression of NHE1 promoted serum-induced CaN/nuclear factor of activated T cells (NFAT) signaling... enhancement of NFAT promoter activity and nuclear translocation |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2730867 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE. Calcineurin translocates to the nucleus with NFAT (Reactome: Translocation of CaN:CaM:NFAT to nucleus). Not the primary localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-4551465 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE. Same as above - calcineurin accompanies NFAT to nucleus (Reactome: Translocation of NFATC1:CaN:CaM to nucleus). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2025890 | ACCEPT | Summary: ACCEPT. Reactome: Calcineurin binds NFATC1,2,3. Cytosolic localization consistent with experimental data. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730849 | ACCEPT | Summary: ACCEPT. Reactome: Calcineurin binds and dephosphorylates NFAT. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730867 | ACCEPT | Summary: ACCEPT. Reactome: Translocation of CaN:CaM:NFAT to nucleus. Cytosol is the starting location. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730872 | ACCEPT | Summary: ACCEPT. Reactome: Activation of Calcineurin. Occurs in cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-4551451 | ACCEPT | Summary: ACCEPT. Reactome: Calcineurin binds and dephosphorylates NFAT1 in response to WNT/Ca2+ signaling. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-4551465 | ACCEPT | Summary: ACCEPT. Reactome: Translocation of NFATC1:CaN:CaM to nucleus. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE. Calcineurin can localize to plasma membrane via AKAP79/150 scaffolding (PMID:17640527). Not primary localization. |
| GO:0005516 calmodulin binding | IDA PMID:11005320 Genetic conservation of the immunophilin-binding domains of ... | ACCEPT | Summary: ACCEPT. The immunophilin-binding domain region (aa 281-414) overlaps with the calmodulin binding domain. The study confirms conservation of this functional region. Supporting Evidence: PMID:11005320 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 |
| GO:0019899 enzyme binding | IDA PMID:11005320 Genetic conservation of the immunophilin-binding domains of ... | KEEP AS NON CORE | 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. Supporting Evidence: PMID:11005320 the major target for the inhibitory actions of the immunosuppressive drugs Tacrolimus (FK506) and Cyclosporin A |
| GO:0042110 T cell activation | TAS PMID:11005320 Genetic conservation of the immunophilin-binding domains of ... | KEEP AS NON CORE | Summary: Calcineurin is required for T cell activation and is the target of cyclosporin A and FK506, but the TAS statement is a broad cellular outcome. The step calcineurin performs is NFAT dephosphorylation within TCR-triggered calcineurin-NFAT signaling, which is the core annotation; T cell activation is kept as a non-core, contextual process (project rule: separate the activity from the pathway outcome). Note the cited paper concerns immunophilin-binding domains of CnA1/CnA2 (abstract only). Supporting Evidence: PMID:11005320 Calcineurin a calmodulin-dependent phosphatase plays a critical role in calcium-dependent activation of T-lymphocytes |
| GO:0046983 protein dimerization activity | IPI PMID:11005320 Genetic conservation of the immunophilin-binding domains of ... | KEEP AS NON CORE | Summary: The catalytic subunit heterodimerizes with calcineurin B. The term is correct but generic; the A-B heterodimer is better represented by part_of calcineurin complex (GO:0005955), which is the core cellular component term. Supporting Evidence: PMID:11005320 Calcineurin is a dimeric protein consisting of distinct A (catalytic) and B (regulatory) subunits |
| GO:0005516 calmodulin binding | IDA PMID:2556704 Cloning of human calcineurin A: evidence for two isozymes an... | ACCEPT | Summary: ACCEPT. Original cloning paper identified calmodulin binding. The polyproline structural domain was proposed to have a role in calmodulin activation. Supporting Evidence: PMID:2556704 A role in the calmodulin activation of calcineurin is proposed for this novel structural element |
| GO:0006468 protein phosphorylation | ISS GO_REF:0000024 | REMOVE | 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. |
| GO:0006470 protein dephosphorylation | ISS GO_REF:0000024 | ACCEPT | Summary: ACCEPT. Protein dephosphorylation is a core function, well supported by experimental data. |
| GO:0016311 dephosphorylation | TAS PMID:2556704 Cloning of human calcineurin A: evidence for two isozymes an... | ACCEPT | 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. Supporting Evidence: PMID:2556704 calcineurin, a calmodulin-regulated protein phosphatase |
| GO:0017156 calcium-ion regulated exocytosis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE. Plausible secondary function based on ortholog data. Calcineurin is involved in calcium-dependent vesicle trafficking. |
| GO:0030346 protein phosphatase 2B binding | IDA PMID:2556704 Cloning of human calcineurin A: evidence for two isozymes an... | KEEP AS NON CORE | Summary: Experimental annotation by the original curator on the cloning paper (abstract only cached). 'Protein phosphatase 2B binding' on a calcineurin catalytic subunit presumably records binding of calcineurin B or calmodulin to the A subunit; it is self-referential and less informative than calcineurin complex membership and calmodulin binding. Not overruled, but non-core. Supporting Evidence: PMID:2556704 A role in the calmodulin activation of calcineurin is proposed for this novel structural element. |
| GO:0033192 calmodulin-dependent protein phosphatase activity | ISS GO_REF:0000024 | ACCEPT | Summary: ACCEPT. Core molecular function. Confirmed by multiple experimental studies. |
| GO:0033192 calmodulin-dependent protein phosphatase activity | TAS PMID:2556704 Cloning of human calcineurin A: evidence for two isozymes an... | ACCEPT | Summary: ACCEPT. Original cloning paper identified calcineurin as a calmodulin-regulated protein phosphatase. Supporting Evidence: PMID:2556704 calcineurin, a calmodulin-regulated protein phosphatase |
| GO:0035774 positive regulation of insulin secretion involved in cellular response to glucose stimulus | ISS GO_REF:0000024 | KEEP AS NON CORE | 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. |
| GO:0050796 regulation of insulin secretion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: KEEP_AS_NON_CORE. Parent term of above. Based on ortholog data. |
| GO:0007165 signal transduction | NAS PMID:8978785 Calcineurin A alpha (PPP3CA), calcineurin A beta (PPP3CB) an... | MARK AS OVER ANNOTATED | 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. Supporting Evidence: PMID:8978785 Calcineurin (also called protein phosphatase-2B) is a calmodulin-regulated protein phosphatase which plays an important role in signal transduction |
| GO:0042098 T cell proliferation | NAS PMID:8978785 Calcineurin A alpha (PPP3CA), calcineurin A beta (PPP3CB) an... | MARK AS OVER ANNOTATED | 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. |
| GO:0045893 positive regulation of DNA-templated transcription | NAS PMID:8978785 Calcineurin A alpha (PPP3CA), calcineurin A beta (PPP3CB) an... | MARK AS OVER ANNOTATED | 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. |
| GO:0007612 learning | TAS PMID:21531385 ANXA7, PPP3CB, DNAJC9, and ZMYND17 genes at chromosome 10q22... | MARK AS OVER ANNOTATED | 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. Supporting Evidence: PMID:21531385 there was significantly lower expression of ANXA7, PPP3CB, and DNAJC9 |
| GO:0007613 memory | TAS PMID:21531385 ANXA7, PPP3CB, DNAJC9, and ZMYND17 genes at chromosome 10q22... | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED. Same GWAS study. No direct functional evidence for PPP3CB involvement in memory. Genetic association only. |
| GO:0048167 regulation of synaptic plasticity | TAS PMID:21531385 ANXA7, PPP3CB, DNAJC9, and ZMYND17 genes at chromosome 10q22... | MARK AS OVER ANNOTATED | 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. |
| GO:0048675 axon extension | TAS PMID:21531385 ANXA7, PPP3CB, DNAJC9, and ZMYND17 genes at chromosome 10q22... | MARK AS OVER ANNOTATED | Summary: MARK_AS_OVER_ANNOTATED. From GWAS study. No direct evidence for PPP3CB involvement in axon extension. Genetic association only. |
| GO:0004722 protein serine/threonine phosphatase activity | NAS PMID:8392375 Molecular cloning of a full-length cDNA encoding the catalyt... | ACCEPT | Summary: ACCEPT. The paper reports molecular cloning of full-length cDNA of the catalytic subunit of calmodulin-dependent protein phosphatase. Core molecular function. Supporting Evidence: PMID:8392375 Molecular cloning of a full-length cDNA encoding the catalytic subunit of human calmodulin-dependent protein phosphatase (calcineurin A alpha). |
| GO:0005509 calcium ion binding | IDA PMID:8524402 Crystal structures of human calcineurin and the human FKBP12... | MARK AS OVER ANNOTATED | Summary: The crystal structure of human calcineurin shows a Zn/Fe binuclear active site in the catalytic subunit; the Ca2+ sites of the heterodimer are the four EF-hands of calcineurin B (PPP3R1), and the catalytic subunit is regulated by Ca2+ indirectly through calcineurin B and calmodulin. Calcium ion binding is therefore an over-annotation for the catalytic subunit (it fits PPP3R1). The abstract-only cache does not show which residues the curator relied on, so the row is not removed. The catalytic metal binding is covered by metal ion binding (GO:0046872). Supporting Evidence: PMID:8524402 the Zn/Fe-containing active site. The metal-site geometry and active-site water structure suggest a catalytic mechanism |
| GO:0005516 calmodulin binding | NAS PMID:8524402 Crystal structures of human calcineurin and the human FKBP12... | ACCEPT | Summary: ACCEPT. Crystal structure paper confirms calmodulin binding capability of calcineurin. |
| GO:0005955 calcineurin complex | IDA PMID:8524402 Crystal structures of human calcineurin and the human FKBP12... | ACCEPT | Summary: ACCEPT. Crystal structure of the calcineurin complex (CaN A + CaN B) and FKBP12-FK506-calcineurin complex determined. Supporting Evidence: PMID:8524402 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 |
| GO:0010508 positive regulation of autophagy | IDA PMID:25720963 Lysosomal calcium signalling regulates autophagy through cal... | NEW | Summary: PPP3CB performs the regulatory step itself: it dephosphorylates TFEB (PPP3CB-specific siRNA and constitutively active PPP3CB 1-474), driving TFEB nuclear import and a lysosomal/autophagy gene program, and PPP3CB/PPP3R1 silencing lowers autophagic flux. A regulation term is appropriate for the enzyme that does the dephosphorylation (comparator: the TFEB kinase MTOR carries regulation-of-autophagy terms for the opposing phosphorylation). Kept non-core relative to the phosphatase activity; the existing IDA rows for positive regulation of lysosome organization and of protein localization to nucleus describe the same mechanism. Supporting Evidence: PMID:25720963 Furthermore, silencing of both PPP3R1 and PPP3CB in HeLa cells resulted in a reduction of the autophagic flux, measured by the degradation of the autophagic substrate p62 PMID:25720963 Our results identify a calcium signaling pathway that originates from the lysosome and regulates autophagy by activating a TFEB-mediated transcriptional program. PMID:37909662 SMURF1 controlled the phosphatase activity of the PPP3CB by promoting the dissociation of its autoinhibitory domain (AID) from its catalytic domain (CD). |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: Interaction with mouse IRAK1 (Q99J34) from the same high-throughput innate-immunity interaction network (PMID:21903422); PPP3CB is not mentioned in the main text of the cached paper, so the hit comes from the supplementary interactome. Removal of the uninformative protein binding term does not mean the interaction is false; the cited paper reports the interaction without evidence for a specific molecular activity of PPP3CB in it, and no informative MF term follows from it. Supporting Evidence: PMID:21903422 Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. |
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Download this section (compressed HTML)Q: Which calcineurin catalytic isoform (PPP3CA or PPP3CB) carries NFAT dephosphorylation downstream of the TCR in human T cells, and are they redundant there? Most T cell studies use pan-calcineurin inhibitors that do not distinguish the isoforms.
Q: Calcineurin anchoring at damaged lysosomes (LGALS3-SMURF1) and at the plasma membrane (AKAP5) is well described; should a conditional lysosomal membrane localization be annotated for PPP3CB, or does GO prefer to record it only on the anchoring proteins?
Q: Does Ca2+/calmodulin fully displace the autoinhibitory domain from the active site, as the canonical model holds, or only reorient it, as the CnA-beta structure suggests (PMID:26794871)?
Experiment: Isoform-selective deletion or degron knock-in of PPP3CA and PPP3CB in primary human CD4 and CD8 T cells, followed by TCR stimulation and measurement of NFATC1/NFATC2 dephosphorylation, nuclear import and IL2 production, to assign isoform contributions to TCR-driven calcineurin-NFAT signaling.
Experiment: Phosphoproteomics after acute PPP3CB versus PPP3CA depletion in Ca2+-stimulated cells to define isoform-preferred substrates, testing whether the CnA-beta proline-rich N-terminus confers distinct substrate selection in vivo.
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