PPP3CB

Existing Annotations Review

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	ACCEPT	Summary: ACCEPT. Phosphoprotein phosphatases are hydrolases. This is a correct but very general parent term. More specific terms also apply.
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...	MARK AS OVER ANNOTATED	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. 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...	MARK AS OVER ANNOTATED	Summary: MARK_AS_OVER_ANNOTATED. Generic protein binding from high-throughput interactome study. Uninformative per curation guidelines. 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...	MARK AS OVER ANNOTATED	Summary: MARK_AS_OVER_ANNOTATED. Generic protein binding from Chr21 protein-protein interaction study. Uninformative. 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...	MARK AS OVER ANNOTATED	Summary: MARK_AS_OVER_ANNOTATED. Generic protein binding from multimodal cell maps study. Uninformative. 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...	ACCEPT	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). 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...	ACCEPT	Summary: ACCEPT. Calcineurin directly binds NFAT1, dephosphorylates it to enable nuclear translocation and transcriptional activation. This is a core function (PMID:8631904). Supporting Evidence: PMID:8631904 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...	MARK AS OVER ANNOTATED	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. 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...	MODIFY	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. Proposed replacements: protein phosphatase 2B binding
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
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...	MODIFY	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. Proposed replacements: protein phosphatase 2B binding 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 ...	ACCEPT	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. 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 ...	ACCEPT	Summary: ACCEPT. Calcineurin forms a heterodimer of catalytic A subunit and regulatory B subunit. The A-B dimerization is essential for calcineurin function. 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...	ACCEPT	Summary: ACCEPT. PPP3CB self-associates as part of the calcineurin complex, and the original cloning study demonstrated interactions between calcineurin subunits.
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...	ACCEPT	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. 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: 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. Supporting Evidence: PMID:25720963 calcineurin activity was not only necessary but sufficient to induce TFEB nuclear translocation

Gene Description

Existing Annotations Review

Core Functions

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.

References

Deep Research

Falcon

📚 Additional Documentation

Notes

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