{"gene":"JPT2","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2021,"finding":"JPT2 (Jupiter microtubule-associated homolog 2 / HN1L) was identified as a direct NAADP-binding protein and TPC (two-pore channel) accessory protein required for endogenous NAADP-evoked Ca2+ signaling from acidic organelles. A clickable NAADP-based photoprobe was used to isolate JPT2 as an NAADP-binding protein, and JPT2 knockout abolished TPC-dependent Ca2+ release and impaired SARS-CoV-2 pseudovirus translocation through the endolysosomal system.","method":"Clickable NAADP photoaffinity probe, pulldown/isolation of binding proteins, gene knockout (Jurkat/primary cells), Ca2+ imaging, pseudovirus entry assay","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 — photoaffinity labeling demonstrating direct binding, KO with defined functional phenotype, multiple orthogonal methods, replicated across two independent papers in same issue","pmids":["33758061"],"is_preprint":false},{"year":2021,"finding":"HN1L/JPT2 directly binds NAADP (demonstrated by photoaffinity labeling of recombinant protein) and connects NAADP generation to Ca2+ microdomain formation in T cells by coprecipitating with RYR1 (type 1 ryanodine receptors) in a TCR/CD3-dependent manner, enabling NAADP to activate Ca2+ release from the ER through RYR channels. Gene deletion of Hn1l/Jpt2 decreased initial Ca2+ microdomains and delayed/reduced global Ca2+ signaling amplitude.","method":"Photoaffinity labeling of recombinant HN1L/JPT2 with NAADP probe, gene deletion in Jurkat and primary rat T cells, Ca2+ microdomain imaging, co-immunoprecipitation with RYRs, colocalization","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding shown by photoaffinity on recombinant protein, reciprocal Co-IP, KO with specific Ca2+ phenotype, consistent with parallel paper","pmids":["33758062"],"is_preprint":false},{"year":2004,"finding":"HN1 and HN1L (JPT2) were cloned and their subcellular localization characterized: HN1 localizes to the nucleus, while HN1L localizes to both the nucleus and cytoplasm, as determined by GFP fusion expression.","method":"GFP fusion protein expression, subcellular localization imaging, Western blot","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 — single localization experiment without functional consequence linked","pmids":["15094197"],"is_preprint":false},{"year":2019,"finding":"HN1L/JPT2 promotes HCC cell growth and metastasis through a transcriptional axis: HN1L transcriptionally upregulates METTL13 in an AP-2γ-dependent manner, which in turn promotes cell proliferation and metastasis by upregulating TCF3 and ZEB1. HN1L also induces epithelial-mesenchymal transition.","method":"shRNA knockdown, ectopic overexpression, in vitro proliferation/invasion assays, in vivo xenograft, chromatin/transcription analysis","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2-3 — loss-of-function with defined pathway placement, but mechanism of HN1L transcriptional activity not fully resolved at molecular level","pmids":["30778199"],"is_preprint":false},{"year":2017,"finding":"HN1L/JPT2 acts as a transcription regulator in triple-negative breast cancer stem cells, binding to upstream sequences of STAT3, LEPTIN RECEPTOR, and MIR-150 to sustain activation of the LEPR-STAT3 signaling axis. HN1L silencing reduced BCSC population and inhibited tumor initiation.","method":"shRNA silencing, xenograft mouse models, gene expression analysis, ChIP/binding assays for upstream consensus sequences","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — KO with defined cellular phenotype and pathway placement, binding to regulatory sequences shown","pmids":["29249663"],"is_preprint":false},{"year":2020,"finding":"HN1L/JPT2 promotes breast cancer cell invasion and metastasis by interacting with HSPA9 and affecting the expression of HMGB1, as determined by mass spectrometry and functional assays.","method":"Mass spectrometry, co-immunoprecipitation, wound healing/transwell invasion assays, shRNA knockdown, nude mice metastasis model","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 — interaction identified by MS and Co-IP with functional consequence in migration/invasion, single lab","pmids":["33191617"],"is_preprint":false},{"year":2017,"finding":"HN1L/JPT2 knockdown causes cell cycle arrest in NSCLC by interfering with the MAPK pathway via interaction with RASA4 protein.","method":"shRNA knockdown, co-immunoprecipitation/interaction with RASA4, cell cycle analysis, xenograft tumorigenicity","journal":"Cancer biology & therapy","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP/interaction with RASA4, single lab, limited mechanistic follow-up","pmids":["29053395"],"is_preprint":false}],"current_model":"JPT2 (HN1L) is an NAADP-binding protein that forms part of the NAADP receptor complex, directly binding NAADP and associating with two-pore channels (TPCs) and ryanodine receptors (RYR1) to transduce NAADP signals into Ca2+ release from acidic organelles (via TPCs) and the ER (via RYR1), thereby governing Ca2+ microdomain formation during T cell activation and controlling endolysosomal trafficking events including coronaviral entry; additionally, JPT2 has been implicated as a transcriptional regulator in cancer contexts through interactions with HSPA9/HMGB1 and the LEPR-STAT3 axis."},"narrative":{"teleology":[{"year":2004,"claim":"Initial cloning of HN1L/JPT2 established that, unlike its paralog HN1 which is nuclear, JPT2 distributes to both nucleus and cytoplasm, raising the question of whether it has dual functional compartments.","evidence":"GFP-fusion protein expression and subcellular imaging in cultured cells","pmids":["15094197"],"confidence":"Low","gaps":["Single overexpression-based localization without endogenous antibody validation","No functional consequence of localization was demonstrated","Endogenous protein distribution not confirmed"]},{"year":2017,"claim":"Two studies linked JPT2 to oncogenic signaling: one showed JPT2 sustains LEPR–STAT3 signaling in breast cancer stem cells by binding upstream regulatory sequences of STAT3, LEPR, and MIR-150, while another implicated JPT2 in MAPK pathway regulation via interaction with RASA4 in NSCLC, establishing JPT2 as a candidate transcriptional and signaling regulator in cancer.","evidence":"shRNA knockdown, xenograft models, ChIP/binding assays (breast cancer); Co-IP with RASA4, cell cycle analysis, xenograft (NSCLC)","pmids":["29249663","29053395"],"confidence":"Medium","gaps":["The RASA4 interaction rests on a single Co-IP without reciprocal validation","How a small protein without canonical DNA-binding domains engages upstream regulatory sequences is unresolved","Whether these cancer phenotypes relate to JPT2's Ca²⁺ signaling role is unknown"]},{"year":2019,"claim":"Mechanistic dissection in hepatocellular carcinoma revealed that JPT2 transcriptionally upregulates METTL13 through AP-2γ, which in turn drives proliferation and EMT via TCF3/ZEB1, placing JPT2 at the top of a defined transcriptional cascade promoting metastasis.","evidence":"shRNA knockdown, overexpression, in vivo xenograft, chromatin/transcription analysis in HCC cell lines","pmids":["30778199"],"confidence":"Medium","gaps":["The molecular mechanism by which JPT2 activates AP-2γ-dependent transcription is not defined","Whether JPT2's transcriptional role requires its NAADP-binding capacity is untested"]},{"year":2020,"claim":"Identification of HSPA9 as a JPT2-interacting partner and HMGB1 as a downstream effector provided an additional molecular axis through which JPT2 promotes breast cancer invasion and metastasis.","evidence":"Mass spectrometry, co-immunoprecipitation, functional invasion/metastasis assays with shRNA knockdown","pmids":["33191617"],"confidence":"Medium","gaps":["The HSPA9 interaction was identified by a single MS/Co-IP study from one laboratory","How HSPA9 binding leads to HMGB1 expression change is mechanistically undefined","Relationship to NAADP/Ca²⁺ signaling axis is unexplored"]},{"year":2021,"claim":"Two concurrent landmark studies resolved a decades-old question in Ca²⁺ signaling by identifying JPT2 as the direct NAADP-binding protein that transduces NAADP signals into Ca²⁺ release — JPT2 associates with TPCs to mediate Ca²⁺ release from acidic organelles and with RYR1 to trigger ER Ca²⁺ release, governing Ca²⁺ microdomains essential for T cell activation and endolysosomal trafficking including coronaviral entry.","evidence":"Clickable NAADP photoaffinity probe on recombinant protein, gene knockout in Jurkat and primary T cells, Ca²⁺ microdomain imaging, co-immunoprecipitation with RYR1 and TPCs, SARS-CoV-2 pseudovirus entry assays","pmids":["33758061","33758062"],"confidence":"High","gaps":["Structural basis of NAADP binding by JPT2 is unknown — no crystal or cryo-EM structure exists","How JPT2 switches between TPC and RYR1 association is not defined","Whether JPT2's nuclear/transcriptional roles are mechanistically independent of NAADP binding remains unresolved"]},{"year":null,"claim":"The relationship between JPT2's well-established NAADP/Ca²⁺ signaling function and its reported transcriptional activities in cancer remains entirely unresolved — whether these represent genuinely distinct functions or are linked through Ca²⁺-dependent mechanisms is unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of JPT2 or its NAADP-binding domain exists","Whether cancer-associated transcriptional phenotypes require NAADP binding or Ca²⁺ signaling has not been tested","The stoichiometry and dynamics of JPT2 within TPC and RYR complexes are uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4]}],"complexes":["NAADP receptor complex (with TPCs)","NAADP-RYR1 complex"],"partners":["TPC1","TPC2","RYR1","HSPA9","RASA4"],"other_free_text":[]},"mechanistic_narrative":"JPT2 (also known as HN1L) is a direct NAADP-binding protein that functions as an essential accessory subunit of the NAADP receptor complex, coupling the second messenger NAADP to Ca²⁺ release from intracellular stores. JPT2 associates with two-pore channels (TPCs) on acidic organelles and with type 1 ryanodine receptors (RYR1) on the ER, and its genetic deletion abolishes NAADP-evoked Ca²⁺ signaling, impairs Ca²⁺ microdomain formation during T cell receptor activation, and blocks SARS-CoV-2 pseudovirus translocation through the endolysosomal system [PMID:33758061, PMID:33758062]. In cancer contexts, JPT2 has been reported to function as a transcriptional regulator that sustains LEPR–STAT3 signaling in breast cancer stem cells and promotes epithelial–mesenchymal transition and metastasis through AP-2γ-dependent upregulation of METTL13 in hepatocellular carcinoma [PMID:29249663, PMID:30778199]. JPT2 localizes to both the nucleus and cytoplasm, consistent with roles in both Ca²⁺ signal transduction and transcriptional regulation [PMID:15094197]."},"prefetch_data":{"uniprot":{"accession":"Q9H910","full_name":"Jupiter microtubule associated homolog 2","aliases":["Hematological and neurological expressed 1-like protein","HN1-like protein"],"length_aa":190,"mass_kda":20.1,"function":"Nicotinic acid adenine dinucleotide phosphate (NAADP) binding protein required for NAADP-evoked intracellular calcium release (PubMed:33758061, PubMed:33758062). Confers NAADP-sensitivity to the two pore channels (TPCs) complex (PubMed:33758061). Enables NAADP to activate Ca(2+) release from the endoplasmic reticulum through ryanodine receptors (PubMed:33758062) (Microbial infection) Involved in the endolysosomal trafficking of human coronavirus SARS-CoV-2","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9H910/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JPT2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/JPT2","total_profiled":1310},"omim":[{"mim_id":"619241","title":"JUPITER MICROTUBULE-ASSOCIATED HOMOLOG 2; JPT2","url":"https://www.omim.org/entry/619241"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":116.7}],"url":"https://www.proteinatlas.org/search/JPT2"},"hgnc":{"alias_symbol":["FLJ13092","L11","KIAA1426"],"prev_symbol":["C16orf34","HN1L"]},"alphafold":{"accession":"Q9H910","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H910","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H910-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H910-F1-predicted_aligned_error_v6.png","plddt_mean":60.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=JPT2","jax_strain_url":"https://www.jax.org/strain/search?query=JPT2"},"sequence":{"accession":"Q9H910","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H910.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H910/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H910"}},"corpus_meta":[{"pmid":"12842086","id":"PMC_12842086","title":"Regulation of HDM2 activity by the ribosomal protein 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A clickable NAADP-based photoprobe was used to isolate JPT2 as an NAADP-binding protein, and JPT2 knockout abolished TPC-dependent Ca2+ release and impaired SARS-CoV-2 pseudovirus translocation through the endolysosomal system.\",\n      \"method\": \"Clickable NAADP photoaffinity probe, pulldown/isolation of binding proteins, gene knockout (Jurkat/primary cells), Ca2+ imaging, pseudovirus entry assay\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — photoaffinity labeling demonstrating direct binding, KO with defined functional phenotype, multiple orthogonal methods, replicated across two independent papers in same issue\",\n      \"pmids\": [\"33758061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HN1L/JPT2 directly binds NAADP (demonstrated by photoaffinity labeling of recombinant protein) and connects NAADP generation to Ca2+ microdomain formation in T cells by coprecipitating with RYR1 (type 1 ryanodine receptors) in a TCR/CD3-dependent manner, enabling NAADP to activate Ca2+ release from the ER through RYR channels. Gene deletion of Hn1l/Jpt2 decreased initial Ca2+ microdomains and delayed/reduced global Ca2+ signaling amplitude.\",\n      \"method\": \"Photoaffinity labeling of recombinant HN1L/JPT2 with NAADP probe, gene deletion in Jurkat and primary rat T cells, Ca2+ microdomain imaging, co-immunoprecipitation with RYRs, colocalization\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding shown by photoaffinity on recombinant protein, reciprocal Co-IP, KO with specific Ca2+ phenotype, consistent with parallel paper\",\n      \"pmids\": [\"33758062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HN1 and HN1L (JPT2) were cloned and their subcellular localization characterized: HN1 localizes to the nucleus, while HN1L localizes to both the nucleus and cytoplasm, as determined by GFP fusion expression.\",\n      \"method\": \"GFP fusion protein expression, subcellular localization imaging, Western blot\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single localization experiment without functional consequence linked\",\n      \"pmids\": [\"15094197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HN1L/JPT2 promotes HCC cell growth and metastasis through a transcriptional axis: HN1L transcriptionally upregulates METTL13 in an AP-2γ-dependent manner, which in turn promotes cell proliferation and metastasis by upregulating TCF3 and ZEB1. HN1L also induces epithelial-mesenchymal transition.\",\n      \"method\": \"shRNA knockdown, ectopic overexpression, in vitro proliferation/invasion assays, in vivo xenograft, chromatin/transcription analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — loss-of-function with defined pathway placement, but mechanism of HN1L transcriptional activity not fully resolved at molecular level\",\n      \"pmids\": [\"30778199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HN1L/JPT2 acts as a transcription regulator in triple-negative breast cancer stem cells, binding to upstream sequences of STAT3, LEPTIN RECEPTOR, and MIR-150 to sustain activation of the LEPR-STAT3 signaling axis. HN1L silencing reduced BCSC population and inhibited tumor initiation.\",\n      \"method\": \"shRNA silencing, xenograft mouse models, gene expression analysis, ChIP/binding assays for upstream consensus sequences\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KO with defined cellular phenotype and pathway placement, binding to regulatory sequences shown\",\n      \"pmids\": [\"29249663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HN1L/JPT2 promotes breast cancer cell invasion and metastasis by interacting with HSPA9 and affecting the expression of HMGB1, as determined by mass spectrometry and functional assays.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, wound healing/transwell invasion assays, shRNA knockdown, nude mice metastasis model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — interaction identified by MS and Co-IP with functional consequence in migration/invasion, single lab\",\n      \"pmids\": [\"33191617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HN1L/JPT2 knockdown causes cell cycle arrest in NSCLC by interfering with the MAPK pathway via interaction with RASA4 protein.\",\n      \"method\": \"shRNA knockdown, co-immunoprecipitation/interaction with RASA4, cell cycle analysis, xenograft tumorigenicity\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/interaction with RASA4, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"29053395\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JPT2 (HN1L) is an NAADP-binding protein that forms part of the NAADP receptor complex, directly binding NAADP and associating with two-pore channels (TPCs) and ryanodine receptors (RYR1) to transduce NAADP signals into Ca2+ release from acidic organelles (via TPCs) and the ER (via RYR1), thereby governing Ca2+ microdomain formation during T cell activation and controlling endolysosomal trafficking events including coronaviral entry; additionally, JPT2 has been implicated as a transcriptional regulator in cancer contexts through interactions with HSPA9/HMGB1 and the LEPR-STAT3 axis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"JPT2 (also known as HN1L) is a direct NAADP-binding protein that functions as an essential accessory subunit of the NAADP receptor complex, coupling the second messenger NAADP to Ca²⁺ release from intracellular stores. JPT2 associates with two-pore channels (TPCs) on acidic organelles and with type 1 ryanodine receptors (RYR1) on the ER, and its genetic deletion abolishes NAADP-evoked Ca²⁺ signaling, impairs Ca²⁺ microdomain formation during T cell receptor activation, and blocks SARS-CoV-2 pseudovirus translocation through the endolysosomal system [PMID:33758061, PMID:33758062]. In cancer contexts, JPT2 has been reported to function as a transcriptional regulator that sustains LEPR–STAT3 signaling in breast cancer stem cells and promotes epithelial–mesenchymal transition and metastasis through AP-2γ-dependent upregulation of METTL13 in hepatocellular carcinoma [PMID:29249663, PMID:30778199]. JPT2 localizes to both the nucleus and cytoplasm, consistent with roles in both Ca²⁺ signal transduction and transcriptional regulation [PMID:15094197].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Initial cloning of HN1L/JPT2 established that, unlike its paralog HN1 which is nuclear, JPT2 distributes to both nucleus and cytoplasm, raising the question of whether it has dual functional compartments.\",\n      \"evidence\": \"GFP-fusion protein expression and subcellular imaging in cultured cells\",\n      \"pmids\": [\"15094197\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single overexpression-based localization without endogenous antibody validation\",\n        \"No functional consequence of localization was demonstrated\",\n        \"Endogenous protein distribution not confirmed\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two studies linked JPT2 to oncogenic signaling: one showed JPT2 sustains LEPR–STAT3 signaling in breast cancer stem cells by binding upstream regulatory sequences of STAT3, LEPR, and MIR-150, while another implicated JPT2 in MAPK pathway regulation via interaction with RASA4 in NSCLC, establishing JPT2 as a candidate transcriptional and signaling regulator in cancer.\",\n      \"evidence\": \"shRNA knockdown, xenograft models, ChIP/binding assays (breast cancer); Co-IP with RASA4, cell cycle analysis, xenograft (NSCLC)\",\n      \"pmids\": [\"29249663\", \"29053395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The RASA4 interaction rests on a single Co-IP without reciprocal validation\",\n        \"How a small protein without canonical DNA-binding domains engages upstream regulatory sequences is unresolved\",\n        \"Whether these cancer phenotypes relate to JPT2's Ca²⁺ signaling role is unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mechanistic dissection in hepatocellular carcinoma revealed that JPT2 transcriptionally upregulates METTL13 through AP-2γ, which in turn drives proliferation and EMT via TCF3/ZEB1, placing JPT2 at the top of a defined transcriptional cascade promoting metastasis.\",\n      \"evidence\": \"shRNA knockdown, overexpression, in vivo xenograft, chromatin/transcription analysis in HCC cell lines\",\n      \"pmids\": [\"30778199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The molecular mechanism by which JPT2 activates AP-2γ-dependent transcription is not defined\",\n        \"Whether JPT2's transcriptional role requires its NAADP-binding capacity is untested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of HSPA9 as a JPT2-interacting partner and HMGB1 as a downstream effector provided an additional molecular axis through which JPT2 promotes breast cancer invasion and metastasis.\",\n      \"evidence\": \"Mass spectrometry, co-immunoprecipitation, functional invasion/metastasis assays with shRNA knockdown\",\n      \"pmids\": [\"33191617\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The HSPA9 interaction was identified by a single MS/Co-IP study from one laboratory\",\n        \"How HSPA9 binding leads to HMGB1 expression change is mechanistically undefined\",\n        \"Relationship to NAADP/Ca²⁺ signaling axis is unexplored\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Two concurrent landmark studies resolved a decades-old question in Ca²⁺ signaling by identifying JPT2 as the direct NAADP-binding protein that transduces NAADP signals into Ca²⁺ release — JPT2 associates with TPCs to mediate Ca²⁺ release from acidic organelles and with RYR1 to trigger ER Ca²⁺ release, governing Ca²⁺ microdomains essential for T cell activation and endolysosomal trafficking including coronaviral entry.\",\n      \"evidence\": \"Clickable NAADP photoaffinity probe on recombinant protein, gene knockout in Jurkat and primary T cells, Ca²⁺ microdomain imaging, co-immunoprecipitation with RYR1 and TPCs, SARS-CoV-2 pseudovirus entry assays\",\n      \"pmids\": [\"33758061\", \"33758062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of NAADP binding by JPT2 is unknown — no crystal or cryo-EM structure exists\",\n        \"How JPT2 switches between TPC and RYR1 association is not defined\",\n        \"Whether JPT2's nuclear/transcriptional roles are mechanistically independent of NAADP binding remains unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The relationship between JPT2's well-established NAADP/Ca²⁺ signaling function and its reported transcriptional activities in cancer remains entirely unresolved — whether these represent genuinely distinct functions or are linked through Ca²⁺-dependent mechanisms is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of JPT2 or its NAADP-binding domain exists\",\n        \"Whether cancer-associated transcriptional phenotypes require NAADP binding or Ca²⁺ signaling has not been tested\",\n        \"The stoichiometry and dynamics of JPT2 within TPC and RYR complexes are uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\n      \"NAADP receptor complex (with TPCs)\",\n      \"NAADP-RYR1 complex\"\n    ],\n    \"partners\": [\n      \"TPC1\",\n      \"TPC2\",\n      \"RYR1\",\n      \"HSPA9\",\n      \"RASA4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}