{"gene":"JPT2","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2021,"finding":"JPT2 directly binds NAADP (demonstrated by photoaffinity labeling with a 'clickable' NAADP-based photoprobe) and functions as a TPC accessory protein required for endogenous NAADP-evoked Ca2+ release from acidic organelles through two-pore channels (TPCs). JPT2 was also required for translocation of SARS-CoV-2 pseudovirus through the endolysosomal system.","method":"Clickable NAADP-based photoprobe (photoaffinity labeling), pulldown/isolation of binding proteins, Ca2+ signaling assays, pseudovirus trafficking assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct photoaffinity labeling established NAADP binding, functional Ca2+ assays confirmed TPC dependence, replicated in companion paper same issue","pmids":["33758061"],"is_preprint":false},{"year":2021,"finding":"HN1L/JPT2 directly binds NAADP (demonstrated by photoaffinity labeling of recombinant protein) and co-precipitates with ryanodine receptors (RYR1) in a TCR/CD3-dependent manner. Gene deletion of Hn1l/Jpt2 in Jurkat and primary rat T cells decreased Ca2+ microdomain formation and delayed/reduced global Ca2+ signaling, placing JPT2 as a link between NAADP generation and RYR1-mediated Ca2+ release from the ER during T cell activation.","method":"Photoaffinity labeling of recombinant protein, gene knockout/deletion (CRISPR), co-immunoprecipitation, Ca2+ microdomain imaging","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding demonstrated by photoaffinity labeling on recombinant protein, reciprocal co-IP with RYR1, KO functional phenotype, replicated in companion paper","pmids":["33758062"],"is_preprint":false},{"year":2023,"finding":"Recombinant JPT2 binds NAADP with high affinity, and endogenous JPT2 independently associates with both TPC1 and TPC2. Knockout and rescue analyses showed that JPT2 is required for NAADP-evoked Ca2+ signaling and contributes to endolysosomal trafficking of pseudotyped coronavirus particles. JPT2 and LSM12 act convergently through TPCs.","method":"Biochemical binding assays (recombinant protein), co-immunoprecipitation (endogenous TPC1/TPC2), knockout cell lines with rescue, Ca2+ signaling assays, pseudovirus trafficking","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (biochemical binding, Co-IP, KO/rescue, functional Ca2+ assays) in single rigorous study","pmids":["37607218"],"is_preprint":false},{"year":2004,"finding":"HN1L (JPT2) encodes a ~20 kDa protein that localizes to both the nucleus and cytoplasm, as determined by GFP fusion expression and Western blot.","method":"GFP fusion protein expression, Western blot, subcellular localization imaging","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — GFP fusion localization confirmed by Western blot, but no functional consequence linked to localization","pmids":["15094197"],"is_preprint":false},{"year":2017,"finding":"HN1L/JPT2 binds to a putative consensus upstream sequence of STAT3, LEPR, and MIR-150, functioning as a transcription regulator that sustains LEPR-STAT3 pathway activation in triple-negative breast cancer stem cells.","method":"ChIP/transcription binding assay, shRNA knockdown with BCSC functional readouts (sphere formation, tumor initiation)","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — transcription factor binding assay reported, functional KD phenotype established, but single lab and limited mechanistic resolution in abstract","pmids":["29249663"],"is_preprint":false},{"year":2017,"finding":"HN1L/JPT2 promotes cell proliferation in NSCLC by interacting with RASA4 protein, thereby interfering with the MAPK pathway; knockdown causes G1/S cell cycle arrest.","method":"shRNA knockdown, co-immunoprecipitation (interaction with RASA4), cell cycle analysis, in vivo tumor growth","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying RASA4 interaction, functional KD phenotype, single lab","pmids":["29053395"],"is_preprint":false},{"year":2019,"finding":"HN1L/JPT2 transcriptionally upregulates METTL13 in an AP-2γ-dependent manner in hepatocellular carcinoma, which then promotes cell proliferation and metastasis by upregulating TCF3 and ZEB1.","method":"shRNA knockdown, overexpression, transcriptional reporter/ChIP (AP-2γ dependent), in vitro and in vivo functional assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — transcriptional regulation mechanism shown via multiple functional assays, but primarily single-lab work with indirect mechanistic evidence in abstract","pmids":["30778199"],"is_preprint":false},{"year":2020,"finding":"HN1L/JPT2 interacts with HSPA9 and affects HMGB1 expression to promote invasion and metastasis of breast cancer cells.","method":"Co-immunoprecipitation, mass spectrometry (interaction with HSPA9), shRNA knockdown, in vitro invasion assays, in vivo metastasis model","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/MS interaction with HSPA9, downstream HMGB1 effect not mechanistically dissected, single lab","pmids":["33191617"],"is_preprint":false},{"year":2022,"finding":"HN1L/JPT2 activates transcription of PLK1 by interacting with transcription factor AP-2γ, leading to increased Cyclin D1 and Slug expression and promoting ESCC metastasis and chemotherapy resistance.","method":"Co-immunoprecipitation (AP-2γ interaction), loss/gain-of-function in ESCC cells, in vivo tumor models, PLK1 inhibitor rescue experiment","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with AP-2γ, functional KD/OE with mechanistic rescue by PLK1 inhibitor, single lab","pmids":["36476988"],"is_preprint":false},{"year":2021,"finding":"HN1L/JPT2 binds to FOXP2 and positively regulates TGF-β expression via upregulation of FOXP2, promoting cancer stem cell properties in prostate cancer.","method":"Co-immunoprecipitation (FOXP2 interaction), shRNA knockdown, TGF-β overexpression rescue experiments","journal":"Cell biology international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for FOXP2 binding, downstream pathway inferred from rescue, single lab","pmids":["34519127"],"is_preprint":false},{"year":2024,"finding":"JPT2 deficiency in trophoblast cells inhibits adhesion, migration, and invasion through inhibition of the JNK/ACKR3 axis (rather than through Ca2+ mobilization), and promotes M1 macrophage polarization by accumulation of citrate and ROS via inhibition of the JNK/IL-6 axis.","method":"Loss-of-function (JPT2 knockdown/knockout), transcriptomics, JNK pathway analysis, macrophage polarization assays, AAV9-JPT2 rescue in abortion-prone mice","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (transcriptomics, functional assays, in vivo rescue), single lab but comprehensive mechanistic dissection","pmids":["38417123"],"is_preprint":false},{"year":2024,"finding":"Oxalate exposure upregulates JPT2, which mediates crystal-cell adhesion and macrophage inflammatory polarization via PI3K/AKT signaling and inhibits production of succinic acid semialdehyde in macrophages; JPT2 deficiency in mice inhibited kidney stone mineralization.","method":"Genetic knockdown/knockout of JPT2 in cells and mice, transcriptomics, untargeted metabolomics, in vivo kidney stone model","journal":"Journal of pharmaceutical analysis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomic and metabolomic analyses plus in vivo genetic model, single lab","pmids":["39035219"],"is_preprint":false},{"year":2026,"finding":"In Jpt2/Hn1l knockout mice, JPT2/HN1L is required for NAADP-mediated Ca2+ release specifically in CD4+ T cells (TCR/CD3-stimulated global Ca2+ elevations and early Ca2+ microdomains significantly decreased), but is dispensable for NAADP-mediated Ca2+ signaling in cardiomyocytes, mast cells, and platelets, demonstrating cell-type specificity.","method":"Germline Jpt2/Hn1l knockout mice, Ca2+ imaging (global and microdomain), platelet aggregation assays, cell-type-specific functional analysis","journal":"Cell calcium","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic knockout mouse model with multiple cell types tested, functional Ca2+ imaging with multiple orthogonal readouts","pmids":["42224927"],"is_preprint":false},{"year":2025,"finding":"JPT2 localizes within the lumen of singlet microtubules in a C-terminal-dependent manner, modulates the distribution of α-tubulin acetyltransferase MEC17 (inhibiting its luminal accessibility/activity), and its luminal localization is markedly reduced by Paclitaxel treatment.","method":"Proximity-labeling (BioID) to distinguish intraluminal vs external proteins, mass spectrometry, mutagenesis (C-terminal deletion), microtubule-binding assays, Paclitaxel treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — proximity labeling plus mutagenesis, but single lab, novel finding not yet replicated","pmids":["41468432"],"is_preprint":false},{"year":2026,"finding":"JPT2 is an intrinsically disordered protein (confirmed by circular dichroism and NMR spectroscopy) that undergoes liquid-liquid phase separation under low Na+ or molecular crowding conditions. JPT2 condensates recruit LSM12, a fluorescent NAADP analog, tubulin, and interact with polymerized microtubules and lysosomes from human cell lines.","method":"Circular dichroism, NMR spectroscopy, multiple orthogonal phase separation assays, condensate recruitment assays with purified components","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous biophysical methods (NMR, CD) confirming disorder and phase separation, but preprint not yet peer-reviewed","pmids":["41542395"],"is_preprint":true},{"year":2024,"finding":"JPT2 functions as a transcription co-factor that activates transcription of LEPR in an AP-2γ-dependent manner and activates STAT3 signaling in trophoblast cells; silencing LEPR abolished the pro-proliferative/migratory effects of JPT2 overexpression.","method":"Gain- and loss-of-function experiments in HTR-8/SVneo trophoblast cells, transcriptomics, LEPR silencing rescue experiment","journal":"Journal of endocrinological investigation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional assays with rescue, but mechanistic details of AP-2γ interaction not directly demonstrated in abstract, single lab","pmids":["38907823"],"is_preprint":false},{"year":2025,"finding":"STMN1 physically binds HN1L/JPT2 in gastric cancer cells (demonstrated by co-immunoprecipitation), and HN1L overexpression reverses the effects of STMN1 knockdown on stemness and STAT3/PD-L1 signaling.","method":"Co-immunoprecipitation, overexpression rescue experiments, in vivo xenograft model","journal":"Discover oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for STMN1-HN1L interaction, functional rescue, single lab","pmids":["40035993"],"is_preprint":false}],"current_model":"JPT2 (HN1L) is an intrinsically disordered, NAADP-binding protein that serves as an essential accessory subunit of the NAADP receptor complex, directly binding NAADP with high affinity and independently associating with two-pore channels (TPC1/2) on endolysosomes and with ryanodine receptor 1 (RYR1) on the ER to mediate NAADP-evoked Ca2+ release in a cell-type-specific manner (required in T cells, dispensable in cardiomyocytes, platelets, and mast cells); it can also undergo liquid-liquid phase separation to compartmentalize NAADP signaling components, and separately localizes within the microtubule lumen via its C-terminus where it regulates the acetyltransferase MEC17 and modulates Paclitaxel sensitivity."},"narrative":{"mechanistic_narrative":"JPT2 (HN1L) is an intrinsically disordered, NAADP-binding protein that serves as an essential accessory component of NAADP-evoked Ca2+ signaling, coupling the second messenger NAADP to Ca2+-release channels [PMID:33758061, PMID:33758062]. It directly binds NAADP, demonstrated by photoaffinity labeling of recombinant protein, and is required for NAADP-evoked Ca2+ release from acidic organelles through two-pore channels, with which it physically associates (TPC1 and TPC2) [PMID:33758061, PMID:37607218]. In T cells, JPT2 co-precipitates with ryanodine receptor 1 in a TCR/CD3-dependent manner and links NAADP to RYR1-mediated ER Ca2+ release, shaping Ca2+ microdomains during T cell activation [PMID:33758062]. This NAADP-channel coupling is cell-type-specific: germline knockout mice require JPT2 for NAADP-mediated Ca2+ signaling in CD4+ T cells but not in cardiomyocytes, mast cells, or platelets [PMID:42224927]. JPT2 acts convergently with LSM12 through TPCs and contributes to endolysosomal trafficking, including translocation of pseudotyped coronavirus particles [PMID:33758061, PMID:37607218]. As an intrinsically disordered protein, JPT2 can undergo liquid-liquid phase separation, forming condensates that recruit LSM12, an NAADP analog, tubulin, microtubules, and lysosomes [PMID:41542395]. Independently of Ca2+ signaling, JPT2 localizes within the lumen of singlet microtubules via its C-terminus, where it restricts the luminal accessibility of the alpha-tubulin acetyltransferase MEC17 and its luminal localization is reduced by Paclitaxel [PMID:41468432]. A separate body of work positions JPT2 as a pro-tumorigenic transcriptional/co-factor and interaction hub across multiple cancers, where it activates transcriptional programs (e.g. PLK1 via AP-2gamma, METTL13, LEPR-STAT3) and interacts with partners including RASA4 to drive proliferation, metastasis, and stemness [PMID:29053395, PMID:30778199, PMID:36476988].","teleology":[{"year":2004,"claim":"Before any function was assigned, the basic gene product and its compartments were established, showing HN1L/JPT2 is a small protein distributed between nucleus and cytoplasm.","evidence":"GFP fusion expression and Western blot subcellular localization","pmids":["15094197"],"confidence":"Medium","gaps":["No molecular function linked to either localization","No interaction partners identified"]},{"year":2017,"claim":"First mechanistic roles placed HN1L/JPT2 in cancer signaling, as both a transcription regulator sustaining LEPR-STAT3 in breast cancer stem cells and a RASA4-interacting modulator of MAPK driving proliferation in NSCLC.","evidence":"ChIP/transcription binding and shRNA knockdown (BCSC); Co-IP with RASA4 and cell-cycle analysis (NSCLC)","pmids":["29249663","29053395"],"confidence":"Medium","gaps":["Direct DNA-binding versus co-factor role not resolved","RASA4 interaction from single Co-IP without reciprocal validation"]},{"year":2019,"claim":"Extended the transcriptional model by showing JPT2 upregulates METTL13 in an AP-2gamma-dependent manner to promote hepatocellular carcinoma proliferation and metastasis.","evidence":"shRNA/overexpression, transcriptional reporter/ChIP, in vitro and in vivo assays","pmids":["30778199"],"confidence":"Medium","gaps":["Whether JPT2 binds DNA directly or only via AP-2gamma unclear","Single-lab evidence"]},{"year":2020,"claim":"Identified additional protein partners (HSPA9) and a downstream HMGB1 effect in breast cancer invasion, broadening the JPT2 interactome.","evidence":"Co-IP/mass spectrometry, shRNA knockdown, invasion and metastasis models","pmids":["33191617"],"confidence":"Low","gaps":["Single Co-IP/MS interaction not reciprocally validated","Mechanistic link to HMGB1 not dissected"]},{"year":2021,"claim":"Resolved the core molecular activity: JPT2 directly binds NAADP and acts as a TPC accessory protein required for NAADP-evoked Ca2+ release, establishing it as the long-sought NAADP-binding component upstream of two-pore channels.","evidence":"Clickable NAADP photoaffinity probe, pulldown, Ca2+ assays, pseudovirus trafficking; replicated in companion paper","pmids":["33758061","33758062"],"confidence":"High","gaps":["Structural basis of NAADP binding not defined","How JPT2 transmits binding to channel gating unknown"]},{"year":2021,"claim":"Defined the channel target in T cells, showing JPT2 couples NAADP to RYR1-mediated ER Ca2+ release in a TCR/CD3-dependent fashion and shapes Ca2+ microdomains during T cell activation.","evidence":"Photoaffinity labeling of recombinant protein, CRISPR knockout, reciprocal Co-IP with RYR1, Ca2+ microdomain imaging","pmids":["33758062"],"confidence":"High","gaps":["Whether RYR1 and TPC coupling are mutually exclusive unclear","Stoichiometry of the receptor complex undefined"]},{"year":2021,"claim":"Added further cancer transcriptional partners, showing JPT2 binds FOXP2 to upregulate TGF-beta and promote prostate cancer stem cell properties.","evidence":"Co-IP with FOXP2, shRNA knockdown, TGF-beta rescue","pmids":["34519127"],"confidence":"Low","gaps":["Single Co-IP for FOXP2 binding","Downstream pathway inferred from rescue only"]},{"year":2022,"claim":"Provided a mechanistically rescue-validated transcriptional model in ESCC, where JPT2-AP-2gamma activates PLK1 to drive Cyclin D1/Slug, metastasis, and chemoresistance.","evidence":"Co-IP with AP-2gamma, loss/gain-of-function, in vivo models, PLK1 inhibitor rescue","pmids":["36476988"],"confidence":"Medium","gaps":["Direct promoter occupancy by JPT2 not shown","Single-lab work"]},{"year":2023,"claim":"Strengthened the NAADP receptor model by showing high-affinity NAADP binding, independent endogenous association with both TPC1 and TPC2, and convergence with LSM12 through TPCs.","evidence":"Recombinant binding assays, endogenous Co-IP, knockout/rescue, Ca2+ assays, pseudovirus trafficking","pmids":["37607218"],"confidence":"High","gaps":["Architecture of the JPT2-LSM12-TPC complex unresolved","How two accessory proteins converge on the same channel unclear"]},{"year":2024,"claim":"Revealed Ca2+-independent functions in reproductive and renal/inflammatory contexts, with JPT2 acting through JNK/ACKR3 and JNK/IL-6 axes in trophoblasts and macrophages and through PI3K/AKT in oxalate-induced kidney stone formation.","evidence":"Knockdown/knockout, transcriptomics, metabolomics, macrophage polarization assays, in vivo rescue (AAV9) and stone models","pmids":["38417123","39035219","38907823"],"confidence":"Medium","gaps":["Direct molecular target linking JPT2 to JNK/PI3K signaling not identified","Relationship to NAADP/transcriptional roles unclear"]},{"year":2025,"claim":"Uncovered a distinct cytoskeletal role: JPT2 localizes within the microtubule lumen via its C-terminus, restricting MEC17 luminal access and being displaced by Paclitaxel, linking it to microtubule acetylation and taxane sensitivity.","evidence":"BioID proximity labeling, mass spectrometry, C-terminal deletion mutagenesis, microtubule-binding and Paclitaxel assays","pmids":["41468432"],"confidence":"Medium","gaps":["Functional consequence of altered acetylation on cell physiology unclear","Not independently replicated"]},{"year":2025,"claim":"Added a gastric cancer interaction, showing STMN1 physically binds HN1L/JPT2 and JPT2 overexpression rescues STMN1-loss effects on stemness and STAT3/PD-L1 signaling.","evidence":"Co-IP, overexpression rescue, xenograft model","pmids":["40035993"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation","Mechanism of STAT3/PD-L1 regulation not dissected"]},{"year":2026,"claim":"Established cell-type specificity of the NAADP function in vivo, showing JPT2 is required for NAADP-mediated Ca2+ signaling in CD4+ T cells but dispensable in cardiomyocytes, mast cells, and platelets.","evidence":"Germline Jpt2/Hn1l knockout mice, global and microdomain Ca2+ imaging, platelet aggregation assays","pmids":["42224927"],"confidence":"High","gaps":["What substitutes for JPT2 in non-T cells is unknown","Molecular basis of cell-type selectivity undefined"]},{"year":2026,"claim":"Defined the biophysical basis for compartmentalization, showing JPT2 is intrinsically disordered and undergoes liquid-liquid phase separation forming condensates that recruit NAADP-signaling and cytoskeletal components.","evidence":"Circular dichroism, NMR, phase separation and condensate recruitment assays (preprint)","pmids":["41542395"],"confidence":"Medium","gaps":["Physiological role of condensates in Ca2+ signaling not demonstrated in cells","Preprint, not peer-reviewed"]},{"year":null,"claim":"It remains unresolved how JPT2's NAADP/Ca2+-coupling role, its nuclear transcriptional/co-factor activities in cancer, and its microtubule-lumen function mechanistically relate within a single protein.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of JPT2 bound to NAADP or to TPC/RYR1","No unifying model linking disordered phase separation to its multiple compartment-specific functions","Direct DNA binding versus co-factor role in transcription unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,8]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[13]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[13]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,8]}],"complexes":[],"partners":["TPC1","TPC2","RYR1","LSM12","RASA4","HSPA9","STMN1"],"other_free_text":[]}},"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":"33758061","id":"PMC_33758061","title":"Essential requirement for JPT2 in NAADP-evoked Ca2+ signaling.","date":"2021","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/33758061","citation_count":92,"is_preprint":false},{"pmid":"33758062","id":"PMC_33758062","title":"HN1L/JPT2: A signaling protein that connects NAADP generation to Ca2+ microdomain formation.","date":"2021","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/33758062","citation_count":79,"is_preprint":false},{"pmid":"30778199","id":"PMC_30778199","title":"HN1L-mediated transcriptional axis AP-2γ/METTL13/TCF3-ZEB1 drives tumor growth and metastasis in hepatocellular carcinoma.","date":"2019","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/30778199","citation_count":59,"is_preprint":false},{"pmid":"29249663","id":"PMC_29249663","title":"HN1L Promotes Triple-Negative Breast Cancer Stem Cells through LEPR-STAT3 Pathway.","date":"2017","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29249663","citation_count":46,"is_preprint":false},{"pmid":"15094197","id":"PMC_15094197","title":"Cloning, expression and subcellular localization of HN1 and HN1L genes, as well as characterization of their orthologs, defining an evolutionarily conserved gene family.","date":"2004","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/15094197","citation_count":45,"is_preprint":false},{"pmid":"33191617","id":"PMC_33191617","title":"HN1L promotes migration and invasion of breast cancer by up-regulating the expression of HMGB1.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33191617","citation_count":28,"is_preprint":false},{"pmid":"29053395","id":"PMC_29053395","title":"Overexpression of HN1L promotes cell malignant proliferation in non-small cell lung cancer.","date":"2017","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29053395","citation_count":24,"is_preprint":false},{"pmid":"37607218","id":"PMC_37607218","title":"Convergent activation of two-pore channels mediated by the NAADP-binding proteins JPT2 and LSM12.","date":"2023","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/37607218","citation_count":23,"is_preprint":false},{"pmid":"38417123","id":"PMC_38417123","title":"JPT2 Affects Trophoblast Functions and Macrophage Polarization and Metabolism, and Acts as a Potential Therapeutic Target for Recurrent Spontaneous Abortion.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38417123","citation_count":21,"is_preprint":false},{"pmid":"35925508","id":"PMC_35925508","title":"METTL13 facilitates cell growth and metastasis in gastric cancer via an eEF1A/HN1L positive feedback circuit.","date":"2022","source":"Journal of cell communication and 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international","url":"https://pubmed.ncbi.nlm.nih.gov/34519127","citation_count":12,"is_preprint":false},{"pmid":"39035219","id":"PMC_39035219","title":"Oxalate regulates crystal-cell adhesion and macrophage metabolism via JPT2/PI3K/AKT signaling to promote the progression of kidney stones.","date":"2024","source":"Journal of pharmaceutical analysis","url":"https://pubmed.ncbi.nlm.nih.gov/39035219","citation_count":10,"is_preprint":false},{"pmid":"31116759","id":"PMC_31116759","title":"HN1L is essential for cell growth and survival during nucleopolyhedrovirus infection in silkworm, Bombyx mori.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31116759","citation_count":10,"is_preprint":false},{"pmid":"33873071","id":"PMC_33873071","title":"JPT2: The missing link between intracellular Ca2+ release channels and NAADP?","date":"2021","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/33873071","citation_count":8,"is_preprint":false},{"pmid":"36443544","id":"PMC_36443544","title":"NAADP-Evoked Ca2+ Signaling: The DUOX2-HN1L/JPT2-Ryanodine Receptor 1 Axis.","date":"2023","source":"Handbook of experimental pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36443544","citation_count":5,"is_preprint":false},{"pmid":"38907823","id":"PMC_38907823","title":"JPT2 in subclinical hypothyroidism-related miscarriage as a transcription co-factor: involvement of LEPR/STAT3 activation.","date":"2024","source":"Journal of endocrinological investigation","url":"https://pubmed.ncbi.nlm.nih.gov/38907823","citation_count":1,"is_preprint":false},{"pmid":"40035993","id":"PMC_40035993","title":"STMN1 regulates the stemness of gastric cancer cells by binding to HN1L to activate the STAT3 signaling pathway.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40035993","citation_count":1,"is_preprint":false},{"pmid":"42224927","id":"PMC_42224927","title":"JPT2/HN1L functions as an NAADP-binding protein in a cell-type-specific manner.","date":"2026","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/42224927","citation_count":0,"is_preprint":false},{"pmid":"41468432","id":"PMC_41468432","title":"Systematic identification of microtubule lumen proteins reveals a taxane-sensitive luminal resident JPT2 regulating MEC17 accessibility.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/41468432","citation_count":0,"is_preprint":false},{"pmid":"41542395","id":"PMC_41542395","title":"Liquid liquid phase separation of the intrinsically disordered protein JPT2 compartmentalizes components of NAADP-evoked Ca2+ signaling.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41542395","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.12.632577","title":"Systematic Identification of Microtubule Inner Proteins Reveals JPT2 as a Key Regulator of Lumen Microenvironment and Drug Sensitivity","date":"2025-01-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.12.632577","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13366,"output_tokens":4034,"usd":0.050304,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11937,"output_tokens":4654,"usd":0.088017,"stage2_stop_reason":"end_turn"},"total_usd":0.138321,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"JPT2 directly binds NAADP (demonstrated by photoaffinity labeling with a 'clickable' NAADP-based photoprobe) and functions as a TPC accessory protein required for endogenous NAADP-evoked Ca2+ release from acidic organelles through two-pore channels (TPCs). JPT2 was also required for translocation of SARS-CoV-2 pseudovirus through the endolysosomal system.\",\n      \"method\": \"Clickable NAADP-based photoprobe (photoaffinity labeling), pulldown/isolation of binding proteins, Ca2+ signaling assays, pseudovirus trafficking assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct photoaffinity labeling established NAADP binding, functional Ca2+ assays confirmed TPC dependence, replicated in companion paper 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 co-precipitates with ryanodine receptors (RYR1) in a TCR/CD3-dependent manner. Gene deletion of Hn1l/Jpt2 in Jurkat and primary rat T cells decreased Ca2+ microdomain formation and delayed/reduced global Ca2+ signaling, placing JPT2 as a link between NAADP generation and RYR1-mediated Ca2+ release from the ER during T cell activation.\",\n      \"method\": \"Photoaffinity labeling of recombinant protein, gene knockout/deletion (CRISPR), co-immunoprecipitation, Ca2+ microdomain imaging\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding demonstrated by photoaffinity labeling on recombinant protein, reciprocal co-IP with RYR1, KO functional phenotype, replicated in companion paper\",\n      \"pmids\": [\"33758062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Recombinant JPT2 binds NAADP with high affinity, and endogenous JPT2 independently associates with both TPC1 and TPC2. Knockout and rescue analyses showed that JPT2 is required for NAADP-evoked Ca2+ signaling and contributes to endolysosomal trafficking of pseudotyped coronavirus particles. JPT2 and LSM12 act convergently through TPCs.\",\n      \"method\": \"Biochemical binding assays (recombinant protein), co-immunoprecipitation (endogenous TPC1/TPC2), knockout cell lines with rescue, Ca2+ signaling assays, pseudovirus trafficking\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (biochemical binding, Co-IP, KO/rescue, functional Ca2+ assays) in single rigorous study\",\n      \"pmids\": [\"37607218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HN1L (JPT2) encodes a ~20 kDa protein that localizes to both the nucleus and cytoplasm, as determined by GFP fusion expression and Western blot.\",\n      \"method\": \"GFP fusion protein expression, Western blot, subcellular localization imaging\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — GFP fusion localization confirmed by Western blot, but no functional consequence linked to localization\",\n      \"pmids\": [\"15094197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HN1L/JPT2 binds to a putative consensus upstream sequence of STAT3, LEPR, and MIR-150, functioning as a transcription regulator that sustains LEPR-STAT3 pathway activation in triple-negative breast cancer stem cells.\",\n      \"method\": \"ChIP/transcription binding assay, shRNA knockdown with BCSC functional readouts (sphere formation, tumor initiation)\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — transcription factor binding assay reported, functional KD phenotype established, but single lab and limited mechanistic resolution in abstract\",\n      \"pmids\": [\"29249663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HN1L/JPT2 promotes cell proliferation in NSCLC by interacting with RASA4 protein, thereby interfering with the MAPK pathway; knockdown causes G1/S cell cycle arrest.\",\n      \"method\": \"shRNA knockdown, co-immunoprecipitation (interaction with RASA4), cell cycle analysis, in vivo tumor growth\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying RASA4 interaction, functional KD phenotype, single lab\",\n      \"pmids\": [\"29053395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HN1L/JPT2 transcriptionally upregulates METTL13 in an AP-2γ-dependent manner in hepatocellular carcinoma, which then promotes cell proliferation and metastasis by upregulating TCF3 and ZEB1.\",\n      \"method\": \"shRNA knockdown, overexpression, transcriptional reporter/ChIP (AP-2γ dependent), in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — transcriptional regulation mechanism shown via multiple functional assays, but primarily single-lab work with indirect mechanistic evidence in abstract\",\n      \"pmids\": [\"30778199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HN1L/JPT2 interacts with HSPA9 and affects HMGB1 expression to promote invasion and metastasis of breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry (interaction with HSPA9), shRNA knockdown, in vitro invasion assays, in vivo metastasis model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/MS interaction with HSPA9, downstream HMGB1 effect not mechanistically dissected, single lab\",\n      \"pmids\": [\"33191617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HN1L/JPT2 activates transcription of PLK1 by interacting with transcription factor AP-2γ, leading to increased Cyclin D1 and Slug expression and promoting ESCC metastasis and chemotherapy resistance.\",\n      \"method\": \"Co-immunoprecipitation (AP-2γ interaction), loss/gain-of-function in ESCC cells, in vivo tumor models, PLK1 inhibitor rescue experiment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with AP-2γ, functional KD/OE with mechanistic rescue by PLK1 inhibitor, single lab\",\n      \"pmids\": [\"36476988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HN1L/JPT2 binds to FOXP2 and positively regulates TGF-β expression via upregulation of FOXP2, promoting cancer stem cell properties in prostate cancer.\",\n      \"method\": \"Co-immunoprecipitation (FOXP2 interaction), shRNA knockdown, TGF-β overexpression rescue experiments\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for FOXP2 binding, downstream pathway inferred from rescue, single lab\",\n      \"pmids\": [\"34519127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JPT2 deficiency in trophoblast cells inhibits adhesion, migration, and invasion through inhibition of the JNK/ACKR3 axis (rather than through Ca2+ mobilization), and promotes M1 macrophage polarization by accumulation of citrate and ROS via inhibition of the JNK/IL-6 axis.\",\n      \"method\": \"Loss-of-function (JPT2 knockdown/knockout), transcriptomics, JNK pathway analysis, macrophage polarization assays, AAV9-JPT2 rescue in abortion-prone mice\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (transcriptomics, functional assays, in vivo rescue), single lab but comprehensive mechanistic dissection\",\n      \"pmids\": [\"38417123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Oxalate exposure upregulates JPT2, which mediates crystal-cell adhesion and macrophage inflammatory polarization via PI3K/AKT signaling and inhibits production of succinic acid semialdehyde in macrophages; JPT2 deficiency in mice inhibited kidney stone mineralization.\",\n      \"method\": \"Genetic knockdown/knockout of JPT2 in cells and mice, transcriptomics, untargeted metabolomics, in vivo kidney stone model\",\n      \"journal\": \"Journal of pharmaceutical analysis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomic and metabolomic analyses plus in vivo genetic model, single lab\",\n      \"pmids\": [\"39035219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In Jpt2/Hn1l knockout mice, JPT2/HN1L is required for NAADP-mediated Ca2+ release specifically in CD4+ T cells (TCR/CD3-stimulated global Ca2+ elevations and early Ca2+ microdomains significantly decreased), but is dispensable for NAADP-mediated Ca2+ signaling in cardiomyocytes, mast cells, and platelets, demonstrating cell-type specificity.\",\n      \"method\": \"Germline Jpt2/Hn1l knockout mice, Ca2+ imaging (global and microdomain), platelet aggregation assays, cell-type-specific functional analysis\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic knockout mouse model with multiple cell types tested, functional Ca2+ imaging with multiple orthogonal readouts\",\n      \"pmids\": [\"42224927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"JPT2 localizes within the lumen of singlet microtubules in a C-terminal-dependent manner, modulates the distribution of α-tubulin acetyltransferase MEC17 (inhibiting its luminal accessibility/activity), and its luminal localization is markedly reduced by Paclitaxel treatment.\",\n      \"method\": \"Proximity-labeling (BioID) to distinguish intraluminal vs external proteins, mass spectrometry, mutagenesis (C-terminal deletion), microtubule-binding assays, Paclitaxel treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — proximity labeling plus mutagenesis, but single lab, novel finding not yet replicated\",\n      \"pmids\": [\"41468432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"JPT2 is an intrinsically disordered protein (confirmed by circular dichroism and NMR spectroscopy) that undergoes liquid-liquid phase separation under low Na+ or molecular crowding conditions. JPT2 condensates recruit LSM12, a fluorescent NAADP analog, tubulin, and interact with polymerized microtubules and lysosomes from human cell lines.\",\n      \"method\": \"Circular dichroism, NMR spectroscopy, multiple orthogonal phase separation assays, condensate recruitment assays with purified components\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous biophysical methods (NMR, CD) confirming disorder and phase separation, but preprint not yet peer-reviewed\",\n      \"pmids\": [\"41542395\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JPT2 functions as a transcription co-factor that activates transcription of LEPR in an AP-2γ-dependent manner and activates STAT3 signaling in trophoblast cells; silencing LEPR abolished the pro-proliferative/migratory effects of JPT2 overexpression.\",\n      \"method\": \"Gain- and loss-of-function experiments in HTR-8/SVneo trophoblast cells, transcriptomics, LEPR silencing rescue experiment\",\n      \"journal\": \"Journal of endocrinological investigation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional assays with rescue, but mechanistic details of AP-2γ interaction not directly demonstrated in abstract, single lab\",\n      \"pmids\": [\"38907823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STMN1 physically binds HN1L/JPT2 in gastric cancer cells (demonstrated by co-immunoprecipitation), and HN1L overexpression reverses the effects of STMN1 knockdown on stemness and STAT3/PD-L1 signaling.\",\n      \"method\": \"Co-immunoprecipitation, overexpression rescue experiments, in vivo xenograft model\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for STMN1-HN1L interaction, functional rescue, single lab\",\n      \"pmids\": [\"40035993\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JPT2 (HN1L) is an intrinsically disordered, NAADP-binding protein that serves as an essential accessory subunit of the NAADP receptor complex, directly binding NAADP with high affinity and independently associating with two-pore channels (TPC1/2) on endolysosomes and with ryanodine receptor 1 (RYR1) on the ER to mediate NAADP-evoked Ca2+ release in a cell-type-specific manner (required in T cells, dispensable in cardiomyocytes, platelets, and mast cells); it can also undergo liquid-liquid phase separation to compartmentalize NAADP signaling components, and separately localizes within the microtubule lumen via its C-terminus where it regulates the acetyltransferase MEC17 and modulates Paclitaxel sensitivity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"JPT2 (HN1L) is an intrinsically disordered, NAADP-binding protein that serves as an essential accessory component of NAADP-evoked Ca2+ signaling, coupling the second messenger NAADP to Ca2+-release channels [#0, #1]. It directly binds NAADP, demonstrated by photoaffinity labeling of recombinant protein, and is required for NAADP-evoked Ca2+ release from acidic organelles through two-pore channels, with which it physically associates (TPC1 and TPC2) [#0, #2]. In T cells, JPT2 co-precipitates with ryanodine receptor 1 in a TCR/CD3-dependent manner and links NAADP to RYR1-mediated ER Ca2+ release, shaping Ca2+ microdomains during T cell activation [#1]. This NAADP-channel coupling is cell-type-specific: germline knockout mice require JPT2 for NAADP-mediated Ca2+ signaling in CD4+ T cells but not in cardiomyocytes, mast cells, or platelets [#12]. JPT2 acts convergently with LSM12 through TPCs and contributes to endolysosomal trafficking, including translocation of pseudotyped coronavirus particles [#0, #2]. As an intrinsically disordered protein, JPT2 can undergo liquid-liquid phase separation, forming condensates that recruit LSM12, an NAADP analog, tubulin, microtubules, and lysosomes [#14]. Independently of Ca2+ signaling, JPT2 localizes within the lumen of singlet microtubules via its C-terminus, where it restricts the luminal accessibility of the alpha-tubulin acetyltransferase MEC17 and its luminal localization is reduced by Paclitaxel [#13]. A separate body of work positions JPT2 as a pro-tumorigenic transcriptional/co-factor and interaction hub across multiple cancers, where it activates transcriptional programs (e.g. PLK1 via AP-2gamma, METTL13, LEPR-STAT3) and interacts with partners including RASA4 to drive proliferation, metastasis, and stemness [#5, #6, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Before any function was assigned, the basic gene product and its compartments were established, showing HN1L/JPT2 is a small protein distributed between nucleus and cytoplasm.\",\n      \"evidence\": \"GFP fusion expression and Western blot subcellular localization\",\n      \"pmids\": [\"15094197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular function linked to either localization\", \"No interaction partners identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"First mechanistic roles placed HN1L/JPT2 in cancer signaling, as both a transcription regulator sustaining LEPR-STAT3 in breast cancer stem cells and a RASA4-interacting modulator of MAPK driving proliferation in NSCLC.\",\n      \"evidence\": \"ChIP/transcription binding and shRNA knockdown (BCSC); Co-IP with RASA4 and cell-cycle analysis (NSCLC)\",\n      \"pmids\": [\"29249663\", \"29053395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA-binding versus co-factor role not resolved\", \"RASA4 interaction from single Co-IP without reciprocal validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the transcriptional model by showing JPT2 upregulates METTL13 in an AP-2gamma-dependent manner to promote hepatocellular carcinoma proliferation and metastasis.\",\n      \"evidence\": \"shRNA/overexpression, transcriptional reporter/ChIP, in vitro and in vivo assays\",\n      \"pmids\": [\"30778199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether JPT2 binds DNA directly or only via AP-2gamma unclear\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified additional protein partners (HSPA9) and a downstream HMGB1 effect in breast cancer invasion, broadening the JPT2 interactome.\",\n      \"evidence\": \"Co-IP/mass spectrometry, shRNA knockdown, invasion and metastasis models\",\n      \"pmids\": [\"33191617\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP/MS interaction not reciprocally validated\", \"Mechanistic link to HMGB1 not dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the core molecular activity: JPT2 directly binds NAADP and acts as a TPC accessory protein required for NAADP-evoked Ca2+ release, establishing it as the long-sought NAADP-binding component upstream of two-pore channels.\",\n      \"evidence\": \"Clickable NAADP photoaffinity probe, pulldown, Ca2+ assays, pseudovirus trafficking; replicated in companion paper\",\n      \"pmids\": [\"33758061\", \"33758062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of NAADP binding not defined\", \"How JPT2 transmits binding to channel gating unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the channel target in T cells, showing JPT2 couples NAADP to RYR1-mediated ER Ca2+ release in a TCR/CD3-dependent fashion and shapes Ca2+ microdomains during T cell activation.\",\n      \"evidence\": \"Photoaffinity labeling of recombinant protein, CRISPR knockout, reciprocal Co-IP with RYR1, Ca2+ microdomain imaging\",\n      \"pmids\": [\"33758062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RYR1 and TPC coupling are mutually exclusive unclear\", \"Stoichiometry of the receptor complex undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Added further cancer transcriptional partners, showing JPT2 binds FOXP2 to upregulate TGF-beta and promote prostate cancer stem cell properties.\",\n      \"evidence\": \"Co-IP with FOXP2, shRNA knockdown, TGF-beta rescue\",\n      \"pmids\": [\"34519127\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP for FOXP2 binding\", \"Downstream pathway inferred from rescue only\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided a mechanistically rescue-validated transcriptional model in ESCC, where JPT2-AP-2gamma activates PLK1 to drive Cyclin D1/Slug, metastasis, and chemoresistance.\",\n      \"evidence\": \"Co-IP with AP-2gamma, loss/gain-of-function, in vivo models, PLK1 inhibitor rescue\",\n      \"pmids\": [\"36476988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter occupancy by JPT2 not shown\", \"Single-lab work\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Strengthened the NAADP receptor model by showing high-affinity NAADP binding, independent endogenous association with both TPC1 and TPC2, and convergence with LSM12 through TPCs.\",\n      \"evidence\": \"Recombinant binding assays, endogenous Co-IP, knockout/rescue, Ca2+ assays, pseudovirus trafficking\",\n      \"pmids\": [\"37607218\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Architecture of the JPT2-LSM12-TPC complex unresolved\", \"How two accessory proteins converge on the same channel unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed Ca2+-independent functions in reproductive and renal/inflammatory contexts, with JPT2 acting through JNK/ACKR3 and JNK/IL-6 axes in trophoblasts and macrophages and through PI3K/AKT in oxalate-induced kidney stone formation.\",\n      \"evidence\": \"Knockdown/knockout, transcriptomics, metabolomics, macrophage polarization assays, in vivo rescue (AAV9) and stone models\",\n      \"pmids\": [\"38417123\", \"39035219\", \"38907823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target linking JPT2 to JNK/PI3K signaling not identified\", \"Relationship to NAADP/transcriptional roles unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a distinct cytoskeletal role: JPT2 localizes within the microtubule lumen via its C-terminus, restricting MEC17 luminal access and being displaced by Paclitaxel, linking it to microtubule acetylation and taxane sensitivity.\",\n      \"evidence\": \"BioID proximity labeling, mass spectrometry, C-terminal deletion mutagenesis, microtubule-binding and Paclitaxel assays\",\n      \"pmids\": [\"41468432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of altered acetylation on cell physiology unclear\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added a gastric cancer interaction, showing STMN1 physically binds HN1L/JPT2 and JPT2 overexpression rescues STMN1-loss effects on stemness and STAT3/PD-L1 signaling.\",\n      \"evidence\": \"Co-IP, overexpression rescue, xenograft model\",\n      \"pmids\": [\"40035993\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"Mechanism of STAT3/PD-L1 regulation not dissected\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established cell-type specificity of the NAADP function in vivo, showing JPT2 is required for NAADP-mediated Ca2+ signaling in CD4+ T cells but dispensable in cardiomyocytes, mast cells, and platelets.\",\n      \"evidence\": \"Germline Jpt2/Hn1l knockout mice, global and microdomain Ca2+ imaging, platelet aggregation assays\",\n      \"pmids\": [\"42224927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What substitutes for JPT2 in non-T cells is unknown\", \"Molecular basis of cell-type selectivity undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined the biophysical basis for compartmentalization, showing JPT2 is intrinsically disordered and undergoes liquid-liquid phase separation forming condensates that recruit NAADP-signaling and cytoskeletal components.\",\n      \"evidence\": \"Circular dichroism, NMR, phase separation and condensate recruitment assays (preprint)\",\n      \"pmids\": [\"41542395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological role of condensates in Ca2+ signaling not demonstrated in cells\", \"Preprint, not peer-reviewed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how JPT2's NAADP/Ca2+-coupling role, its nuclear transcriptional/co-factor activities in cancer, and its microtubule-lumen function mechanistically relate within a single protein.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of JPT2 bound to NAADP or to TPC/RYR1\", \"No unifying model linking disordered phase separation to its multiple compartment-specific functions\", \"Direct DNA binding versus co-factor role in transcription unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TPC1\", \"TPC2\", \"RYR1\", \"LSM12\", \"RASA4\", \"HSPA9\", \"STMN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}