Affinage

JPT2

Jupiter microtubule associated homolog 2 · UniProt Q9H910

Length
190 aa
Mass
20.1 kDa
Annotated
2026-06-10
22 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2004 Medium

    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

    PMID:15094197

    Open questions at the time
    • No molecular function linked to either localization
    • No interaction partners identified
  2. 2017 Medium

    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)

    PMID:29053395 PMID:29249663

    Open questions at the time
    • Direct DNA-binding versus co-factor role not resolved
    • RASA4 interaction from single Co-IP without reciprocal validation
  3. 2019 Medium

    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

    PMID:30778199

    Open questions at the time
    • Whether JPT2 binds DNA directly or only via AP-2gamma unclear
    • Single-lab evidence
  4. 2020 Low

    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

    PMID:33191617

    Open questions at the time
    • Single Co-IP/MS interaction not reciprocally validated
    • Mechanistic link to HMGB1 not dissected
  5. 2021 High

    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

    PMID:33758061 PMID:33758062

    Open questions at the time
    • Structural basis of NAADP binding not defined
    • How JPT2 transmits binding to channel gating unknown
  6. 2021 High

    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

    PMID:33758062

    Open questions at the time
    • Whether RYR1 and TPC coupling are mutually exclusive unclear
    • Stoichiometry of the receptor complex undefined
  7. 2021 Low

    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

    PMID:34519127

    Open questions at the time
    • Single Co-IP for FOXP2 binding
    • Downstream pathway inferred from rescue only
  8. 2022 Medium

    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

    PMID:36476988

    Open questions at the time
    • Direct promoter occupancy by JPT2 not shown
    • Single-lab work
  9. 2023 High

    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

    PMID:37607218

    Open questions at the time
    • Architecture of the JPT2-LSM12-TPC complex unresolved
    • How two accessory proteins converge on the same channel unclear
  10. 2024 Medium

    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

    PMID:38417123 PMID:38907823 PMID:39035219

    Open questions at the time
    • Direct molecular target linking JPT2 to JNK/PI3K signaling not identified
    • Relationship to NAADP/transcriptional roles unclear
  11. 2025 Medium

    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

    PMID:41468432

    Open questions at the time
    • Functional consequence of altered acetylation on cell physiology unclear
    • Not independently replicated
  12. 2025 Low

    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

    PMID:40035993

    Open questions at the time
    • Single Co-IP without reciprocal validation
    • Mechanism of STAT3/PD-L1 regulation not dissected
  13. 2026 High

    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

    PMID:42224927

    Open questions at the time
    • What substitutes for JPT2 in non-T cells is unknown
    • Molecular basis of cell-type selectivity undefined
  14. 2026 Medium

    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)

    PMID:41542395

    Open questions at the time
    • Physiological role of condensates in Ca2+ signaling not demonstrated in cells
    • Preprint, not peer-reviewed

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005764 lysosome 2 GO:0005634 nucleus 1 GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
HSPA9LSM12RASA4RYR1STMN1TPC1TPC2

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 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. Clickable NAADP-based photoprobe (photoaffinity labeling), pulldown/isolation of binding proteins, Ca2+ signaling assays, pseudovirus trafficking assays Science signaling High 33758061
2021 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. Photoaffinity labeling of recombinant protein, gene knockout/deletion (CRISPR), co-immunoprecipitation, Ca2+ microdomain imaging Science signaling High 33758062
2023 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. Biochemical binding assays (recombinant protein), co-immunoprecipitation (endogenous TPC1/TPC2), knockout cell lines with rescue, Ca2+ signaling assays, pseudovirus trafficking Science signaling High 37607218
2004 HN1L (JPT2) encodes a ~20 kDa protein that localizes to both the nucleus and cytoplasm, as determined by GFP fusion expression and Western blot. GFP fusion protein expression, Western blot, subcellular localization imaging Gene Medium 15094197
2017 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. ChIP/transcription binding assay, shRNA knockdown with BCSC functional readouts (sphere formation, tumor initiation) Stem cell reports Medium 29249663
2017 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. shRNA knockdown, co-immunoprecipitation (interaction with RASA4), cell cycle analysis, in vivo tumor growth Cancer biology & therapy Medium 29053395
2019 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. shRNA knockdown, overexpression, transcriptional reporter/ChIP (AP-2γ dependent), in vitro and in vivo functional assays Cell death and differentiation Medium 30778199
2020 HN1L/JPT2 interacts with HSPA9 and affects HMGB1 expression to promote invasion and metastasis of breast cancer cells. Co-immunoprecipitation, mass spectrometry (interaction with HSPA9), shRNA knockdown, in vitro invasion assays, in vivo metastasis model Journal of cellular and molecular medicine Low 33191617
2022 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. Co-immunoprecipitation (AP-2γ interaction), loss/gain-of-function in ESCC cells, in vivo tumor models, PLK1 inhibitor rescue experiment Cell death & disease Medium 36476988
2021 HN1L/JPT2 binds to FOXP2 and positively regulates TGF-β expression via upregulation of FOXP2, promoting cancer stem cell properties in prostate cancer. Co-immunoprecipitation (FOXP2 interaction), shRNA knockdown, TGF-β overexpression rescue experiments Cell biology international Low 34519127
2024 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. Loss-of-function (JPT2 knockdown/knockout), transcriptomics, JNK pathway analysis, macrophage polarization assays, AAV9-JPT2 rescue in abortion-prone mice Advanced science Medium 38417123
2024 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. Genetic knockdown/knockout of JPT2 in cells and mice, transcriptomics, untargeted metabolomics, in vivo kidney stone model Journal of pharmaceutical analysis Medium 39035219
2026 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. Germline Jpt2/Hn1l knockout mice, Ca2+ imaging (global and microdomain), platelet aggregation assays, cell-type-specific functional analysis Cell calcium High 42224927
2025 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. Proximity-labeling (BioID) to distinguish intraluminal vs external proteins, mass spectrometry, mutagenesis (C-terminal deletion), microtubule-binding assays, Paclitaxel treatment Proceedings of the National Academy of Sciences of the United States of America Medium 41468432
2026 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. Circular dichroism, NMR spectroscopy, multiple orthogonal phase separation assays, condensate recruitment assays with purified components bioRxivpreprint Medium 41542395
2024 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. Gain- and loss-of-function experiments in HTR-8/SVneo trophoblast cells, transcriptomics, LEPR silencing rescue experiment Journal of endocrinological investigation Low 38907823
2025 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. Co-immunoprecipitation, overexpression rescue experiments, in vivo xenograft model Discover oncology Low 40035993

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Essential requirement for JPT2 in NAADP-evoked Ca2+ signaling. Science signaling 92 33758061
2021 HN1L/JPT2: A signaling protein that connects NAADP generation to Ca2+ microdomain formation. Science signaling 79 33758062
2019 HN1L-mediated transcriptional axis AP-2γ/METTL13/TCF3-ZEB1 drives tumor growth and metastasis in hepatocellular carcinoma. Cell death and differentiation 59 30778199
2017 HN1L Promotes Triple-Negative Breast Cancer Stem Cells through LEPR-STAT3 Pathway. Stem cell reports 46 29249663
2004 Cloning, expression and subcellular localization of HN1 and HN1L genes, as well as characterization of their orthologs, defining an evolutionarily conserved gene family. Gene 45 15094197
2020 HN1L promotes migration and invasion of breast cancer by up-regulating the expression of HMGB1. Journal of cellular and molecular medicine 28 33191617
2017 Overexpression of HN1L promotes cell malignant proliferation in non-small cell lung cancer. Cancer biology & therapy 24 29053395
2023 Convergent activation of two-pore channels mediated by the NAADP-binding proteins JPT2 and LSM12. Science signaling 23 37607218
2024 JPT2 Affects Trophoblast Functions and Macrophage Polarization and Metabolism, and Acts as a Potential Therapeutic Target for Recurrent Spontaneous Abortion. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 21 38417123
2022 METTL13 facilitates cell growth and metastasis in gastric cancer via an eEF1A/HN1L positive feedback circuit. Journal of cell communication and signaling 19 35925508
2021 HN1L promotes invasion and metastasis of the esophagogastric junction adenocarcinoma. Thoracic cancer 15 33471419
2022 HN1L/AP-2γ/PLK1 signaling drives tumor progression and chemotherapy resistance in esophageal squamous cell carcinoma. Cell death & disease 13 36476988
2021 HN1L promotes stem cell-like properties by regulating TGF-β signaling pathway through targeting FOXP2 in prostate cancer. Cell biology international 12 34519127
2024 Oxalate regulates crystal-cell adhesion and macrophage metabolism via JPT2/PI3K/AKT signaling to promote the progression of kidney stones. Journal of pharmaceutical analysis 10 39035219
2019 HN1L is essential for cell growth and survival during nucleopolyhedrovirus infection in silkworm, Bombyx mori. PloS one 10 31116759
2021 JPT2: The missing link between intracellular Ca2+ release channels and NAADP? Cell calcium 8 33873071
2023 NAADP-Evoked Ca2+ Signaling: The DUOX2-HN1L/JPT2-Ryanodine Receptor 1 Axis. Handbook of experimental pharmacology 5 36443544
2025 STMN1 regulates the stemness of gastric cancer cells by binding to HN1L to activate the STAT3 signaling pathway. Discover oncology 1 40035993
2024 JPT2 in subclinical hypothyroidism-related miscarriage as a transcription co-factor: involvement of LEPR/STAT3 activation. Journal of endocrinological investigation 1 38907823
2026 Liquid liquid phase separation of the intrinsically disordered protein JPT2 compartmentalizes components of NAADP-evoked Ca2+ signaling. bioRxiv : the preprint server for biology 0 41542395
2026 JPT2/HN1L functions as an NAADP-binding protein in a cell-type-specific manner. Cell calcium 0 42224927
2025 Systematic identification of microtubule lumen proteins reveals a taxane-sensitive luminal resident JPT2 regulating MEC17 accessibility. Proceedings of the National Academy of Sciences of the United States of America 0 41468432

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