Affinage

JAK3

Tyrosine-protein kinase JAK3 · UniProt P52333

Length
1124 aa
Mass
125.1 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 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

JAK3 is a hematopoietically expressed non-receptor tyrosine kinase that transduces signals from common gamma-chain (γc) cytokine receptors and is essential for lymphoid development (PMID:8022485, PMID:7481769). It associates selectively with the cytoplasmic tail of IL-2Rγ (γc) while JAK1 binds IL-2Rβ, and both associations are required for IL-2 signaling; reconstitution of JAK3 confers cytokine responsiveness to otherwise unresponsive cells (PMID:7973659). JAK3 is activated by IL-2, IL-4, and IL-7 across T cells, B cells, and monocytes (PMID:8022485, PMID:7957877, PMID:7538655, PMID:7535338), where it transphosphorylates JAK1, phosphorylates IL-2Rβ and γc, and selectively phosphorylates STAT3 and STAT5 (but not STAT1), defining JAK3-dependent and JAK3-independent arms of cytokine signaling (PMID:8986719, PMID:10037026). Beyond STAT activation, JAK3 phosphorylates the PI3-kinase p85 subunit to drive IL-7-induced proliferation (PMID:7662955) and sustains STAT5 in two temporal waves required for cyclin expression and S-phase entry in proliferating T cells (PMID:27018889). Kinase activity is autoregulated by activation-loop residues Y980 (activating) and Y981 (inhibitory) (PMID:9391116), and downstream survival is mediated through Bax/Bcl-2 control of thymocyte survival (PMID:11134353). JAK3 protein levels are controlled by NOTCH-driven ubiquitination via an ASB2/SKP2–Cullin1/Cullin5 E3 ligase complex that engages distinct JAK3 domains (PMID:21969365), and the kinase is negatively regulated by BLNK binding (PMID:19047679). Loss-of-function JAK3 mutations cause autosomal recessive T-B+NK- SCID in humans, while activating pseudokinase-domain and kinase-domain mutations are oncogenic in NK/T-cell lymphoma and T-ALL (PMID:7659163, PMID:9354668, PMID:28284718, PMID:35411095). A unique active-site Cys-909 confers JAK3 selectivity to covalent ATP-competitive inhibitors (PMID:25552479, PMID:30423248, PMID:31082193).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1994 High

    Establishing that JAK3 physically couples to and is activated by γc cytokine receptors answered how lymphoid cytokine receptors, which lack intrinsic kinase activity, transduce signals.

    Evidence Reciprocal Co-IP, phosphorylation assays, domain-deletion mapping, and functional reconstitution in fibroblasts for IL-2R and IL-7

    PMID:7518579 PMID:7957877 PMID:7973659 PMID:8022485

    Open questions at the time
    • Did not define which downstream substrates JAK3 phosphorylates
    • Stoichiometry and order of JAK1/JAK3 receptor association not resolved
  2. 1995 High

    Knockout mice and SCID patient mutations established that JAK3 is genetically required for lymphoid development, linking the biochemistry to organismal immunodeficiency.

    Evidence Independent gene-targeted knockout mice with immune phenotyping plus patient DNA sequencing with protein-level confirmation

    PMID:7481769 PMID:7659163 PMID:8777722

    Open questions at the time
    • Did not distinguish thymic vs peripheral requirements
    • Survival vs proliferation mechanism of lymphopenia not yet defined
  3. 1995 Medium

    Mapping JAK3 activation to multiple γc cytokines and to PI3-kinase p85 broadened its signaling outputs beyond the STAT axis.

    Evidence Co-IP, kinase activity, and PI3-kinase activity assays in T cells, B cells, and monocytes following IL-2/IL-4/IL-7 stimulation

    PMID:7535338 PMID:7538655 PMID:7594533 PMID:7662955

    Open questions at the time
    • Single-lab Co-IPs for several receptor associations
    • Relative contribution of PI3K vs STAT arms to proliferation not quantified
  4. 1996 High

    Genetic dissection of JAK3-deficient cells defined which cytokine-induced phosphorylation events strictly require JAK3 versus those merely enhanced by it.

    Evidence JAK3-deficient B cell lines tested for IL-2- and IL-4-induced phosphorylation of receptors, JAKs, STATs, and IRS proteins

    PMID:8986719

    Open questions at the time
    • Molecular basis for differential JAK3 dependence between IL-2 and IL-4 not resolved
  5. 1997 High

    Identifying activation-loop tyrosines Y980/Y981 with opposing regulatory roles answered how JAK3 catalytic activity is intrinsically tuned.

    Evidence Site-directed mutagenesis with in vitro and cellular kinase and substrate phosphorylation assays

    PMID:9391116

    Open questions at the time
    • Structural mechanism of Y981 autoinhibition not defined
    • In vivo phosphorylation kinetics of these sites not mapped
  6. 1997 High

    Conditional reconstitution and patient mutation analysis separated JAK3's developmental from its peripheral maintenance role and linked specific mutations to biochemical defects.

    Evidence Retroviral conditional reconstitution in mice and patient-derived lymphoblastoid lines with IL-2/IL-4-induced phosphorylation readouts

    PMID:9016869 PMID:9354668

    Open questions at the time
    • Mechanism by which a JH2 pseudokinase mutation causes constitutive activation not structurally defined
  7. 1999 Medium

    In vitro reconstitution established the hierarchy and substrate specificity between JAK3 and JAK1 in the IL-2 receptor complex.

    Evidence Recombinant baculovirus kinase components in in vitro transphosphorylation and STAT/receptor substrate assays

    PMID:10037026

    Open questions at the time
    • In vitro recombinant system may not reflect receptor-assembled stoichiometry
    • Single lab
  8. 2001 High

    Genetic epistasis identified Bax/Bcl-2 as the survival effector downstream of JAK3, explaining the cellular basis of lymphopenia, and extended JAK3 function to platelets.

    Evidence JAK3/Bax double-knockout mice with Bcl-2 retroviral rescue; JAK3-deficient platelets with pharmacological inhibition and aggregation assays

    PMID:11134353 PMID:11278899

    Open questions at the time
    • Direct molecular link from JAK3 to Bax/Bcl-2 transcription not established
    • Platelet JAK3 substrate specificity beyond STAT1/STAT3 unclear
  9. 2004 Medium

    Demonstrating JAK3 involvement in chemokine receptor signaling extended its role beyond γc cytokines to progenitor migration.

    Evidence Jak3-/- mice in transwell migration assays toward CXCL12/CCL25 with pharmacological inhibition controls

    PMID:15147562

    Open questions at the time
    • Direct biochemical coupling of JAK3 to CCR9/CXCR4 not shown
    • Substrates in the chemotactic pathway unidentified
  10. 2005 Medium

    JAK3 deficiency studies in dendritic cells revealed an unexpected negative-regulatory role in innate cytokine production.

    Evidence Jak3-/- bone marrow-derived DC cultures with cytokine ELISA and in vivo Th1 differentiation

    PMID:16020505

    Open questions at the time
    • Mechanism of negative regulation of IL-12/IL-10 not defined
    • Single lab
  11. 2008 High

    Identifying BLNK as a direct JAK3-binding inhibitor explained how aberrant JAK3/STAT5 activation drives pre-B leukemogenesis.

    Evidence Reciprocal Co-IP, JAK3-binding-dependent inhibition assays, and BLNK-/- leukemia model

    PMID:19047679

    Open questions at the time
    • Structural basis of BLNK-JAK3 inhibition not resolved
  12. 2009 Medium

    Phosphatase and DC-maturation studies refined upstream regulation of JAK3 and its role in adaptive immune priming.

    Evidence PP2A inhibitor treatments with EMSA and Co-IP; Jak3-/- DC migration assays toward CCL19/CCL21 in vitro and in vivo

    PMID:19759904 PMID:19923221

    Open questions at the time
    • Identity of the Ser/Thr kinase regulating IL-2Rβ-JAK3 association unknown
    • Single-lab observations
  13. 2011 High

    NOTCH-driven ASB2/SKP2-Cullin ubiquitination defined how JAK3 protein abundance is controlled, and oocyte studies linked JAK3 to glucose transport in activated T cells.

    Evidence Co-IP with domain mapping, dominant-negative Cullins, ubiquitination assays; Xenopus oocyte voltage clamp with active vs inactive JAK3 and SGLT1 co-expression

    PMID:21969365 PMID:27595398

    Open questions at the time
    • Whether NOTCH-induced degradation operates in primary lymphocytes physiologically not fully shown
    • Direct vs indirect JAK3 regulation of SGLT1 trafficking unresolved
  14. 2016 High

    Chemical-genetic dissection established that JAK3 kinase activity is required in two temporal waves of STAT5 phosphorylation gating cell-cycle entry.

    Evidence Selective covalent JAK3 inhibitor with inhibitor-resistant C905S mutant rescue, STAT5 time course, and cell-cycle analysis in primary T cells and mice

    PMID:27018889 PMID:27791347

    Open questions at the time
    • Molecular trigger distinguishing first vs second wave not defined
  15. 2014 High

    Defining covalent engagement of the unique active-site Cys-909 explained how isoform-selective JAK3 inhibitors are achieved.

    Evidence In vitro enzyme inhibition, selectivity profiling, crystallography, kinetics, and LC-MS covalent modification across multiple inhibitor chemotypes

    PMID:25552479 PMID:30423248 PMID:31082193

    Open questions at the time
    • Off-target TEC-kinase engagement complicates cellular interpretation of some inhibitors
  16. 2017 Medium

    Oncogenic JAK3 mutations established that gain-of-function signaling drives malignant proliferation and survival, complementing the loss-of-function SCID phenotype.

    Evidence Ba/F3 cytokine-independence transformation assays, structural modeling, and JAK3 inhibitor sensitivity in lymphoma and T-ALL models with BH3 profiling

    PMID:28284718 PMID:35411095

    Open questions at the time
    • Structural mechanism of pseudokinase-domain activation not crystallographically resolved
    • Single-lab functional assays
  17. 2020 Medium

    Non-canonical JAK3 functions were extended to Wnt/Nedd4-2, glioblastoma motility, myogenesis, fibrosis, and the HSC niche, broadening its substrate and tissue scope.

    Evidence Pharmacological/genetic gain- and loss-of-function across periodontal, GBM, myoblast, kidney fibrosis, and bone marrow endothelial models

    PMID:22120524 PMID:26032813 PMID:32433819 PMID:33767339 PMID:33960104

    Open questions at the time
    • Most rely on inhibitors with potential off-target activity
    • Direct JAK3 substrate phosphorylation in these contexts not always demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structural picture of how activation-loop tyrosines, the pseudokinase domain, and oncogenic mutations control JAK3 catalytic state remains unresolved.
  • No full-length JAK3 autoinhibited structure in the corpus
  • Mechanism distinguishing JAK3-dependent from JAK3-independent receptor outputs structurally undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0140657 ATP-dependent activity 2
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2
Partners
BLNKIL2RBIL2RGJAK1PIK3R1SKP2STAT3STAT5
Complex memberships
ASB2/SKP2-Cullin1/Cullin5 E3 ligase complex (substrate)IL-2 receptor complex (with IL-2Rβ/γc and JAK1)

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 JAK3 is physically and functionally coupled to the IL-2 receptor in human peripheral blood T cells and NK cells; IL-2 stimulation induces tyrosine phosphorylation and activation of JAK3. Co-immunoprecipitation, phosphorylation assays in primary human cells Nature High 8022485
1994 JAK1 associates selectively with the serine-rich region of IL-2Rβ, while JAK3 associates selectively with the cytoplasmic tail of IL-2Rγ (common gamma chain); both associations are required for IL-2 signaling. Jak3-negative fibroblasts reconstituted with IL-2R became IL-2-responsive only after additional expression of JAK3 cDNA. Selective co-immunoprecipitation, domain-deletion mutants, functional reconstitution in fibroblasts Science High 7973659
1994 JAK3 is a novel Janus kinase family member identified in hematopoietic cells, containing a double catalytic domain characteristic of the JAK family, with two unique insertions (147 and 28 amino acids) not present in other JAKs; expression is dramatically upregulated during terminal differentiation of hematopoietic cells. PCR-based cloning, cDNA sequencing, expression analysis Oncogene Medium 7518579
1994 JAK3 is selectively tyrosine-phosphorylated and activated by IL-7 stimulation in T cells, and is involved in the IL-7 signaling pathway leading to STAT1α and MAPK p44 phosphorylation. Tyrosine phosphorylation assay, kinase activation assay in T cell clone FEBS letters Medium 7957877
1995 Loss of JAK3 in knockout mice causes profound reductions in thymocytes and severe B and T cell lymphopenia (SCID phenotype), demonstrating that JAK3 is critical for γc cytokine signaling and lymphoid development. Gene targeting/knockout mouse, flow cytometry, functional lymphocyte assays Science High 7481769
1995 Homozygous JAK3 mutations (Tyr100Cys missense and a 151-bp deletion causing frameshift) in T-B+ SCID patients result in markedly reduced JAK3 protein levels, establishing that JAK3 loss-of-function causes autosomal recessive SCID in humans. Genetic sequencing of patient DNA, protein expression analysis Nature High 7659163
1995 JAK3-deficient mice show severe and specific defects in lymphoid cells (B cell precursors, thymocytes, T and B cells in spleen) with intact myeloid/erythroid colony formation, and T cells fail to respond to IL-2, IL-4, or IL-7. Homologous recombination knockout, flow cytometry, colony formation assay, cytokine response assays Immunity High 8777722
1995 JAK3 is physically associated with IL-4R and becomes tyrosine phosphorylated following IL-4 receptor triggering in human B cells, suggesting direct participation in IL-4 signal transduction. Co-immunoprecipitation, phosphorylation assays Oncogene Medium 7538655
1995 JAK3 is expressed in human monocytes and is tyrosine phosphorylated in response to IL-2, IL-4, and IL-7 (but not IFN-γ or GM-CSF), consistent with its association with common gamma-chain-containing receptors; JAK3 expression is strongly induced by IFN-γ or LPS. Immunoprecipitation, Western blot, phosphorylation assays in monocytes Journal of Experimental Medicine Medium 7535338
1995 JAK3 associates with the p85 subunit of PI3-kinase in an IL-7-dependent manner in T cells and mediates tyrosine phosphorylation of p85, thereby regulating IL-7-induced PI3-kinase activation and T cell proliferation. Co-immunoprecipitation, PI3-kinase activity assay, kinase inhibition, proliferation assay Blood Medium 7662955
1995 JAK3 is expressed in normal human B cells and is activated (tyrosine phosphorylated) by IL-4 and IL-7 stimulation; IL-4 activates both JAK3 and JAK1 phosphotransferase activity in B cells. Immunoprecipitation, kinase activity assays in B cells Journal of Immunology Medium 7594533
1996 IL-2-induced phosphorylation of IL-2Rβ, JAK1, and STAT5 all require JAK3, whereas IL-4-mediated phosphorylation of JAK1, STAT6, and IRS-1/2 does not require JAK3 but is enhanced by JAK3; this defines JAK3-dependent and JAK3-independent arms of cytokine signaling. JAK3-deficient B cell lines, Western blot for phosphorylation, cytokine stimulation Immunity High 8986719
1997 Tyrosine residue Y980 in the JAK3 kinase domain activation loop positively regulates kinase activity, while Y981 negatively regulates it; JAK3 autophosphorylates on multiple sites including Y980 and Y981, and optimal phosphorylation of other sites depends on Y980. Mutation Y980F reduces phosphorylation of substrates γc and STAT5A; Y981F has greatly increased kinase activity. Site-directed mutagenesis of Y980/Y981, kinase activity assays, substrate phosphorylation assays in vitro and in cells PNAS High 9391116
1997 Peripheral expression of JAK3 is required to maintain T lymphocyte function; restoration of JAK3 in the thymus (but loss in peripheral T cells) rescues T cell development including CD8+, γδ, and NK cells, but peripheral T cells lacking JAK3 remain functionally defective. Conditional reconstitution with retroviral JAK3 expression, flow cytometry, functional T cell assays Journal of Experimental Medicine High 9016869
1997 Several patient-derived JAK3 mutations in SCID result in specific biochemical defects: all four patients showed abnormal JAK3 tyrosine phosphorylation in response to IL-2 and IL-4, with absent IL-2-mediated STAT5 phosphorylation. A JH2 pseudokinase domain mutation (Cys759Arg) caused constitutive, unregulated JAK3 tyrosine phosphorylation unresponsive to serum starvation or cytokine stimulation. Patient-derived lymphoblastoid B cell lines, IL-2/IL-4 stimulation, Western blot for JAK3 and STAT5 phosphorylation Blood High 9354668
1999 JAK3 unilaterally transphosphorylates kinase-dead JAK1, but JAK1 cannot phosphorylate kinase-dead JAK3, suggesting JAK3 activation precedes JAK1 activation in the IL-2R system. JAK3 phosphorylates both IL-2Rβ and IL-2Rγc, while JAK1 phosphorylates only IL-2Rβ. JAK3 phosphorylates STAT3 and STAT5 but not STAT1, while JAK1 phosphorylates STAT1, STAT3, and STAT5, indicating differential substrate specificity. Recombinant baculovirus-produced kinase components, in vitro transphosphorylation assays, co-expression with receptor subunits Leukemia & lymphoma Medium 10037026
2001 JAK3 regulates T lymphopoiesis at least in part through selective regulation of Bax and Bcl-2: JAK3-deficient thymocytes have elevated Bax and reduced Bcl-2. Genetic deletion of Bax in JAK3-null mice markedly increases thymocyte and peripheral T-cell numbers, while deletion of p53 or Fas does not rescue lymphopenia, demonstrating Bax-dependent survival signaling downstream of JAK3. Genetic epistasis (JAK3/Bax double knockout mice), Bcl-2 retroviral rescue in bone marrow transplant, flow cytometry Molecular and Cellular Biology High 11134353
2001 JAK3 is a regulator of platelet function: thrombin induces tyrosine phosphorylation of JAK3 substrates STAT1 and STAT3 in platelets, and JAK3-deficient mouse platelets show decreased STAT1/STAT3 phosphorylation. JAK3 inhibition blocks thrombin-induced platelet shape change, degranulation/serotonin release, and aggregation. JAK3-deficient mouse platelets, pharmacological JAK3 inhibition (WHI-P131), phosphorylation assays, platelet aggregation assays, in vivo bleeding time Journal of Biological Chemistry Medium 11278899
2004 Jak3 is required for chemokine-induced migration of T-cell progenitors and thymocytes; bone marrow progenitors and thymocytes from Jak3-/- mice have decreased chemotactic responses to CXCL12 and CCL25. Jak3 is involved in signaling through CCR9 and CXCR4, and pharmacological Jak3 inhibition in wild-type cells decreases chemotactic responses, without affecting chemokine receptor mRNA levels. Jak3-/- mice, transwell migration assays, pharmacological JAK3 inhibition, RT-PCR for receptor expression Immunology Medium 15147562
2005 Jak3 deficiency enhances dendritic cell survival and increases production of IL-12 and IL-10 in response to TLR ligands, with enhanced Th1 differentiation in vivo; bone marrow-derived DCs from Jak3-/- mice develop normally in vitro but express lower levels of proapoptotic proteins. This identifies JAK3 as an unexpected negative regulator of DC cytokine production. Jak3-/- mice, bone marrow-derived DC culture, cytokine ELISA, flow cytometry, in vivo Th1 differentiation Blood Medium 16020505
2008 BLNK suppresses pre-B-cell leukemogenesis through direct binding to and inhibition of JAK3; BLNK-deficient pre-B leukemia cells have constitutively active JAK3/STAT5 signaling driven by autocrine IL-7, and exogenously expressed BLNK inhibited JAK3 signaling in a JAK3-binding-dependent manner. Co-immunoprecipitation of BLNK-JAK3, JAK3/STAT5 inhibition assays, retroviral reconstitution, BLNK-/- mouse model Blood High 19047679
2009 PP2A (but not PP1) counteracts serine/threonine phosphorylation of JAK3 and IL-2Rβ; inhibition of PP2A diminishes IL-2-induced tyrosine phosphorylation of IL-2Rβ, JAK3, and STAT5, and abolishes STAT5 DNA binding. Serine/threonine phosphorylation of IL-2Rβ by a staurosporine-sensitive kinase blocks its association with JAK3 and IL-2Rγ. Phosphoamino acid analysis, phosphatase inhibitor treatments (calyculin A), co-immunoprecipitation, EMSA for STAT5 DNA binding Journal of Biological Chemistry Medium 19923221
2009 Jak3 is involved in CCR7-mediated dendritic cell maturation and migration: Jak3-/- DCs show reduced co-stimulatory molecule expression and impaired chemotactic responses to CCL19/CCL21 in vitro and in vivo, with reduced capacity for DC-mediated T lymphocyte activation. Jak3-/- mice, flow cytometry, in vitro and in vivo migration assays, contact hypersensitivity experiment PloS one Medium 19759904
2011 NOTCH signaling promotes ubiquitination and degradation of JAK3 via a non-canonical dimeric E3 ligase complex (ASB2/SKP2 bridging Cullin1 and Cullin5). ASB2 interacts with the FERM and pseudo-kinase domains of JAK3, while SKP2 associates with the kinase domain. The R980W JAK3 mutant shows diminished SKP2 interaction and resistance to NOTCH/ASB2-induced degradation. Co-immunoprecipitation of JAK3 with ASB2/SKP2, dominant-negative Cullin mutants, ubiquitination assays, domain mapping Journal of Biological Chemistry High 21969365
2011 JAK3 inhibition potentiates myoblast differentiation; during differentiation, JAK3 is initially activated then decreases. JAK3 inhibition increases MHC, myogenin, MyoD, MEF2 expression and promotes myotube formation through antagonistic STAT1/STAT3 activities and modulation of AKT and ERK pathways. Pharmacological JAK3 inhibition (WHIp154), siRNA knockdown of JAK3, C2C12 myoblast differentiation assay, Western blot Cellular signalling Medium 22120524
2014 Tricyclic JAK3 inhibitors form a covalent interaction with Cys-909 in the active site of JAK3 and are irreversible, ATP-competitive inhibitors of JAK3 enzyme activity in vitro, with high selectivity against other JAK isoforms (exploiting the unique active-site cysteine of JAK3). In vitro enzyme inhibition assays, cell-based assays, selectivity profiling against kinase panel Journal of Biological Chemistry High 25552479
2015 JAK3 mediates IL-4/IL-13-induced STAT6 activation in monocytes, driving their differentiation into fibroblasts (α-SMA and ECM protein expression); JAK3 inhibition (CP690,550) or STAT6 deficiency abolishes this effect in vitro and in vivo in obstructed kidney model. Pharmacological JAK3 inhibition, STAT6 KO mice, bone marrow transplant with STAT6-/- donor cells, obstructive nephropathy model JASN Medium 26032813
2016 JAK3 kinase activity is required in two distinct temporal waves for IL-2-driven T cell proliferation: an early first wave and a more JAK3-sensitive second wave of STAT5 phosphorylation ~10-20 h after IL-2 stimulation. Selective inhibition of the second wave blocks cyclin expression and S-phase entry. A JAK3 inhibitor-resistant C905S mutant rescued all effects, confirming on-target specificity. Selective covalent JAK3 inhibitor (JAK3i), inhibitor-resistant JAK3 mutant (C905S), STAT5 phosphorylation time course, cell cycle analysis in primary CD4+ T cells and mice Nature Chemical Biology High 27018889
2017 Novel JAK3 pseudokinase domain mutations (H583Y, G589D) in extranodal NK/T-cell lymphoma are oncogenic and drive cytokine-independent proliferation in Ba/F3 cells, inhibitable by tofacitinib; these mutations are located at the pseudokinase-kinase domain interface based on structural modeling. Ba/F3 functional transformation assay, IL-3 independence assay, tofacitinib inhibition, structural modeling American Journal of Pathology Medium 28284718
2018 Cyanamide-based JAK3 inhibitors covalently engage Cys909 in the JAK3 active site (confirmed by crystallography and kinetic studies) and selectively inhibit JAK3, validating that selective JAK3 inhibition is sufficient to drive JAK1/JAK3-mediated cellular responses. X-ray crystallography, kinetic assays, LC-MS covalent modification confirmation, cell-based assays Journal of Medicinal Chemistry High 30423248
2019 PF-06651600 (ritlecitinib) is an irreversible JAK3 inhibitor that achieves selectivity by covalent interaction with unique Cys-909 in the JAK3 catalytic domain (replaced by serine in JAK1, JAK2, TYK2). The compound also inhibits TEC family kinases (BTK, BMX, ITK, RLK, TEC) via equivalent cysteines. Inhibition of cytolytic function in CD8+ T cells and NK cells by PF-06651600 is driven by TEC kinase inhibition. Biochemical selectivity profiling, covalent interaction mapping, cell-based cytolytic assays with kinase-selective rescues ACS Chemical Biology High 31082193
2020 JAK3 phosphorylates and inactivates Nedd4-2 (an E3 ubiquitin ligase), reducing Wnt3 ubiquitination and increasing Wnt3 protein levels, which activates Wnt3a/Dvl3/β-catenin signaling to suppress pro-inflammatory cytokine production in innate immune cells during P. gingivalis infection. Gain- and loss-of-function (JAK3 inhibition, Wnt3a inhibition), immunoprecipitation, in vitro and in vivo periodontal disease model, JAK3 inhibitor treatment FASEB Journal Medium 32433819
2021 In glioblastoma cells, CTRP8-RXFP1 signaling activates a JAK3-STAT3-Cdc42 axis that promotes F-actin remodeling, filopodia formation, and cell motility. JAK3 inhibition (tofacitinib) blocks Cdc42 activity and RXFP1-JAK3-STAT3-driven actin remodeling and migration. JAK3 inhibitor treatment, STAT3 inhibitor, F-actin/filopodia imaging, Cdc42 activity assays, GBM cell migration assays Molecular Oncology Medium 33960104
2021 Jak3 is expressed in bone marrow endothelial cells (not just hematopoietic cells), and Jak3-/- bone marrow niche is deleterious for maintenance of long-term repopulating hematopoietic stem cells (LT-HSCs); JAK3-overexpressing endothelial cells have increased capacity to expand LT-HSCs in vitro. Jak3-/- mice, endothelial cell sorting, LT-HSC co-culture assays, flow cytometry Communications Biology Medium 33767339
2022 Activating JAK3 mutations in T-ALL directly suppress mitochondrial apoptosis; pharmacological JAK3 inhibition reverses mitochondrial apoptotic blockade, reduces MEK, ERK, and BCL2 phosphorylation, and creates BCL2 dependence in JAK3-mutant T-ALL cells. JAK3 inhibitor combined with glucocorticoids showed synergy in vitro and in vivo. BH3 profiling, JAK3 inhibitors (mechanistically distinct), phosphorylation assays, in vivo mouse leukemia model Leukemia Medium 35411095
2016 PF-06651600 (JAK3-selective inhibitor) can inhibit Th1 and Th17 cell differentiation and preserves JAK1-dependent anti-inflammatory signaling (IL-10 suppression of LPS-induced TNFα/IL-1β), demonstrating functional differentiation of JAK3-selective vs. pan-JAK or JAK1-selective inhibition in immune cells. Cell-based Th1/Th17 differentiation assays, macrophage cytokine assays, rat adjuvant-induced arthritis model, mouse EAE model ACS Chemical Biology Medium 27791347
1996 The JAK3 gene consists of 19 exons and 18 introns and is localized to human chromosome 19p13.1; the kinase (JH1) and pseudokinase (JH2) domains have dissimilar genomic organization. Genomic sequencing, FISH chromosomal localization Genomics Medium 8921370
2011 JAK3 expression in activated cytotoxic T cells upregulates SGLT1 (Na+-coupled glucose carrier) activity by increasing SGLT1 protein abundance in the cell membrane, enhancing glucose uptake into activated lymphocytes. Dual electrode voltage clamp in Xenopus oocytes co-expressing JAK3 and SGLT1, glucose uptake assays, flow cytometry Cellular Physiology and Biochemistry Medium 27595398

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 689 7659163
1994 Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature 543 8022485
1994 Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science (New York, N.Y.) 541 7973659
1995 Defective lymphoid development in mice lacking Jak3. Science (New York, N.Y.) 538 7481769
1995 Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. Immunity 397 8777722
2008 Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 170 18559588
2016 Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS chemical biology 163 27791347
1994 JAK3: a novel JAK kinase associated with terminal differentiation of hematopoietic cells. Oncogene 133 7518579
2019 PF-06651600, a Dual JAK3/TEC Family Kinase Inhibitor. ACS chemical biology 126 31082193
1995 Regulation of JAK3 expression in human monocytes: phosphorylation in response to interleukins 2, 4, and 7. The Journal of experimental medicine 114 7535338
1997 Structural and functional basis for JAK3-deficient severe combined immunodeficiency. Blood 111 9354668
1996 Signaling via IL-2 and IL-4 in JAK3-deficient severe combined immunodeficiency lymphocytes: JAK3-dependent and independent pathways. Immunity 103 8986719
2015 JAK3/STAT6 Stimulates Bone Marrow-Derived Fibroblast Activation in Renal Fibrosis. Journal of the American Society of Nephrology : JASN 99 26032813
2008 BLNK suppresses pre-B-cell leukemogenesis through inhibition of JAK3. Blood 99 19047679
1997 Distinct tyrosine phosphorylation sites in JAK3 kinase domain positively and negatively regulate its enzymatic activity. Proceedings of the National Academy of Sciences of the United States of America 99 9391116
2006 Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma. Leukemia 96 16932349
2005 Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs. Immunological reviews 96 15661026
2004 Jak3 and the pathogenesis of severe combined immunodeficiency. Molecular immunology 95 15220007
2011 Malignant cutaneous T-cell lymphoma cells express IL-17 utilizing the Jak3/Stat3 signaling pathway. The Journal of investigative dermatology 93 21346774
2020 RNA Sequencing Keloid Transcriptome Associates Keloids With Th2, Th1, Th17/Th22, and JAK3-Skewing. Frontiers in immunology 81 33329590
2014 Tricyclic covalent inhibitors selectively target Jak3 through an active site thiol. The Journal of biological chemistry 81 25552479
2004 Mutations in genes required for T-cell development: IL7R, CD45, IL2RG, JAK3, RAG1, RAG2, ARTEMIS, and ADA and severe combined immunodeficiency: HuGE review. Genetics in medicine : official journal of the American College of Medical Genetics 81 14726805
2014 Recurrent mutation of JAK3 in T-cell prolymphocytic leukemia. Genes, chromosomes & cancer 79 24446122
2007 The specificity of JAK3 kinase inhibitors. Blood 79 18094329
2001 Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency. Human mutation 79 11668610
2000 Of genes and phenotypes: the immunological and molecular spectrum of combined immune deficiency. Defects of the gamma(c)-JAK3 signaling pathway as a model. Immunological reviews 78 11213805
2016 Essential biphasic role for JAK3 catalytic activity in IL-2 receptor signaling. Nature chemical biology 76 27018889
2015 Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma. Oncotarget 75 26244872
2009 JAK3: a two-faced player in hematological disorders. The international journal of biochemistry & cell biology 73 19747563
2021 Selective inhibition of JAK3 signaling is sufficient to reverse alopecia areata. JCI insight 72 33830087
1997 Peripheral expression of Jak3 is required to maintain T lymphocyte function. The Journal of experimental medicine 69 9016869
1995 Regulation of JAK3 expression and activation in human B cells and B cell malignancies. Journal of immunology (Baltimore, Md. : 1950) 68 7594533
1995 JAK3 protein tyrosine kinase mediates interleukin-7-induced activation of phosphatidylinositol-3' kinase. Blood 67 7662955
1997 The role of Jak3 in lymphoid development, activation, and signaling. Current opinion in immunology 64 9287175
2018 Identification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent Inhibitors. Journal of medicinal chemistry 58 30423248
2004 JAK3 inhibition, a viable new modality of immunosuppression for solid organ transplants. Trends in molecular medicine 55 15519279
1995 Protein kinases in human breast cancer. Breast cancer research and treatment 55 7612897
1994 JAK3 Janus kinase is involved in interleukin 7 signal pathway. FEBS letters 53 7957877
2001 Jak3 selectively regulates Bax and Bcl-2 expression to promote T-cell development. Molecular and cellular biology 52 11134353
2001 Role of a JAK3-dependent biochemical signaling pathway in platelet activation and aggregation. The Journal of biological chemistry 51 11278899
2014 Selective inhibitors of the Janus kinase Jak3--Are they effective? Bioorganic & medicinal chemistry letters 48 25217444
2005 Jak3 negatively regulates dendritic-cell cytokine production and survival. Blood 48 16020505
2017 Novel JAK3-Activating Mutations in Extranodal NK/T-Cell Lymphoma, Nasal Type. The American journal of pathology 47 28284718
2001 Unexpected and variable phenotypes in a family with JAK3 deficiency. Genes and immunity 47 11781709
2016 JAK3-STAT pathway blocking benefits in experimental lupus nephritis. Arthritis research & therapy 45 27278657
2017 Jak3 deficiency blocks innate lymphoid cell development. Mucosal immunology 44 28513593
2004 Impaired chemokine-induced migration during T-cell development in the absence of Jak 3. Immunology 43 15147562
2013 Inhibitors of JAK2 and JAK3: an update on the patent literature 2010 - 2012. Expert opinion on therapeutic patents 41 23367873
1998 T cell development and activation in Jak3-deficient mice. Journal of leukocyte biology 40 9620658
2014 Cooperating JAK1 and JAK3 mutants increase resistance to JAK inhibitors. Blood 39 25352124
2009 Protein phosphatase 2A regulates interleukin-2 receptor complex formation and JAK3/STAT5 activation. The Journal of biological chemistry 39 19923221
1999 Dysregulated myelopoiesis in mice lacking Jak3. Blood 38 10419884
2015 Oncostatin M Promotes Osteoblastic Differentiation of Human Vascular Smooth Muscle Cells Through JAK3-STAT3 Pathway. Journal of cellular biochemistry 36 25735629
2021 PHF6 and JAK3 mutations cooperate to drive T-cell acute lymphoblastic leukemia progression. Leukemia 35 34465864
1996 Genomic sequence, organization, and chromosomal localization of human JAK3. Genomics 35 8921370
2018 Discovery of a highly selective JAK3 inhibitor for the treatment of rheumatoid arthritis. Scientific reports 34 29588471
2018 B-cell differentiation and IL-21 response in IL2RG/JAK3 SCID patients after hematopoietic stem cell transplantation. Blood 34 29728406
2023 Improvements in immune/melanocyte biomarkers with JAK3/TEC family kinase inhibitor ritlecitinib in vitiligo. The Journal of allergy and clinical immunology 33 37777018
2004 Is JAK3 a new drug target for immunomodulation-based therapies? Trends in pharmacological sciences 33 15491777
2023 JAK3 inhibitor suppresses multipotent ILC2s and attenuates steroid-resistant asthma. Science advances 32 38117887
2017 Recent advances in JAK3 inhibition: Isoform selectivity by covalent cysteine targeting. Bioorganic & medicinal chemistry letters 31 28844493
1999 Differential substrate recognition capabilities of Janus family protein tyrosine kinases within the interleukin 2 receptor (IL2R) system: Jak3 as a potential molecular target for treatment of leukemias with a hyperactive Jak-Stat signaling machinery. Leukemia & lymphoma 31 10037026
2010 Recent patents in the discovery of small molecule inhibitors of JAK3. Expert opinion on therapeutic patents 29 20402545
2009 Jak3 is involved in dendritic cell maturation and CCR7-dependent migration. PloS one 29 19759904
2006 Oncostatin M decreases adiponectin expression and induces dedifferentiation of adipocytes by JAK3- and MEK-dependent pathways. The international journal of biochemistry & cell biology 29 17081797
2005 Jak3 activation is significantly associated with ALK expression in anaplastic large cell lymphoma. Human pathology 28 16153455
2018 LncRNA-Jak3:Jak3 coexpressed pattern regulates monosodium urate crystal-induced osteoclast differentiation through Nfatc1/Ctsk expression. Environmental toxicology 27 30387921
1997 JAK3: expression and mapping to chromosome 19p12-13.1. Experimental hematology 27 9168059
2003 JAK3 inhibition as a new concept for immune suppression. Current opinion in investigational drugs (London, England : 2000) 26 14758768
1995 JAK3 associates with the human interleukin 4 receptor and is tyrosine phosphorylated following receptor triggering. Oncogene 26 7538655
2011 JAK3 in clear cell renal cell carcinoma: mutational screening and clinical implications. Urologic oncology 25 21868263
2004 Therapeutic potential of Janus kinase 3 (JAK3) inhibitors. Current pharmaceutical design 25 15180539
2021 Novel CTRP8-RXFP1-JAK3-STAT3 axis promotes Cdc42-dependent actin remodeling for enhanced filopodia formation and motility in human glioblastoma cells. Molecular oncology 24 33960104
2019 JAK3-selective inhibitor peficitinib for the treatment of rheumatoid arthritis. Expert review of clinical pharmacology 24 31059310
2011 A mechanism underlying NOTCH-induced and ubiquitin-mediated JAK3 degradation. The Journal of biological chemistry 23 21969365
2022 JAK3 inhibitors for the treatment of inflammatory and autoimmune diseases: a patent review (2016-present). Expert opinion on therapeutic patents 21 34949146
2022 JAK3 mutations and mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia. Leukemia 21 35411095
2011 Inhibition of the signalling kinase JAK3 alleviates inflammation in monoarthritic rats. British journal of pharmacology 21 21434883
2011 Targeting JAK3 in kidney transplantation: current status and future options. Current opinion in organ transplantation 21 21971513
2000 Molecular modeling of the Jak3 kinase domains and structural basis for severe combined immunodeficiency. Clinical immunology (Orlando, Fla.) 20 10900158
2024 Janus Kinase 3 (JAK3): A Critical Conserved Node in Immunity Disrupted in Immune Cell Cancer and Immunodeficiency. International journal of molecular sciences 19 38474223
2022 CCL2-targeted ginkgolic acid exerts anti-glioblastoma effects by inhibiting the JAK3-STAT1/PI3K-AKT signaling pathway. Life sciences 19 36396110
2020 JAK3 restrains inflammatory responses and protects against periodontal disease through Wnt3a signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 32433819
2017 Selective Downregulation of JAK2 and JAK3 by an ATP-Competitive pan-JAK Inhibitor. ACS chemical biology 19 28318222
2016 Compounds from Polyphaga plancyi and their inhibitory activities against JAK3 and DDR1 kinases. Fitoterapia 19 27642041
2019 Design and synthesis of boron-containing diphenylpyrimidines as potent BTK and JAK3 dual inhibitors. Bioorganic & medicinal chemistry 18 31843459
2019 IL-7-Mediated IL-7R-JAK3/STAT5 signalling pathway contributes to chemotherapeutic sensitivity in non-small-cell lung cancer. Cell proliferation 17 31599032
2017 Design and Synthesis of a Highly Selective JAK3 Inhibitor for the Treatment of Rheumatoid Arthritis. Archiv der Pharmazie 17 28944566
2016 Expression of JAK3 Sensitive Na+ Coupled Glucose Carrier SGLT1 in Activated Cytotoxic T Lymphocytes. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 17 27595398
2016 Transforming Mutations of Jak3 (A573V and M511I) Show Differential Sensitivity to Selective Jak3 Inhibitors. Clinical cancer drugs 17 29046866
2020 IL-21 promotes osteoblastic differentiation of human valvular interstitial cells through the JAK3/STAT3 pathway. International journal of medical sciences 16 33173427
2010 JAK3 pathway is constitutively active in B-lineage acute lymphoblastic leukemia. Expert review of anticancer therapy 16 21070101
2010 Absence of gain-of-function JAK1 and JAK3 mutations in adult T cell leukemia/lymphoma. International journal of hematology 15 20697856
2004 Janus kinase-3 (JAK3) inhibition: a novel immunosuppressive option for allogeneic transplantation. Transplant international : official journal of the European Society for Organ Transplantation 15 15368094
2024 Melatonin enhances NK cell function in aged mice by increasing T-bet expression via the JAK3-STAT5 signaling pathway. Immunity & ageing : I & A 14 39237911
2021 Endothelial Jak3 expression enhances pro-hematopoietic angiocrine function in mice. Communications biology 14 33767339
2019 Current Status in the Discovery of Covalent Janus Kinase 3 (JAK3) Inhibitors. Mini reviews in medicinal chemistry 14 31288716
2011 Role of JAK3 in myogenic differentiation. Cellular signalling 14 22120524
2006 Targeting JAK3 and BTK tyrosine kinases with rationally-designed inhibitors. Current drug targets 14 16515530
2005 Activation of the Jak3 pathway and myeloid differentiation. Leukemia & lymphoma 14 15621777

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