Affinage

JAK1

Tyrosine-protein kinase JAK1 · UniProt P23458

Round 2 corrected
Length
1154 aa
Mass
133.3 kDa
Annotated
2026-04-28
130 papers in source corpus 36 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

JAK1 is a non-receptor tyrosine kinase that serves as an obligatory signaling intermediate for three major cytokine receptor families—class II cytokine receptors (IFN-α/β, IFN-γ), γc-containing receptors (IL-2, IL-4, IL-7, IL-9), and gp130-containing receptors (IL-6 family)—and is essential for vertebrate viability (PMID:9590172). JAK1 constitutively associates with cytokine receptor subunits (gp130, IL-2Rβ, IFNAR) via its N-terminal FERM domain and, upon ligand-induced receptor dimerization, undergoes trans-phosphorylation with a partner JAK (JAK2, JAK3, or TYK2) to phosphorylate STAT transcription factors (STAT1, STAT3, STAT5, STAT6), with isoform specificity determined primarily by receptor-binding domains rather than kinase catalytic selectivity (PMID:8272872, PMID:7973659, PMID:9001223). JAK1 activity is allosterically regulated by its pseudokinase (JH2) domain, which is required for both basal autoinhibition and cytokine-induced activation, and is further tuned by post-translational modifications including covalent cysteine modification by itaconate at C715/C816/C943/C1130, acetylation at K1109 by HDAC1, viral PB2-directed ubiquitination at K859/K860, and competitive receptor-proximal regulators such as SOCS1 and TRAF6 (PMID:31892268, PMID:35235776, PMID:36097295, PMID:36271046, PMID:39384195, PMID:21155952). Beyond canonical JAK-STAT signaling, JAK1 phosphorylates non-STAT substrates including PD-L1 (Tyr112) to stabilize its glycosylation and promote immune evasion, and Sirt1 (Tyr280/301) to establish a negative-feedback loop on STAT3 transcriptional activity (PMID:31305264, PMID:29789426).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1993 High

    Establishing that JAK1 is genetically required for interferon signaling resolved whether individual JAK family members have non-redundant roles, demonstrating that JAK1 is indispensable for both IFN-α/β and IFN-γ responses through reciprocal dependence with TYK2 and JAK2, respectively.

    Evidence Genetic complementation of JAK1-deficient mutant cell lines with JAK1 cDNA; interferon signaling assays

    PMID:8232552

    Open questions at the time
    • Mechanism of JAK1 activation at the receptor was unknown
    • No in vivo demonstration of JAK1 requirement
  2. 1994 High

    Identification of constitutive JAK1 association with gp130, IL-2Rβ, and LIF receptor β subunits established the paradigm that JAK1 pre-assembles on diverse cytokine receptor chains and is activated by ligand-induced receptor dimerization, explaining how a single kinase services multiple receptor families.

    Evidence Co-immunoprecipitation and tyrosine phosphorylation assays in IL-6-, IL-2-, and CNTF/LIF-stimulated cells; reconstitution in JAK3-negative fibroblasts

    PMID:7973658 PMID:7973659 PMID:8272872 PMID:8272873

    Open questions at the time
    • Structural basis of JAK1-receptor interaction was unresolved
    • Which STAT transcription factors are direct JAK1 substrates was unclear
  3. 1997 High

    Chimeric JAK1/JAK2 constructs and dominant-negative kinase mutants demonstrated that receptor specificity resides in JAK N-terminal domains rather than kinase catalytic selectivity, and established that JAK1 acts upstream of TYK2 in IFN-α signaling, defining the epistatic order of JAK activation.

    Evidence Chimeric JAK1/JAK2 complementation in JAK-deficient cell lines; dominant-negative kinase-dead JAK1 with IFN-α reporter assays

    PMID:9001223 PMID:9212064 PMID:9249040

    Open questions at the time
    • Role of the pseudokinase domain in JAK1 regulation was not yet understood
    • In vivo consequences of JAK1 loss were unknown
  4. 1998 High

    JAK1 knockout mice die perinatally with failure to respond to class II cytokine receptors, γc-containing receptors, and gp130-containing receptors, establishing the non-redundant in vivo requirement for JAK1 across three major receptor families and distinguishing its role from JAK2 and JAK3.

    Evidence JAK1 germline knockout mice; ex vivo cytokine response assays across multiple pathways

    PMID:9590172

    Open questions at the time
    • Conditional tissue-specific requirements were unexplored
    • Mechanism of perinatal lethality was not fully defined
  5. 2007 High

    Demonstration that JAK1-STAT1-STAT3 downstream of LIF maintains myoblast proliferation and prevents premature differentiation expanded JAK1 function beyond immunity into developmental biology and stem/progenitor cell regulation.

    Evidence siRNA knockdown of JAK1/STAT1/STAT3 in primary myoblasts; differentiation and proliferation assays

    PMID:17908914

    Open questions at the time
    • Whether JAK1 has kinase-independent scaffolding roles in myoblasts was not addressed
    • In vivo muscle regeneration phenotype was not tested
  6. 2010 Medium

    Discovery that TRAF6 competes with JAK1 for the same IL-2Rβ binding site revealed a receptor-proximal competitive inhibition mechanism governing JAK1 activation, broadening the regulatory logic beyond SOCS-mediated feedback.

    Evidence TRAF6-knockout MEFs; IL-2Rβ binding-site mutagenesis; JAK1 phosphorylation assays

    PMID:21155952

    Open questions at the time
    • Generality of competitive receptor-site regulation for other JAK1-associated receptors was unknown
    • In vivo immune consequences of TRAF6-JAK1 competition not tested
  7. 2016 High

    Gain-of-function JAK1 mutations in mice causing pruritic dermatitis with Th2 skewing, loss-of-function JAK1/2 mutations in tumors conferring anti-PD-1 resistance, and AJUBA-mediated sequestration of JAK1 from IFN-γR collectively established JAK1 as a critical node in immune surveillance and tumor immune evasion.

    Evidence JAK1 gain-of-function knock-in mice; JAK1-mutant melanoma cell lines with IFN-γ stimulation; AJUBA-JAK1 FERM domain co-IP and STAT1 phosphorylation assays

    PMID:27111231 PMID:27893714 PMID:27903500

    Open questions at the time
    • Full spectrum of JAK1 somatic mutations in human cancer was not catalogued
    • Whether AJUBA regulation is tissue-specific was unresolved
  8. 2018 Medium

    Identification of Sirt1 (Y280/Y301) as a direct JAK1 substrate that feeds back to suppress STAT3 acetylation revealed a non-STAT substrate that creates a negative-feedback loop within IL-6/JAK1/STAT3 signaling.

    Evidence Site-directed mutagenesis of Sirt1 phosphorylation sites; IL-6 stimulation; STAT3 acetylation assays

    PMID:29789426

    Open questions at the time
    • In vivo physiological relevance of Sirt1 phosphorylation by JAK1 not demonstrated
    • Whether other HDAC family members are JAK1 substrates was unknown
  9. 2019 High

    Discovery that JAK1 phosphorylates PD-L1 at Tyr112 to recruit STT3A glycosyltransferase and stabilize PD-L1, combined with demonstration that JAK1 pseudokinase domain is essential for IL-2/STAT5 and IFN-γ/STAT1 signaling, advanced understanding of both non-STAT substrates and allosteric JH2-dependent regulation.

    Evidence In vitro kinase assays, PD-L1 Y112 mutagenesis, STT3A co-IP, in vivo anti-IL-6 combination therapy; JH2 structure-based mutagenesis in JAK-deficient cell lines

    PMID:31305264 PMID:31892268

    Open questions at the time
    • Whether PD-L1 Tyr112 phosphorylation occurs in all tumor types was unresolved
    • Crystal structure of full-length JAK1 with JH2-JH1 interface was lacking
  10. 2019 High

    Conditional JAK1 deletion in NK cells revealed a non-redundant requirement for JAK1 (but not JAK2) in NK cell development, survival, and tumor surveillance, clarifying tissue-specific JAK isoform dependencies within innate immunity.

    Evidence Conditional Jak1 knockout in NKp46+ cells; flow cytometry; tumor surveillance assays

    PMID:30671064

    Open questions at the time
    • Specific cytokine(s) driving JAK1-dependent NK survival not fully defined
    • Whether JAK1 has kinase-independent roles in NK cells was untested
  11. 2022 High

    Identification of druggable allosteric cysteine C817 in the JAK1 pseudokinase domain, and covalent modification of multiple JAK1 cysteines by itaconate, established that JAK1 can be selectively inhibited through non-active-site mechanisms, opening isoform-selective therapeutic strategies.

    Evidence Chemical proteomics with electrophilic compounds; C817A mutagenesis; itaconate covalent modification of C715/C816/C943/C1130 with kinase activity assays and in vivo M2 macrophage polarization

    PMID:35235776 PMID:36097295

    Open questions at the time
    • In vivo efficacy and selectivity of C817-targeting compounds not yet established in disease models
    • Whether endogenous itaconate concentrations reach inhibitory thresholds in tissues was unknown
  12. 2022 Medium

    Demonstrations that influenza PB2 targets JAK1 K859/K860 for ubiquitination, EHBP1L1 competes with SOCS1 to stabilize JAK1, and HDAC1 deacetylates K1109 to prevent proteasomal degradation collectively revealed a complex post-translational regulatory network controlling JAK1 protein stability.

    Evidence Ubiquitination assays for PB2-JAK1; SOCS1-EHBP1L1 competition co-IPs; mass spectrometry identification of K1109 acetylation; proteasome inhibitor assays

    PMID:36271046 PMID:36775874 PMID:39384195

    Open questions at the time
    • Whether K859/K860 ubiquitination and K1109 acetylation are coordinated or independent was unknown
    • E3 ligase mediating PB2-directed ubiquitination not identified
  13. 2024 Medium

    Discovery of a non-canonical JAK1 activation mechanism (chemotherapy-induced SQ phosphorylation releasing JH2 autoinhibition) driving STAT6-GAS6 chemoresistance, and STING-dependent facilitation of JAK1 phosphorylation in endothelial cells, revealed context-dependent activation modes beyond canonical receptor-driven trans-phosphorylation.

    Evidence Phospho-profiling and JAK1 filgotinib inhibition in Ewing sarcoma; STING-JAK1 co-IP with C91 palmitoylation mutagenesis in endothelial cells

    PMID:38906855 PMID:39817453

    Open questions at the time
    • Structural basis of SQ-site-mediated JH2 release not resolved
    • Whether STING-JAK1 interaction occurs in non-endothelial cell types was untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of full-length JAK1 showing the complete JH1-JH2-FERM-SH2 domain architecture in an autoinhibited state, together with systematic identification of the full non-STAT substrate repertoire, remains unresolved.
  • No full-length JAK1 crystal or cryo-EM structure published
  • Comprehensive non-STAT substrate identification by unbiased phosphoproteomics is lacking
  • Tissue-specific JAK1 functions beyond immune and muscle lineages are poorly defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005829 cytosol 4
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-168256 Immune System 8 R-HSA-1643685 Disease 7 R-HSA-1266738 Developmental Biology 2
Partners
AJUBAEHBP1L1JAK2JAK3SOCS1STAT1STAT3TYK2

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 JAK1 is required for both interferon-alpha/beta and interferon-gamma signal transduction; a JAK1-deficient cell line is completely defective in interferon response, and complementation with JAK1 restores it. JAK1 and TYK2 show reciprocal interdependence in IFN-alpha signaling, and JAK1 and JAK2 show reciprocal interdependence in IFN-gamma signaling, likely reflecting requirements for correct assembly of interferon receptor complexes. Genetic complementation of JAK1-deficient mutant cell lines with JAK1 cDNA; functional interferon signaling assays Nature High 8232552
1994 JAK1 constitutively associates with the IL-6 signal transducer gp130, and upon IL-6 stimulation, JAK1 is tyrosine phosphorylated and the transcription factor APRF (STAT3) associates with gp130, establishing JAK1 as a direct component of IL-6/gp130 receptor signaling. Co-immunoprecipitation, tyrosine phosphorylation assays in IL-6-stimulated cells Science High 8272872
1994 JAK1 selectively associates with the serine-rich region of the IL-2 receptor beta chain (IL-2Rβ), while JAK3 associates with the gamma-c chain; both regions are necessary for IL-2 signaling, and JAK1 and JAK3 are functionally activated by this selective receptor association. Co-immunoprecipitation of JAK1/JAK3 with IL-2R subunits; functional reconstitution in Jak3-negative fibroblasts Science High 7973658 7973659
1994 JAK1 (along with JAK2, JAK3, and TYK2) constitutively associates with the beta receptor components (gp130 and LIF receptor beta) of the CNTF/LIF/OSM/IL-6 cytokine family receptors, and kinase activation occurs upon ligand-induced dimerization of these receptor components. Biochemical association assays; ligand-induced receptor dimerization studies Science High 8272873
1997 In IFN-gamma signaling, JAK1-JAK2 chimera studies reveal that the amino-terminal region of JAK2 (not the pseudokinase domain) is required for association with the IFN-gamma receptor subunit and STAT1 activation. A JAK1-JAK2 chimera containing JAK1 amino-terminal domains linked to JAK2 pseudokinase and kinase domains can reconstitute JAK-STAT signaling in JAK1-deficient U4C cells, indicating that JAK isoform specificity lies primarily in structural receptor interactions rather than substrate specificity of the kinase domains. Chimeric JAK1/JAK2 constructs expressed in JAK-deficient mutant cell lines; complementation assays Molecular and cellular biology High 9001223
1997 JAK2 but not JAK1 is required for prolactin-induced receptor phosphorylation, STAT activation, and beta-lactoglobulin induction; JAK1 is phosphorylated in response to prolactin but is dispensable for PRL-dependent signaling in this pathway. JAK1-, JAK2-, and STAT1-deficient mutant cell lines; functional complementation; beta-lactoglobulin transcription assay Molecular endocrinology High 9212064
1997 Kinase-deficient (dominant-negative) mutants of JAK1 suppress IFN-alpha-induced transcription and STAT phosphorylation independently, and Jak1 functions upstream of Tyk2 in the IFN-alpha signaling cascade. Dominant-negative kinase-deficient mutants; IFN-alpha-dependent reporter-gene assay; STAT phosphorylation analysis European journal of biochemistry High 9249040
1998 JAK1 knockout mice are runted, fail to nurse, and die perinatally. JAK1-deficient cells fail to manifest biological responses to cytokines utilizing class II cytokine receptors (IFN-alpha/beta, IFN-gamma), gamma-c-containing receptors (IL-2, IL-4, IL-7, IL-9), and gp130-containing receptors (IL-6 family), demonstrating JAK1 plays an obligatory and non-redundant role in signaling through these three receptor families. JAK1 germline knockout mice; cytokine response assays in JAK1-null cells Cell High 9590172
1998 The hepatitis B virus X protein (HBx) physically interacts with JAK1 protein, specifically elevating JAK1 tyrosine phosphorylation and in vitro kinase activity (but not JAK2 or TYK2), leading to constitutive activation of STAT3 and STAT5 and STAT-dependent transcription. Stable HBx-expressing cell lines; in vitro kinase assay; protein-protein interaction (co-immunoprecipitation) The Journal of biological chemistry Medium 9738022
2003 JAK1 deficiency in v-Abl-transformed pre-B cells impairs IFN-gamma-induced growth arrest and apoptosis but does not affect in vitro transformation itself, demonstrating that JAK1 mediates an intrinsic IFN-gamma-dependent tumor surveillance mechanism rather than promoting tumorigenesis. JAK1-deficient cells; v-Abl transformation; tumor transplantation into SCID and nude mice; IFN-gamma response assays Blood High 12576323
2007 JAK1-STAT1-STAT3 constitutes a signaling pathway downstream of leukemia inhibitory factor that promotes myoblast proliferation and prevents premature differentiation. JAK1 knockdown in primary and immortalized myoblasts induces precocious differentiation with accelerated induction of MyoD, MEF2, p21Cip1, p27Kip1, and faster Id1 downregulation. siRNA knockdown of JAK1/STAT1/STAT3 in primary and immortalized myoblasts; differentiation and proliferation assays The Journal of cell biology High 17908914
2011 Activating mutations in the JAK1 hinge region (Phe958, Pro960) render JAK1 constitutively active and confer resistance to ATP-competitive JAK inhibitors. Mutation of the homologous Tyr931 in JAK2 similarly confers resistance. These mutations promote autonomous cell proliferation via JAK-STAT pathway activation. Spontaneous cellular transformation screen; sequencing of JAK1 mutants; cell proliferation assays; inhibitor sensitivity testing Haematologica Medium 21393331
2014 ER stress activates the JAK1/STAT3 inflammatory axis in astrocytes in a PERK-dependent manner; JAK1 phosphorylates PERK, and disruption of PERK abrogates ER stress-induced STAT3 activation and downstream IL-6/chemokine gene expression. This defines a PERK/JAK1/STAT3 feed-forward neuroinflammatory loop. Pharmacological ER stress induction; JAK1 inhibition; PERK knockdown; co-immunoprecipitation; phosphorylation assays in glial cells and EAE mouse model Molecular and cellular biology Medium 25113558
2016 JAK1/2 loss-of-function mutations in tumor cells ablate IFN-gamma receptor signaling, preventing interferon-gamma-induced PD-L1 expression and leading to primary resistance to anti-PD-1 immunotherapy. Analysis of JAK1/2-mutant melanoma cell lines; IFN-gamma stimulation assays; PD-L1 expression measurement Cancer discovery High 27903500
2016 A gain-of-function single amino acid substitution in JAK1 (in the tyrosine kinase domain) in mice leads to hyperactivation of JAK1, causing overexpression of skin serine proteases, disruption of skin barrier function, and spontaneous pruritic dermatitis with a Th2-biased immune response. Knock-in mouse model; pharmacological JAK1 inhibition; protease expression analysis; skin barrier function assays The Journal of clinical investigation High 27111231
2016 The LIM protein AJUBA specifically binds the FERM domain of JAK1, dissociating JAK1 from the IFN-gamma receptor and thereby inhibiting STAT1 phosphorylation and nuclear translocation, suppressing IFN-gamma-induced IFIT2 expression and apoptosis in colorectal cancer cells. Co-immunoprecipitation; domain mapping; STAT1 phosphorylation assays; gene expression analysis Oncogene Medium 27893714
2018 JAK1 directly phosphorylates Sirt1 at tyrosine residues 280 and 301 (located in the histone deacetylase catalytic domain) in response to IL-6 stimulation; this phosphorylation promotes Sirt1 interaction with STAT3 and enhances Sirt1 suppression of STAT3 acetylation and transcriptional activity, constituting a negative feedback loop of the JAK1-STAT3 pathway. Co-immunoprecipitation; site-directed mutagenesis; IL-6 stimulation assays; STAT3 acetylation assays The Journal of biological chemistry Medium 29789426
2019 IL-6-activated JAK1 phosphorylates PD-L1 at Tyr112, which recruits the ER-associated N-glycosyltransferase STT3A to catalyze PD-L1 glycosylation and maintain PD-L1 protein stability, thereby promoting cancer immune evasion. In vitro kinase assay; phosphorylation site mutagenesis; glycosylation assays; Co-IP of JAK1-PD-L1-STT3A; animal model with anti-IL-6 combination therapy The Journal of clinical investigation High 31305264
2019 In CML stem cells, JAK1 (not JAK2) is the STAT3-activating kinase mediating therapy-resistant, IL-6-driven extrinsic STAT3 activation; selective JAK1 inhibition plus Bcr-Abl inhibition reduces colony formation, proliferation, and induces apoptosis even in quiescent leukemic stem cells. JAK1/2-selective inhibitors; genetic inactivation of JAK1; IL-6-blocking peptide; primary human CD34+ CML cells; transgenic CML mouse model Leukemia Medium 30842608
2019 JAK1 is required for NK cell development and peripheral NK cell survival; conditional deletion of JAK1 (but not JAK2) in NKp46+ NK cells leads to near-complete loss of NK cells in spleen, blood, and liver and impaired NK cell-mediated tumor surveillance, demonstrating a non-redundant role for JAK1 in NK cell biology. Conditional knockout mice (Jak1Ncr1Cre); flow cytometry; tumor surveillance assays Frontiers in immunology High 30671064
2019 The JAK1 pseudokinase domain (JH2) is essential for IL-2-induced STAT5 activation (both JH1 and JH2 required), whereas in IFN-gamma signaling, JAK1 JH2 rather than kinase activity is required for STAT1 activation. Mutation of L633 in the JH2 αC-helix reduces basal and cytokine-induced STAT activation, and de-stabilization of JH2 ATP-binding disturbs the regulatory JH1-JH2 interaction. JAK-deficient cell lines; structure-based mutagenesis; cytokine signaling assays for IL-2, IFN-gamma, IFN-alpha Cancers Medium 31892268
2021 SARS-CoV-2 infection of lung epithelial cells induces complement gene expression through the interferon-JAK1/2-STAT1 signaling axis; ruxolitinib (a JAK1/2 inhibitor) normalizes interferon signature genes and complement transcripts induced by SARS-CoV-2 in lung epithelial cell lines, and inhibits C3a protein production, but does not affect NF-κB-regulated genes. SARS-CoV-2 infection of lung epithelial cell lines; JAK1/2 inhibitor treatment; transcriptomics; complement protein measurement Science immunology Medium 33827897
2022 Itaconate and its derivative 4-octyl itaconate (OI) directly modify JAK1 by covalent modification at multiple cysteine residues (C715, C816, C943, C1130), inhibit JAK1 kinase activity, and suppress JAK1 and STAT6 phosphorylation in response to IL-4, IL-13, IFN-beta, and IFN-gamma, thereby inhibiting M2 macrophage polarization in vitro and in vivo. Direct biochemical modification assay; JAK1 kinase activity assay; phosphorylation analysis; in vivo M2 macrophage polarization model Cell metabolism High 35235776
2022 An isoform-restricted allosteric cysteine (C817) in the JAK1 pseudokinase domain (absent from JAK2 and JAK3, but also present as C838 in TYK2) is druggable by electrophilic compounds; covalent engagement of C817 blocks JAK1-dependent trans-phosphorylation and cytokine signaling without impairing JAK2-dependent cytokine signaling. C817A JAK1 mutant cells are insensitive to these allosteric inhibitors. Chemical proteomics (activity-based protein profiling); electrophilic compound library screen; C817A mutagenesis; JAK1-dependent vs. JAK2-dependent cytokine signaling assays Nature chemical biology High 36097295
2022 The influenza A virus PB2 protein targets mammalian JAK1 at lysine residues K859 and K860 for ubiquitination and proteasomal degradation, reducing cellular sensitivity to IFNs by suppressing STAT1/STAT2 activation and ISG expression. Co-immunoprecipitation; ubiquitination assays; JAK1 degradation assays; IFN signaling readouts Nature communications Medium 36271046
2022 JAK1 directly interacts with the TGF-beta receptor I subunit (TβRI) in lung fibroblasts; constitutively active STAT3 (requiring JAK1) represses myofibroblast transdifferentiation, while transcriptional silencing of unphosphorylated STAT3 suppresses TGF-beta/SMAD3 signaling and reduces myofibroblast differentiation, establishing noncanonical JAK1/STAT3 regulation of TGF-beta fibrotic signaling. Co-immunoprecipitation of JAK1 with TβRI; siRNA silencing; pharmacological JAK1 inhibition (upadacitinib); primary human lung fibroblasts; in vivo fibrosis model American journal of physiology. Lung cellular and molecular physiology Medium 36283961
2022 DPYSL2 (dihydropyrimidinase-like 2) interacts with JAK1, and this binding is required for JAK1-dependent STAT3 activation and subsequent vimentin expression, promoting breast cancer cell migration and metastasis. Co-immunoprecipitation; DPYSL2 knockout; STAT3 phosphorylation assays; cell migration and invasion assays; in vivo metastasis model The Journal of cell biology Medium 35575798
2023 EHBP1L1 interacts with and stabilizes JAK1 protein by competing with SOCS1 for JAK1 binding, thereby protecting JAK1 from proteasomal degradation, elevating JAK1/STAT1/PD-L1 signaling, and forming an immunosuppressive tumor microenvironment in renal cell carcinoma. Co-immunoprecipitation; proteasome inhibitor assays; SOCS1 competition assays; EHBP1L1 depletion; in vivo PDX models Advanced science Medium 36775874
2024 HDAC1 deacetylates JAK1 at lysine 1109; HDAC1 inhibition by SAHA increases K1109 acetylation of JAK1, promoting its proteasomal degradation and reducing STAT3-driven FGL1 transcription, thereby enhancing antitumor CD8+ T cell immunity in lung adenocarcinoma. Co-immunoprecipitation; mass spectrometry; chromatin immunoprecipitation; acetylation assays; proteasome degradation assays; in vivo mouse tumor models Journal for immunotherapy of cancer Medium 39384195
2024 IFN-I stimulation induces physical interaction between STING and JAK1 in endothelial cells, promoting JAK1 phosphorylation in a manner requiring STING palmitoylation at Cysteine 91 (but not STING's C-terminal tail domain); STING acts downstream of IFNAR in endothelium to facilitate JAK1-STAT signaling and tumor vessel normalization. Co-immunoprecipitation of STING and JAK1; STING palmitoylation site mutagenesis (C91); IFN-I signaling assays in endothelial cells; in vivo tumor models The Journal of clinical investigation Medium 39817453
2024 Chemotherapy-induced JAK1-SQ phosphorylation releases JAK1 pseudokinase domain inhibition, enabling an alternative non-canonical JAK1 activation mechanism that leads to STAT6 nuclear translocation, transcription and secretion of the TAM kinase ligand GAS6, and autocrine/paracrine chemoresistance in Ewing sarcoma. Phospho-profiling; JAK1 filgotinib inhibition; STAT6 nuclear translocation assays; GAS6 secretion assays; in vitro and in vivo chemosensitization studies Nature communications Medium 38906855
2010 TRAF6 negatively regulates IL-2-induced JAK1-Erk pathway activation by binding to a site on the IL-2R beta chain that overlaps with the JAK1-binding site; a beta-chain mutation that inactivates TRAF6 binding but retains JAK1 binding abrogates TRAF6-dependent reduction in JAK1 activation, demonstrating competitive regulation of JAK1 at the receptor. TRAF6-knockout cells; IL-2 signaling reconstitution in MEF cells; beta-chain binding site mutagenesis; Jak1 phosphorylation assays Genes to cells Medium 21155952
2020 TROY (an orphan TNF receptor superfamily member) physically interacts with JAK1, and increased TROY expression increases JAK1 phosphorylation; TROY-mediated STAT3 phosphorylation and transcriptional activity are dependent on JAK1, as JAK1 inhibition by ruxolitinib or JAK1 siRNA knockdown significantly inhibits TROY-induced STAT3 activation and GBM cell migration. Co-immunoprecipitation of TROY and JAK1; JAK1 siRNA knockdown; ruxolitinib treatment; STAT3 phosphorylation and transcriptional activity assays; cell migration assays Neoplasia Medium 32629176
2016 Generation of conditional Jak1 knockout mice confirmed that JAK1 deficiency results in impaired tyrosine phosphorylation and activation of downstream STATs 1, 3, and 6 in fibroblasts, and that JAK1-null embryos are visibly smaller starting at E15.5 and die perinatally with signs of apnea. Cre/lox-based conditional knockout mice; STAT phosphorylation analysis in primary fibroblasts Genesis High 27671227
2021 Activation of the JAK1/STAT3 signaling pathway leads to hepatic inflammation, increased hepatic FGF23 synthesis, and imbalanced FGF23 cleavage (massive increase in inactive C-terminal fragment and elevated intact FGF23), as well as high calcitriol levels and low parathyroid hormone production, identifying JAK1 as a central regulator of mineral homeostasis. Jak1 activation mouse model; FGF23 measurement; calcitriol/PTH assays; hepatic inflammation analysis FASEB journal Medium 33475190

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Mechanisms of type-I- and type-II-interferon-mediated signalling. Nature reviews. Immunology 2780 15864272
2018 Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nature reviews. Clinical oncology 2427 29405201
1995 Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 1763 7543024
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1998 Jaks and STATs: biological implications. Annual review of immunology 1413 9597132
2008 Identification of host proteins required for HIV infection through a functional genomic screen. Science (New York, N.Y.) 1165 18187620
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2016 Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations. Cancer discovery 1073 27903500
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2010 Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. The New England journal of medicine 978 20843246
1994 Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science (New York, N.Y.) 929 8272873
2009 A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 843 19490893
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
1992 A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell 803 1386289
1993 Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science (New York, N.Y.) 772 8493579
1993 A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. Science (New York, N.Y.) 744 7690989
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
1993 The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature 729 8232552
1994 Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science (New York, N.Y.) 728 8272872
1994 Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell 725 7510216
2012 Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 708 22939624
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1998 Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell 662 9590172
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Genome-scale RNAi screen for host factors required for HIV replication. Cell host & microbe 627 18976975
1994 Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science (New York, N.Y.) 600 7973658
1998 Stat3 activation by Src induces specific gene regulation and is required for cell transformation. Molecular and cellular biology 572 9566874
2005 A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 568 16273093
1994 Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science (New York, N.Y.) 540 7973659
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2011 Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation. Nature cell biology 490 21423176
2019 IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion. The Journal of clinical investigation 301 31305264
2022 Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages. Cell metabolism 251 35235776
2013 Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia 204 23459451
1998 HBx protein of hepatitis B virus activates Jak1-STAT signaling. The Journal of biological chemistry 203 9738022
2014 PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum stress-induced inflammation. Molecular and cellular biology 197 25113558
2015 Reversal of Alopecia Areata Following Treatment With the JAK1/2 Inhibitor Baricitinib. EBioMedicine 183 26137574
1997 A JAK1/JAK2 chimera can sustain alpha and gamma interferon responses. Molecular and cellular biology 180 9001223
2019 Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. The Journal of allergy and clinical immunology 178 31629805
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 168 18559588
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2007 JAK1-STAT1-STAT3, a key pathway promoting proliferation and preventing premature differentiation of myoblasts. The Journal of cell biology 157 17908914
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2010 Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis. IDrugs : the investigational drugs journal 101 20506062
2020 Selective JAK1 Inhibitors for the Treatment of Atopic Dermatitis: Focus on Upadacitinib and Abrocitinib. American journal of clinical dermatology 94 32776305
2018 Aloin suppresses lipopolysaccharide‑induced inflammation by inhibiting JAK1‑STAT1/3 activation and ROS production in RAW264.7 cells. International journal of molecular medicine 81 30066904
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2011 Oncogenic JAK1 and JAK2-activating mutations resistant to ATP-competitive inhibitors. Haematologica 64 21393331
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2019 Upadacitinib and filgotinib: the role of JAK1 selective inhibition in the treatment of rheumatoid arthritis. Drugs in context 52 31692920
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1997 Kinase-deficient forms of Jak1 and Tyk2 inhibit interferon alpha signaling in a dominant manner. European journal of biochemistry 31 9249040
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2024 HDAC inhibitor SAHA enhances antitumor immunity via the HDAC1/JAK1/FGL1 axis in lung adenocarcinoma. Journal for immunotherapy of cancer 28 39384195
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