{"gene":"JAK1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1993,"finding":"JAK1 is required for both interferon-alpha/beta and interferon-gamma signal transduction. A JAK1-deficient cell line was completely defective in interferon response; complementation with JAK1 restored signaling. JAK1 and TYK2 are mutually dependent in the IFN-α pathway, and JAK1 and JAK2 are mutually dependent in the IFN-γ pathway, likely reflecting a requirement for these kinases in correct assembly of interferon receptor complexes.","method":"Genetic complementation of JAK1-deficient mutant cell line; loss-of-function + rescue","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean complementation experiment in JAK1-null cell line, foundational result independently replicated across the field","pmids":["8232552"],"is_preprint":false},{"year":1997,"finding":"Receptor-associated constitutive protein tyrosine phosphatase (PTP) activity controls JAK1 kinase function. Inhibition of PTP activity with pervanadate activates JAKs and leads to JAK1-dependent, IL-4Rα-mediated STAT6 activation independently of receptor dimerization. This indicates that constitutive PTP activity suppresses persistent receptor-linked JAK1 activity.","method":"Pharmacological PTP inhibition (pervanadate), JAK1-deficient cell lines, complementation with IL-4Rα; loss-of-function and rescue","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell lines, genetic complementation, and pharmacological approach converge on same conclusion","pmids":["9238016"],"is_preprint":false},{"year":1997,"finding":"Kinase-deficient dominant-negative forms of JAK1 and TYK2 each independently inhibit IFN-α–induced STAT phosphorylation and transcriptional activation, establishing that JAK1 kinase activity is required upstream of TYK2 in the IFN-α signaling cascade.","method":"Transfection of kinase-deficient mutants; dominant-negative assay; reporter gene assay; STAT phosphorylation analysis","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative mutagenesis with two orthogonal readouts (phosphorylation + reporter), single lab","pmids":["9249040"],"is_preprint":false},{"year":1997,"finding":"Jak1 kinase is required for a specific cell migration (epiboly) and anterior specification in zebrafish embryos. Injection of dominant-negative Jak1 RNA reduces epiboly and decreases goosecoid expression and anterior structures, establishing a developmental role for JAK1 beyond cytokine signaling.","method":"Injection of dominant-negative Jak1 RNA into zebrafish embryos; developmental phenotype analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative in vivo approach in zebrafish, single lab with developmental readout","pmids":["9096349"],"is_preprint":false},{"year":1998,"finding":"Hepatitis B virus HBx protein specifically activates JAK1 (but not JAK2 or TYK2) through direct protein–protein interaction with JAK1, elevating JAK1 tyrosine phosphorylation and kinase activity, and subsequently activating STAT3 and STAT5.","method":"Stable HBx-expressing cell lines; in vitro kinase assay; co-immunoprecipitation; STAT DNA-binding and transcriptional activation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus co-IP demonstrating direct interaction, single lab","pmids":["9738022"],"is_preprint":false},{"year":2003,"finding":"JAK1 is required for IFN-γ–mediated growth arrest and/or apoptosis of v-abl–transformed pre-B cells. JAK1-deficient transformed cells were more tumorigenic in vivo, and their increased tumorigenicity correlated with loss of IFN-γ responsiveness, establishing JAK1's role in intrinsic IFN-γ–dependent tumor surveillance rather than in promotion of tumorigenesis.","method":"Jak1-deficient mouse model; v-abl transformation; in vivo transplantation (SCID/nude mice); IFN-γ response assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function mouse model with clear in vivo phenotype and mechanistic link to IFN-γ signaling","pmids":["12576323"],"is_preprint":false},{"year":2007,"finding":"JAK1 is required for myoblast proliferation and acts as a checkpoint preventing premature differentiation. JAK1 knockdown induces accelerated MyoD, MEF2, p21Cip1, and p27Kip1 induction and faster Id1 downregulation. Downstream, JAK1-STAT1-STAT3 constitutes the pathway through which LIF stimulates myoblast proliferation and represses differentiation.","method":"JAK1 knockdown (siRNA) in primary and immortalized myoblasts; gene expression analysis; cell proliferation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function in two cell types with multiple molecular readouts establishing pathway position","pmids":["17908914"],"is_preprint":false},{"year":2008,"finding":"Myricetin directly binds to JAK1 (and STAT3) with higher affinity for JAK1 than STAT3, inhibiting JAK1 phosphorylation and EGF-induced cell transformation. Ex vivo and in vitro pull-down assays confirmed direct binding; myricetin inhibited JAK1 phosphorylation without affecting EGFR autophosphorylation.","method":"Pull-down assay (ex vivo and in vitro); affinity binding assay; western blot for JAK1 phosphorylation; colony transformation assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by pull-down with affinity data, single lab","pmids":["18995957"],"is_preprint":false},{"year":2008,"finding":"TCPTP (protein tyrosine phosphatase) dephosphorylates and negatively regulates JAK1 and STAT3 signaling during the cell cycle. TCPTP-deficient MEFs show enhanced SFK, JAK1, and STAT3 activation; however, JAK1 and STAT3 (not SFK) signaling was not required for the enhanced G1/S transition observed.","method":"TCPTP knockout MEFs; RNA interference in HeLa cells; pharmacological inhibitors; cell cycle analysis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus RNAi with two orthogonal approaches, single lab","pmids":["18948751"],"is_preprint":false},{"year":2011,"finding":"Activating mutations in JAK1 at Phe958 and Pro960 (hinge region of kinase domain) render JAK1 constitutively active and resistant to ATP-competitive JAK inhibitors. These mutations can both activate JAK1 oncogenically and confer drug resistance.","method":"Spontaneous cellular transformation screen in BaF3 cells; sequencing of JAK1 mutations; inhibitor sensitivity assays","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mutation analysis in cell-based transformation assay, single lab, well-defined readouts","pmids":["21393331"],"is_preprint":false},{"year":2014,"finding":"ER stress activates JAK1 in astrocytes in a PERK-dependent manner. JAK1 phosphorylates PERK, and this PERK/JAK1/STAT3 axis drives IL-6 and chemokine expression. Disruption of PERK abrogates ER stress–induced STAT3 activation.","method":"Pharmacological ER stress induction; PERK disruption; JAK1 inhibition; western blot for STAT3 activation; gene expression analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic/pharmacological perturbations in glial cells, single lab","pmids":["25113558"],"is_preprint":false},{"year":2015,"finding":"CXCL12/CXCR4 signaling promotes immunological synapse formation and T cell activation through Gi and JAK1/JAK2 kinase activation, contributing to actin polymerization at the APC contact site and MTOC polarization.","method":"CXCR4 blockade/downregulation; pharmacological JAK inhibition; actin polymerization assay; MTOC polarization analysis; T cell activation markers","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition combined with receptor downregulation and multiple cellular readouts, single lab","pmids":["25917087"],"is_preprint":false},{"year":2016,"finding":"Loss-of-function JAK1 mutations in tumor cells result in inability to respond to interferon-gamma (IFN-γ), preventing IFN-γ–induced PD-L1 expression and interferon-stimulated gene induction, thereby mediating primary resistance to PD-1 blockade.","method":"Tumor biopsy sequencing; melanoma cell line functional assays; IFN-γ stimulation with PD-L1 expression readout; JAK1/2 mutation characterization","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — human tumor samples plus functional cell line validation with mechanistic readout, replicated in two cancer types","pmids":["27903500"],"is_preprint":false},{"year":2016,"finding":"Biallelic JAK1 missense mutations (P733L and P832S) cause reduced JAK1 and STAT phosphorylation following cytokine stimulation, reduced interferon-regulated gene induction, and dysregulated cytokine production. The P733L mutation is primarily responsible. Reconstitution experiments revealed a phosphorylation-independent role of JAK1 in signal transduction.","method":"Patient-derived cells; exome sequencing; cytokine stimulation assays; STAT phosphorylation; reconstitution experiments in JAK1-deficient cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient-derived cells plus reconstitution experiments with mutation-specific rescue, multiple readouts","pmids":["28008925"],"is_preprint":false},{"year":2016,"finding":"AJUBA LIM protein binds specifically to the FERM domain of JAK1 to dissociate JAK1 from the IFN-γ receptor, inhibiting STAT1 phosphorylation and nuclear translocation, thereby suppressing the JAK1-STAT1-IFIT2 network and promoting cancer cell survival.","method":"Co-immunoprecipitation; domain mapping; STAT1 phosphorylation assay; IFIT2 expression analysis; cell viability and xenograft assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping and functional readouts, single lab","pmids":["27893714"],"is_preprint":false},{"year":2017,"finding":"Conditional Jak1 deletion in hematopoietic stem cells (HSCs) reduces self-renewal, alters lymphoid/myeloid differentiation, decreases competitiveness, prevents cell cycle entry in response to hematopoietic stress, and markedly reduces cytokine sensing including to type I interferons and IL-3. JAK2 constitutive activation cannot fully rescue JAK1 loss in HSCs.","method":"Conditional Jak1 knockout mouse model; in vivo transplantation; cell cycle analysis; cytokine stimulation assays; competitive repopulation assay","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic KO in vivo with multiple orthogonal readouts and non-rescue by JAK2, single lab but rigorous","pmids":["28965767"],"is_preprint":false},{"year":2018,"finding":"JAK1 phosphorylates SIRT1 at tyrosine residues Y280 and Y301 within the histone deacetylase catalytic domain in response to IL-6 stimulation. This phosphorylation does not alter SIRT1 deacetylase activity but is required for SIRT1 interaction with STAT3, enhancing SIRT1 suppression of STAT3 acetylation and transcriptional activity, constituting a negative feedback of the JAK1-STAT3 pathway.","method":"Co-immunoprecipitation; in vitro kinase assay; site-directed mutagenesis (Y280A, Y301A); STAT3 acetylation assay; transcriptional activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis identifying specific phosphorylation sites, plus functional consequence on STAT3, single lab","pmids":["29789426"],"is_preprint":false},{"year":2019,"finding":"IL-6-activated JAK1 directly phosphorylates PD-L1 at Tyr112, which recruits the ER-associated N-glycosyltransferase STT3A to catalyze PD-L1 glycosylation and maintain PD-L1 stability, linking oncogenic IL-6/JAK1 signaling to immune evasion.","method":"In vitro kinase assay; phospho-specific antibody; co-immunoprecipitation; glycosylation assay; mutagenesis of PD-L1 Y112; animal models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with site-specific mutagenesis and co-IP demonstrating direct substrate relationship, single lab but multiple orthogonal methods","pmids":["31305264"],"is_preprint":false},{"year":2019,"finding":"JAK1 (not JAK2) is the STAT3-activating kinase mediating extrinsically activated STAT3 in TKI-treated CML stem cells, driven by IL-6. This was established using selective JAK1/2 inhibitors and genetic inactivation, and combined Bcr-Abl + JAK1 inhibition reduced CML stem cell colony formation and leukemic stem cells.","method":"Selective JAK1/2 inhibitors; genetic JAK1 inactivation; IL-6 blocking peptide; CFU assay; transgenic CML mouse model","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological plus genetic approach identifying JAK1 specifically, single lab","pmids":["30842608"],"is_preprint":false},{"year":2019,"finding":"Conditional deletion of JAK1 (but not JAK2) in NKp46+ NK cells markedly reduces NK cell numbers in bone marrow, spleen, blood, and liver, impairs NK cell development, and impairs NK cell–mediated tumor surveillance. JAK2 is dispensable for NK cell survival and cannot compensate for JAK1 loss.","method":"Conditional NK cell–specific Jak1 knockout (Jak1Ncr1Cre); NK cell number/function assessment; tumor surveillance assay; comparison with JAK2-conditional KO","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with clear phenotypic readouts and JAK2 comparison establishing JAK1-specific function","pmids":["30671064"],"is_preprint":false},{"year":2019,"finding":"TROY (orphan TNF receptor) directly interacts with JAK1, increases JAK1 phosphorylation, and promotes STAT3 phosphorylation and transcriptional activity in a JAK1-dependent manner. JAK1 inhibition or knockdown significantly inhibits TROY-induced STAT3 activation, GBM cell migration, and temozolomide resistance.","method":"Co-immunoprecipitation; JAK1 phosphorylation assay; STAT3 reporter assay; JAK1 siRNA knockdown; ruxolitinib pharmacological inhibition; migration assay","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional knockdown with multiple readouts, single lab","pmids":["32629176"],"is_preprint":false},{"year":2019,"finding":"The JAK1 pseudokinase domain (JH2) has distinct regulatory functions across different receptor complexes: in IL-2 signaling JAK1 is dominant over JAK3 and strictly requires both JH1 and JH2; in IFN-γ signaling both JAK1 and JAK2 are indispensable for STAT1 activation and JAK1 JH2 (rather than kinase activity) is the key requirement. Mutations in the JAK1 JH2 αC-helix (L633) reduce basal and cytokine-induced STAT activation.","method":"JAK-deficient cell lines; structure-based mutagenesis; cytokine stimulation assays; STAT phosphorylation analysis","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-guided mutagenesis in defined cell backgrounds, single lab with multiple cytokine systems","pmids":["31892268"],"is_preprint":false},{"year":2019,"finding":"TRAF6 negatively regulates JAK1 activation in IL-2 signaling by binding to the TRAF6-binding site on the IL-2R β-chain, which overlaps with the JAK1-binding site. A β-chain mutation that inactivates TRAF6 binding while retaining JAK1 binding abrogated TRAF6-dependent reduction in JAK1-Erk pathway activation.","method":"Traf6-knockout T cells and MEFs; IL-2 signaling reconstitution; β-chain binding-site mutagenesis; JAK1 phosphorylation and Erk activation assays","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus receptor mutagenesis defining binding competition, single lab","pmids":["21155952"],"is_preprint":false},{"year":2022,"finding":"Itaconate and 4-octyl itaconate (OI) directly modify JAK1 at multiple cysteine residues (C715, C816, C943, C1130) and inhibit JAK1 kinase activity and phosphorylation, suppressing M2 macrophage polarization in response to IL-4, IL-13, IFN-β, and IFN-γ in vitro and in vivo.","method":"Direct chemical modification identified by mass spectrometry; in vitro kinase activity assay; JAK1 phosphorylation analysis; M2 polarization assays in macrophages and Th2 cells; in vivo OI treatment","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical modification identified by MS plus in vitro kinase assay, multiple cell types, confirmed in vivo","pmids":["35235776"],"is_preprint":false},{"year":2022,"finding":"JAK1 contains a druggable allosteric cysteine (C817) in its non-catalytic pseudokinase domain (absent from JAK2 and JAK3). Electrophilic compounds targeting C817 block JAK1-dependent trans-phosphorylation and cytokine signaling. Cells expressing a C817A JAK1 mutant are insensitive to these allosteric inhibitors, confirming C817 as the functional engagement site.","method":"Chemical proteomics; electrophilic compound library; covalent labeling; C817A mutagenesis; STAT phosphorylation assays; cytokine signaling assays","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — chemical proteomic identification plus mutagenesis confirming functional site, multiple orthogonal assays","pmids":["36097295"],"is_preprint":false},{"year":2022,"finding":"Influenza A virus PB2 protein targets mammalian JAK1 at lysine residues K859 and K860 for ubiquitination and proteasomal degradation, suppressing IFN-α/β signaling and STAT1/STAT2 activation as a mechanism of immune evasion.","method":"Co-immunoprecipitation; ubiquitination assay; site-specific mutagenesis (K859/K860); JAK1 protein level analysis; STAT phosphorylation assay; viral replication assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP plus mutagenesis identifying specific ubiquitination sites with functional consequence on signaling, replicated in multiple IAV subtypes","pmids":["36271046"],"is_preprint":false},{"year":2022,"finding":"DPYSL2 (dihydropyrimidinase-like 2) directly interacts with JAK1, and this binding is required for activating STAT3 and subsequent vimentin expression, promoting breast cancer cell migration and metastasis.","method":"Co-immunoprecipitation; DPYSL2 knockout; migration/invasion assays; STAT3 phosphorylation analysis; in vivo xenograft","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus genetic KO with mechanistic readout, single lab","pmids":["35575798"],"is_preprint":false},{"year":2022,"finding":"JAK1 directly interacts with TGF-β receptor I subunit (TβRI). Silencing JAK1 promotes myofibroblast transdifferentiation; this is mediated via constitutive STAT3 activation that requires JAK1. Silencing unphosphorylated STAT3 suppresses TGF-β signaling, SMAD3 activation, and ECM production, revealing a noncanonical JAK1/STAT3 regulatory axis in lung fibroblasts.","method":"Co-immunoprecipitation; siRNA silencing; upadacitinib pharmacological inhibition; SMAD3 phosphorylation assay; myofibroblast differentiation assay; in vivo fibrosis model","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus siRNA with multiple signaling readouts, single lab","pmids":["36283961"],"is_preprint":false},{"year":2023,"finding":"HDAC1 deacetylates JAK1 at lysine 1109; HDAC inhibition (SAHA) increases JAK1 K1109 acetylation, promoting JAK1 proteasomal degradation and reducing STAT3-driven FGL1 transcription, thereby enhancing CD8+ T cell antitumor activity.","method":"Co-immunoprecipitation; mass spectrometry; site-specific mutagenesis; proteasome inhibitor assay; STAT3 activity assay; chromatin immunoprecipitation; in vivo tumor model","journal":"Journal for immunotherapy of cancer","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mass spectrometry identifying specific modification site, co-IP, mutagenesis, and in vivo validation, single lab with multiple orthogonal methods","pmids":["39384195"],"is_preprint":false},{"year":2023,"finding":"EHBP1L1 interacts with and stabilizes JAK1 protein by competing with SOCS1 for JAK1 binding, thereby protecting JAK1 from proteasomal degradation and maintaining elevated JAK1/STAT1/PD-L1 signaling in renal cell carcinoma.","method":"Co-immunoprecipitation; EHBP1L1 depletion; protein stability assay; proteasome inhibitor rescue; STAT1/PD-L1 expression analysis; PDX tumor model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with competition assay and protein stability readout, single lab","pmids":["36775874"],"is_preprint":false},{"year":2023,"finding":"JAK1 is palmitoylated endogenously in dorsal root ganglion (DRG) neurons and in HEK293T cells. ZDHHC3 and ZDHHC7 are the dominant protein acyltransferases (PATs) for JAK1. Palmitoylation is critical for JAK1 kinase activity (even in vitro) and facilitates transphosphorylation of key activation loop sites, but minimally affects JAK1 localization in neurons. A leukemia-associated JAK1 mutation overrides palmitoylation-dependence of JAK1 activity. JAK1 palmitoylation is required for neuropoietic cytokine-dependent signaling and neuronal survival.","method":"Palmitoylation assay; ZDHHC screening; shRNA knockdown; in vitro kinase assay; neuronal survival assay; cytokine signaling assays; structural modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus genetic identification of PATs with multiple cellular readouts including neuronal survival, single lab with comprehensive approach","pmids":["37356718"],"is_preprint":false},{"year":2023,"finding":"METTL3 deposits m6A on the 3' UTR of JAK1 mRNA to promote JAK1 translation via YTHDF1 recognition, increasing JAK1 protein levels and contributing to STAT3 pathway activation and colorectal cancer progression.","method":"m6A-seq; YTHDF1 co-immunoprecipitation; ribosome profiling; JAK1 reporter assay; METTL3 catalytic mutant","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epitranscriptomic mechanism with co-IP and reader protein, single lab","pmids":["38001065"],"is_preprint":false},{"year":2023,"finding":"JAK1 kinase activity is required for HDV replication. JAK1 inhibition modulates ERK1/2 activation and S-HDAg (small hepatitis delta antigen) phosphorylation, which is crucial for viral replication. Co-immunoprecipitation confirmed JAK1 interaction within the HDV replication complex.","method":"Loss-of-function (siRNA/JAK1 inhibitors); co-immunoprecipitation; ERK1/2 and S-HDAg phosphorylation assays; HDV replication assay in primary human hepatocytes","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional kinase activity assay with viral readout, single lab","pmids":["37925078"],"is_preprint":false},{"year":2024,"finding":"Chemotherapy-induced JAK1 activation occurs through an alternative mechanism: DNA damage induces JAK1-SQ phosphorylation that releases JAK1 pseudokinase domain (JH2) inhibition, allowing JAK1 activation without cytokine receptor engagement. This leads to STAT6 nuclear translocation and GAS6 secretion, activating TAM kinases to confer chemoresistance in Ewing sarcoma.","method":"Phospho-profiling; JAK1 inhibition (filgotinib); STAT6 nuclear translocation assay; GAS6 secretion measurement; in vitro and in vivo chemosensitization assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-profiling with pharmacological inhibition and multiple functional readouts, single lab","pmids":["38906855"],"is_preprint":false},{"year":2025,"finding":"STING acts downstream of IFN-α/β receptor (IFNAR) in endothelial cells and interacts directly with JAK1 upon IFN-I stimulation, promoting JAK1 phosphorylation. This interaction requires STING palmitoylation at Cysteine 91 but not the STING C-terminal tail (CTT) domain, and drives JAK1-STAT signaling for tumor vessel normalization and CD8+ T cell infiltration.","method":"Co-immunoprecipitation; STING palmitoylation-site mutagenesis (C91); IFN-I signaling assays; endothelial-specific STING deletion; JAK1 phosphorylation analysis; in vivo tumor models","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with site-specific mutagenesis and genetic deletion, single lab","pmids":["39817453"],"is_preprint":false}],"current_model":"JAK1 is a non-receptor tyrosine kinase constitutively associated with diverse cytokine receptors that acts as an obligate signaling hub: it heterodimerizes with TYK2 (IFN-α/β), JAK2 (IFN-γ, gp130 cytokines), or JAK3 (γc-chain cytokines) to enable receptor complex assembly, trans-phosphorylation, and downstream STAT activation; its activity is negatively regulated by receptor-associated phosphatases (TCPTP, receptor PTPs), by SOCS1-mediated proteasomal degradation, by HDAC1-dependent acetylation at K1109, and is positively regulated by palmitoylation (via ZDHHC3/7) which facilitates activation-loop transphosphorylation; JAK1 directly phosphorylates substrates beyond STATs including PERK, SIRT1 (Y280/Y301), and PD-L1 (Y112, initiating glycosylation), and is itself targeted for ubiquitination/degradation by viral proteins (IAV PB2 at K859/K860) or stabilized by scaffold proteins (EHBP1L1 competing with SOCS1); an allosteric cysteine in its pseudokinase domain (C817) provides an isoform-selective regulatory site, and the pseudokinase domain (JH2) exerts regulatory control over the kinase domain (JH1) in a receptor context-dependent manner."},"narrative":{"mechanistic_narrative":"JAK1 is a non-receptor tyrosine kinase that serves as an obligate signaling hub for cytokine and interferon receptors, coupling receptor engagement to STAT activation across immune, hematopoietic, and developmental programs [PMID:8232552, PMID:28965767]. It is mutually dependent on partner kinases for interferon signaling — acting with TYK2 in the IFN-α/β pathway and with JAK2 in the IFN-γ pathway — where its activity and pseudokinase (JH2) domain are required for correct receptor complex assembly and STAT phosphorylation [PMID:8232552, PMID:9249040, PMID:31892268]. JAK1 function is non-redundant in vivo: conditional deletion impairs hematopoietic stem cell self-renewal, cytokine sensing, and NK cell development, and JAK2 cannot compensate for its loss [PMID:28965767, PMID:30671064]. Beyond canonical STAT signaling, JAK1 directly phosphorylates a defined set of substrates: PERK during ER stress to drive a PERK/JAK1/STAT3 axis [PMID:25113558], SIRT1 at Y280/Y301 to enable SIRT1-STAT3 negative feedback [PMID:29789426], and PD-L1 at Y112 to recruit STT3A and stabilize PD-L1 glycosylation, linking IL-6/JAK1 signaling to immune evasion [PMID:31305264]. JAK1 activity is tightly controlled by multiple layers: dephosphorylation by receptor-associated PTPs including TCPTP [PMID:9238016, PMID:18948751], proteasomal turnover modulated by SOCS1 competition (antagonized by EHBP1L1) [PMID:36775874], HDAC1-dependent acetylation at K1109 [PMID:39384195], and positive regulation by ZDHHC3/7-mediated palmitoylation that facilitates activation-loop transphosphorylation [PMID:37356718]. Its catalytic state is further shaped by activating hinge mutations that confer drug resistance [PMID:21393331] and by a JAK1-selective allosteric cysteine (C817) in the pseudokinase domain that is targetable by electrophilic inhibitors [PMID:36097295]. Loss-of-function JAK1 mutations abrogate IFN-γ responsiveness and PD-L1 induction, mediating resistance to PD-1 blockade [PMID:27903500], while biallelic missense mutations cause a human immune dysregulation phenotype with impaired cytokine signaling [PMID:28008925].","teleology":[{"year":1993,"claim":"Established that JAK1 is an essential, non-redundant component of interferon signaling, defining its core role as a receptor-coupled kinase required for STAT pathway activation.","evidence":"Genetic complementation of a JAK1-deficient cell line with loss-of-function and rescue across IFN-α/β and IFN-γ responses","pmids":["8232552"],"confidence":"High","gaps":["Did not resolve the molecular basis of receptor complex assembly","Did not establish substrate specificity beyond STATs"]},{"year":1997,"claim":"Defined the kinase hierarchy and constitutive negative regulation of JAK1, showing its kinase activity acts upstream of TYK2 and that receptor-associated PTPs suppress persistent JAK1 activity.","evidence":"Dominant-negative kinase-dead mutants for pathway ordering; pervanadate PTP inhibition with JAK1-deficient cell complementation","pmids":["9249040","9238016"],"confidence":"Medium","gaps":["Identity of the responsible receptor-associated phosphatase not pinned down here","Mechanism of dimerization-independent activation not defined"]},{"year":1997,"claim":"Extended JAK1 function beyond cytokine signaling to embryonic development, indicating a role in morphogenetic movements and patterning.","evidence":"Dominant-negative Jak1 RNA injection in zebrafish with epiboly and goosecoid phenotype readouts","pmids":["9096349"],"confidence":"Medium","gaps":["Dominant-negative may not phenocopy null","Receptor/ligand upstream of developmental JAK1 not identified"]},{"year":1998,"claim":"Showed viral proteins can hijack JAK1 selectively, with HBx directly binding and activating JAK1 to drive STAT3/STAT5.","evidence":"Co-IP, in vitro kinase assay, and STAT DNA-binding assays in HBx-expressing cells","pmids":["9738022"],"confidence":"Medium","gaps":["Binding interface on JAK1 not mapped","Single-lab; physiological relevance to HBV pathogenesis not established here"]},{"year":2003,"claim":"Demonstrated a tumor-suppressive function for JAK1 via IFN-γ-dependent growth arrest, linking JAK1 loss to increased tumorigenicity.","evidence":"Jak1-deficient v-abl-transformed pre-B cells with in vivo transplantation and IFN-γ response assays","pmids":["12576323"],"confidence":"High","gaps":["Did not address JAK1 oncogenic gain-of-function contexts","Downstream effectors of growth arrest not fully defined"]},{"year":2007,"claim":"Positioned JAK1 as a proliferation checkpoint in muscle, acting through a LIF/JAK1-STAT1-STAT3 axis to repress premature differentiation.","evidence":"siRNA knockdown in primary and immortalized myoblasts with differentiation marker and proliferation readouts","pmids":["17908914"],"confidence":"High","gaps":["Direct STAT targets controlling differentiation genes not mapped","Receptor mediating LIF input not specified"]},{"year":2008,"claim":"Identified TCPTP as a specific phosphatase dephosphorylating JAK1 during the cell cycle, refining the negative regulatory machinery.","evidence":"TCPTP-knockout MEFs and HeLa RNAi with cell cycle analysis","pmids":["18948751"],"confidence":"Medium","gaps":["JAK1/STAT3 signaling dispensable for the observed G1/S phenotype, decoupling phosphatase target from function","Direct dephosphorylation site on JAK1 not defined"]},{"year":2008,"claim":"Provided chemical-biology evidence that small molecules can directly engage and inhibit JAK1, with myricetin binding JAK1 to block its phosphorylation.","evidence":"Pull-down/affinity binding assays and phospho-JAK1 western blots with transformation assay","pmids":["18995957"],"confidence":"Medium","gaps":["Binding site not localized","Selectivity over other JAKs not established"]},{"year":2011,"claim":"Showed JAK1 can be oncogenically activated by kinase-domain hinge mutations (F958/P960) that also confer ATP-competitive inhibitor resistance.","evidence":"Spontaneous transformation screen in BaF3 cells with mutation sequencing and inhibitor sensitivity assays","pmids":["21393331"],"confidence":"Medium","gaps":["Structural basis of constitutive activation not solved here","Clinical prevalence not addressed"]},{"year":2011,"claim":"Revealed receptor-level negative regulation through binding-site competition, with TRAF6 occluding the JAK1-binding site on IL-2Rβ.","evidence":"Traf6-knockout T cells/MEFs with IL-2R β-chain binding-site mutagenesis and JAK1/Erk readouts","pmids":["21155952"],"confidence":"Medium","gaps":["Generality across other cytokine receptors not tested","Single-lab"]},{"year":2014,"claim":"Identified a non-canonical activation route in which ER stress activates JAK1 PERK-dependently and JAK1 phosphorylates PERK, defining a PERK/JAK1/STAT3 inflammatory axis.","evidence":"ER stress induction with PERK disruption and JAK1 inhibition in astrocytes","pmids":["25113558"],"confidence":"Medium","gaps":["Direct PERK phosphosites by JAK1 not mapped","Whether interaction is direct not fully established"]},{"year":2015,"claim":"Connected chemokine signaling to cytoskeletal reorganization, showing CXCL12/CXCR4 engages JAK1/JAK2 to support immune synapse formation.","evidence":"Pharmacological JAK inhibition and CXCR4 downregulation with actin/MTOC and T cell activation readouts","pmids":["25917087"],"confidence":"Medium","gaps":["JAK1-specific contribution vs JAK2 not separated","Direct substrates in synapse formation unknown"]},{"year":2016,"claim":"Defined a scaffold-based off-switch in which AJUBA binds the JAK1 FERM domain to dissociate JAK1 from the IFN-γ receptor and suppress STAT1 signaling.","evidence":"Co-IP with domain mapping, STAT1 phosphorylation, IFIT2 readouts, and xenografts","pmids":["27893714"],"confidence":"Medium","gaps":["Stoichiometry of dissociation not quantified","Single-lab"]},{"year":2016,"claim":"Established the clinical consequence of JAK1 loss-of-function, showing tumor JAK1 mutations abolish IFN-γ-induced PD-L1 and ISG induction to drive PD-1 blockade resistance.","evidence":"Tumor biopsy sequencing with melanoma cell line IFN-γ stimulation and PD-L1 readouts","pmids":["27903500"],"confidence":"High","gaps":["Did not enumerate full ISG dependency","Did not address gain-of-function tumor contexts"]},{"year":2016,"claim":"Linked biallelic JAK1 missense mutations to a human immune dysregulation phenotype and uncovered a phosphorylation-independent JAK1 function in signal transduction.","evidence":"Patient-derived cells, exome sequencing, and reconstitution in JAK1-deficient cells","pmids":["28008925"],"confidence":"High","gaps":["Molecular basis of the phosphorylation-independent role not defined","Genotype-phenotype across additional families limited"]},{"year":2018,"claim":"Identified SIRT1 as a direct JAK1 substrate (Y280/Y301), revealing a feedback loop where JAK1 phosphorylation licenses SIRT1 to suppress STAT3 acetylation.","evidence":"In vitro kinase assay, site-directed mutagenesis, and STAT3 acetylation/transcription assays after IL-6","pmids":["29789426"],"confidence":"High","gaps":["Structural consequence of Y280/Y301 phosphorylation not resolved","Single-lab"]},{"year":2019,"claim":"Defined a non-redundant role for JAK1 in NK cell development and tumor surveillance that JAK2 cannot substitute for.","evidence":"NK-specific conditional Jak1 knockout (Ncr1Cre) with developmental, functional, and tumor surveillance readouts versus JAK2 KO","pmids":["30671064"],"confidence":"High","gaps":["Cytokine receptor input(s) driving NK dependence not isolated","Downstream STAT specificity in NK cells not resolved"]},{"year":2019,"claim":"Showed JAK1 directly phosphorylates PD-L1 at Y112 to recruit STT3A for glycosylation-dependent stabilization, mechanistically coupling IL-6/JAK1 to immune evasion.","evidence":"In vitro kinase assay, phospho-specific antibody, PD-L1 Y112 mutagenesis, glycosylation assay, and animal models","pmids":["31305264"],"confidence":"High","gaps":["Whether JAK1-PD-L1 phosphorylation occurs at receptor or ER not localized","Generality across cancer types not fully mapped"]},{"year":2019,"claim":"Demonstrated JAK1-specific (not JAK2) STAT3 activation by extrinsic IL-6 in TKI-treated CML stem cells, nominating JAK1 as a co-target for leukemic stem cell eradication.","evidence":"Selective JAK1/2 inhibitors, genetic JAK1 inactivation, IL-6 blocking, CFU assay, and transgenic CML model","pmids":["30842608"],"confidence":"Medium","gaps":["Direct vs indirect JAK1-STAT3 coupling not dissected","Single-lab"]},{"year":2019,"claim":"Established JAK1 as essential for hematopoietic stem cell self-renewal, stress response, and cytokine sensing, with constitutively active JAK2 unable to rescue JAK1 loss.","evidence":"Conditional Jak1 knockout mice with transplantation, cell cycle, cytokine stimulation, and competitive repopulation assays","pmids":["28965767"],"confidence":"High","gaps":["Specific receptors mediating HSC dependence not isolated","Mechanism of JAK2 non-redundancy not defined"]},{"year":2019,"claim":"Showed an orphan TNF receptor (TROY) can directly engage and activate JAK1 to drive STAT3-dependent glioma malignancy, broadening the receptor partners of JAK1.","evidence":"Co-IP, JAK1 siRNA/ruxolitinib, STAT3 reporter, and migration assays","pmids":["32629176"],"confidence":"Medium","gaps":["Binding region on JAK1 not mapped","Single-lab"]},{"year":2019,"claim":"Dissected the receptor-context-dependent regulatory role of the JAK1 pseudokinase (JH2) domain, showing JH2 (rather than kinase activity) is the key requirement in IFN-γ signaling and that JAK1 is dominant in IL-2 signaling.","evidence":"JAK-deficient cell lines with structure-based JH2 mutagenesis (L633) and STAT phosphorylation assays across cytokine systems","pmids":["31892268"],"confidence":"Medium","gaps":["Structural mechanism of JH2 regulation not solved","Single-lab"]},{"year":2022,"claim":"Identified a JAK1-selective allosteric cysteine (C817) in the pseudokinase domain as a functional, druggable site for isoform-selective inhibition.","evidence":"Chemical proteomics, covalent labeling, and C817A mutagenesis with STAT phosphorylation and cytokine signaling assays","pmids":["36097295"],"confidence":"High","gaps":["How C817 engagement allosterically blocks trans-phosphorylation not structurally resolved"]},{"year":2022,"claim":"Showed an endogenous metabolite (itaconate) directly modifies multiple JAK1 cysteines to inhibit its kinase activity, coupling immunometabolism to JAK1 control.","evidence":"Mass spectrometry of cysteine adducts (C715/C816/C943/C1130), in vitro kinase assay, and macrophage polarization assays in vitro/in vivo","pmids":["35235776"],"confidence":"High","gaps":["Relative contribution of individual cysteines to inhibition not ranked","Endogenous itaconate concentrations achieving inhibition not benchmarked"]},{"year":2022,"claim":"Added a developmental/cancer JAK1 partner with DPYSL2 directly binding JAK1 to enable STAT3-driven migration and metastasis.","evidence":"Co-IP, DPYSL2 knockout, migration/invasion assays, and xenograft","pmids":["35575798"],"confidence":"Medium","gaps":["Whether binding alters JAK1 catalytic activity unclear","Single-lab"]},{"year":2022,"claim":"Revealed a noncanonical JAK1/STAT3 axis controlling TGF-β signaling, with JAK1 binding TβRI and unphosphorylated STAT3 modulating SMAD3 and ECM production in fibroblasts.","evidence":"Co-IP, siRNA, upadacitinib, SMAD3 phosphorylation, and in vivo fibrosis model","pmids":["36283961"],"confidence":"Medium","gaps":["Direction of JAK1 effect (suppressive) mechanistically unusual and not fully resolved","Single-lab"]},{"year":2022,"claim":"Defined a viral immune-evasion strategy where influenza PB2 ubiquitinates JAK1 at K859/K860 for degradation, blunting type I IFN signaling.","evidence":"Co-IP, ubiquitination assay, K859/K860 mutagenesis, and STAT/viral replication readouts across IAV subtypes","pmids":["36271046"],"confidence":"High","gaps":["Host E3 ligase recruited by PB2 not identified","Whether these lysines are used by endogenous turnover unclear"]},{"year":2023,"claim":"Established palmitoylation as a positive regulatory modification, with ZDHHC3/7 palmitoylating JAK1 to enable activation-loop transphosphorylation and kinase activity.","evidence":"Palmitoylation assays, ZDHHC screening/knockdown, in vitro kinase assay, and neuronal survival/cytokine signaling readouts","pmids":["37356718"],"confidence":"High","gaps":["Palmitoylated residue(s) not pinpointed in this summary","How leukemic mutation overrides palmitoylation-dependence not detailed"]},{"year":2023,"claim":"Identified acetylation as a degradative control point, with HDAC1 deacetylating JAK1 at K1109 to stabilize it and sustain STAT3-driven FGL1 transcription.","evidence":"Mass spectrometry, site mutagenesis, proteasome inhibition, ChIP, and in vivo tumor model","pmids":["39384195"],"confidence":"High","gaps":["Acetyltransferase opposing HDAC1 not identified","Single-lab"]},{"year":2023,"claim":"Defined SOCS1-antagonizing stabilization, with EHBP1L1 competing with SOCS1 for JAK1 to protect it from degradation and maintain JAK1/STAT1/PD-L1 signaling.","evidence":"Co-IP competition, protein stability and proteasome rescue assays, and PDX models","pmids":["36775874"],"confidence":"Medium","gaps":["Binding interface overlap with SOCS1 not structurally mapped","Single-lab"]},{"year":2023,"claim":"Added an epitranscriptomic layer, with METTL3-deposited m6A on JAK1 mRNA promoting JAK1 translation via YTHDF1 to amplify STAT3 signaling.","evidence":"m6A-seq, YTHDF1 co-IP, ribosome profiling, and METTL3 catalytic mutant in colorectal cancer","pmids":["38001065"],"confidence":"Medium","gaps":["Specific m6A sites in 3'UTR not functionally validated individually","Single-lab"]},{"year":2023,"claim":"Showed JAK1 kinase activity is co-opted within the HDV replication complex, modulating ERK1/2 and S-HDAg phosphorylation required for replication.","evidence":"siRNA/JAK1 inhibitors, co-IP, and HDV replication assays in primary hepatocytes","pmids":["37925078"],"confidence":"Medium","gaps":["Whether JAK1 phosphorylates S-HDAg directly not established","Single-lab"]},{"year":2024,"claim":"Uncovered a DNA damage-driven, receptor-independent activation mode where JAK1-SQ phosphorylation relieves JH2 autoinhibition to drive STAT6/GAS6/TAM signaling and chemoresistance.","evidence":"Phospho-profiling, filgotinib inhibition, STAT6 translocation, GAS6 secretion, and chemosensitization in Ewing sarcoma","pmids":["38906855"],"confidence":"Medium","gaps":["Kinase responsible for JAK1-SQ phosphorylation not identified","Single-lab"]},{"year":2025,"claim":"Positioned STING as a direct JAK1 partner downstream of IFNAR, with palmitoylated STING (C91) promoting JAK1 phosphorylation to drive tumor vessel normalization.","evidence":"Co-IP, STING C91 palmitoylation-site mutagenesis, endothelial STING deletion, and in vivo tumor models","pmids":["39817453"],"confidence":"Medium","gaps":["How STING palmitoylation enables JAK1 engagement structurally unclear","Single-lab"]},{"year":null,"claim":"How the full network of post-translational modifications (palmitoylation, acetylation, ubiquitination, cysteine modification) and pseudokinase-domain control are integrated to set JAK1 activity in distinct receptor and cellular contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model linking JH2 regulation to receptor context","Cross-talk and hierarchy among competing JAK1 PTMs not established","Substrate selection rules beyond STATs not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[10,16,17,30]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,16,17]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[9,24]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[14,21,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,14,22]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16,17]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,12,19,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,21]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[16,17,28]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[25,28,29,30]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,25,32]}],"complexes":["cytokine receptor-JAK signaling complex"],"partners":["TYK2","JAK2","STAT3","SIRT1","PERK","TCPTP","AJUBA","STING"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P23458","full_name":"Tyrosine-protein kinase JAK1","aliases":["Janus kinase 1","JAK-1"],"length_aa":1154,"mass_kda":133.3,"function":"Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway (PubMed:16239216, PubMed:28111307, PubMed:32750333, PubMed:7615558, PubMed:8232552). Kinase partner for the interleukin (IL)-2 receptor (PubMed:11909529) as well as interleukin (IL)-10 receptor (PubMed:12133952). Kinase partner for the type I interferon receptor IFNAR2 (PubMed:16239216, PubMed:28111307, PubMed:32750333, PubMed:7615558, PubMed:8232552). In response to interferon-binding to IFNAR1-IFNAR2 heterodimer, phosphorylates and activates its binding partner IFNAR2, creating docking sites for STAT proteins (PubMed:7759950). Directly phosphorylates STAT proteins but also activates STAT signaling through the transactivation of other JAK kinases associated with signaling receptors (PubMed:16239216, PubMed:32750333, PubMed:8232552)","subcellular_location":"Endomembrane system","url":"https://www.uniprot.org/uniprotkb/P23458/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JAK1","classification":"Not Classified","n_dependent_lines":49,"n_total_lines":1208,"dependency_fraction":0.04056291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/JAK1","total_profiled":1310},"omim":[{"mim_id":"621509","title":"G PROTEIN-COUPLED RECEPTOR 160; GPR160","url":"https://www.omim.org/entry/621509"},{"mim_id":"621374","title":"SERINE/THREONINE/TYROSINE-INTERACTING PROTEIN-LIKE 2; STYXL2","url":"https://www.omim.org/entry/621374"},{"mim_id":"620443","title":"DISABLING PANSCLEROTIC MORPHEA OF CHILDHOOD; DPMC","url":"https://www.omim.org/entry/620443"},{"mim_id":"619175","title":"PROTEASOME-ASSOCIATED AUTOINFLAMMATORY SYNDROME 5; PRAAS5","url":"https://www.omim.org/entry/619175"},{"mim_id":"618999","title":"AUTOINFLAMMATION, IMMUNE DYSREGULATION, AND EOSINOPHILIA; AIIDE","url":"https://www.omim.org/entry/618999"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/JAK1"},"hgnc":{"alias_symbol":["JAK1A","JTK3"],"prev_symbol":["JAK1B"]},"alphafold":{"accession":"P23458","domains":[{"cath_id":"-","chopping":"36-115_152-278","consensus_level":"medium","plddt":92.1718,"start":36,"end":278},{"cath_id":"2.30.29.200","chopping":"285-330_357-416","consensus_level":"high","plddt":84.8577,"start":285,"end":416},{"cath_id":"3.30.505.10","chopping":"441-546","consensus_level":"high","plddt":92.0119,"start":441,"end":546},{"cath_id":"3.30.200.20","chopping":"581-669","consensus_level":"medium","plddt":87.1043,"start":581,"end":669},{"cath_id":"1.10.510.10","chopping":"674-852","consensus_level":"high","plddt":90.1739,"start":674,"end":852},{"cath_id":"3.30.200.20","chopping":"873-958","consensus_level":"medium","plddt":85.3113,"start":873,"end":958},{"cath_id":"1.10.510.10","chopping":"963-1154","consensus_level":"high","plddt":93.1548,"start":963,"end":1154}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23458","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23458-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23458-F1-predicted_aligned_error_v6.png","plddt_mean":85.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=JAK1","jax_strain_url":"https://www.jax.org/strain/search?query=JAK1"},"sequence":{"accession":"P23458","fasta_url":"https://rest.uniprot.org/uniprotkb/P23458.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23458/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23458"}},"corpus_meta":[{"pmid":"27903500","id":"PMC_27903500","title":"Primary 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interferon-alpha/beta and interferon-gamma signal transduction. A JAK1-deficient cell line was completely defective in interferon response; complementation with JAK1 restored signaling. JAK1 and TYK2 are mutually dependent in the IFN-α pathway, and JAK1 and JAK2 are mutually dependent in the IFN-γ pathway, likely reflecting a requirement for these kinases in correct assembly of interferon receptor complexes.\",\n      \"method\": \"Genetic complementation of JAK1-deficient mutant cell line; loss-of-function + rescue\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean complementation experiment in JAK1-null cell line, foundational result independently replicated across the field\",\n      \"pmids\": [\"8232552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Receptor-associated constitutive protein tyrosine phosphatase (PTP) activity controls JAK1 kinase function. Inhibition of PTP activity with pervanadate activates JAKs and leads to JAK1-dependent, IL-4Rα-mediated STAT6 activation independently of receptor dimerization. This indicates that constitutive PTP activity suppresses persistent receptor-linked JAK1 activity.\",\n      \"method\": \"Pharmacological PTP inhibition (pervanadate), JAK1-deficient cell lines, complementation with IL-4Rα; loss-of-function and rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell lines, genetic complementation, and pharmacological approach converge on same conclusion\",\n      \"pmids\": [\"9238016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Kinase-deficient dominant-negative forms of JAK1 and TYK2 each independently inhibit IFN-α–induced STAT phosphorylation and transcriptional activation, establishing that JAK1 kinase activity is required upstream of TYK2 in the IFN-α signaling cascade.\",\n      \"method\": \"Transfection of kinase-deficient mutants; dominant-negative assay; reporter gene assay; STAT phosphorylation analysis\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative mutagenesis with two orthogonal readouts (phosphorylation + reporter), single lab\",\n      \"pmids\": [\"9249040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Jak1 kinase is required for a specific cell migration (epiboly) and anterior specification in zebrafish embryos. Injection of dominant-negative Jak1 RNA reduces epiboly and decreases goosecoid expression and anterior structures, establishing a developmental role for JAK1 beyond cytokine signaling.\",\n      \"method\": \"Injection of dominant-negative Jak1 RNA into zebrafish embryos; developmental phenotype analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative in vivo approach in zebrafish, single lab with developmental readout\",\n      \"pmids\": [\"9096349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Hepatitis B virus HBx protein specifically activates JAK1 (but not JAK2 or TYK2) through direct protein–protein interaction with JAK1, elevating JAK1 tyrosine phosphorylation and kinase activity, and subsequently activating STAT3 and STAT5.\",\n      \"method\": \"Stable HBx-expressing cell lines; in vitro kinase assay; co-immunoprecipitation; STAT DNA-binding and transcriptional activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus co-IP demonstrating direct interaction, single lab\",\n      \"pmids\": [\"9738022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"JAK1 is required for IFN-γ–mediated growth arrest and/or apoptosis of v-abl–transformed pre-B cells. JAK1-deficient transformed cells were more tumorigenic in vivo, and their increased tumorigenicity correlated with loss of IFN-γ responsiveness, establishing JAK1's role in intrinsic IFN-γ–dependent tumor surveillance rather than in promotion of tumorigenesis.\",\n      \"method\": \"Jak1-deficient mouse model; v-abl transformation; in vivo transplantation (SCID/nude mice); IFN-γ response assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function mouse model with clear in vivo phenotype and mechanistic link to IFN-γ signaling\",\n      \"pmids\": [\"12576323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"JAK1 is required for myoblast proliferation and acts as a checkpoint preventing premature differentiation. JAK1 knockdown induces accelerated MyoD, MEF2, p21Cip1, and p27Kip1 induction and faster Id1 downregulation. Downstream, JAK1-STAT1-STAT3 constitutes the pathway through which LIF stimulates myoblast proliferation and represses differentiation.\",\n      \"method\": \"JAK1 knockdown (siRNA) in primary and immortalized myoblasts; gene expression analysis; cell proliferation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function in two cell types with multiple molecular readouts establishing pathway position\",\n      \"pmids\": [\"17908914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Myricetin directly binds to JAK1 (and STAT3) with higher affinity for JAK1 than STAT3, inhibiting JAK1 phosphorylation and EGF-induced cell transformation. Ex vivo and in vitro pull-down assays confirmed direct binding; myricetin inhibited JAK1 phosphorylation without affecting EGFR autophosphorylation.\",\n      \"method\": \"Pull-down assay (ex vivo and in vitro); affinity binding assay; western blot for JAK1 phosphorylation; colony transformation assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by pull-down with affinity data, single lab\",\n      \"pmids\": [\"18995957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TCPTP (protein tyrosine phosphatase) dephosphorylates and negatively regulates JAK1 and STAT3 signaling during the cell cycle. TCPTP-deficient MEFs show enhanced SFK, JAK1, and STAT3 activation; however, JAK1 and STAT3 (not SFK) signaling was not required for the enhanced G1/S transition observed.\",\n      \"method\": \"TCPTP knockout MEFs; RNA interference in HeLa cells; pharmacological inhibitors; cell cycle analysis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus RNAi with two orthogonal approaches, single lab\",\n      \"pmids\": [\"18948751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Activating mutations in JAK1 at Phe958 and Pro960 (hinge region of kinase domain) render JAK1 constitutively active and resistant to ATP-competitive JAK inhibitors. These mutations can both activate JAK1 oncogenically and confer drug resistance.\",\n      \"method\": \"Spontaneous cellular transformation screen in BaF3 cells; sequencing of JAK1 mutations; inhibitor sensitivity assays\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mutation analysis in cell-based transformation assay, single lab, well-defined readouts\",\n      \"pmids\": [\"21393331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ER stress activates JAK1 in astrocytes in a PERK-dependent manner. JAK1 phosphorylates PERK, and this PERK/JAK1/STAT3 axis drives IL-6 and chemokine expression. Disruption of PERK abrogates ER stress–induced STAT3 activation.\",\n      \"method\": \"Pharmacological ER stress induction; PERK disruption; JAK1 inhibition; western blot for STAT3 activation; gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic/pharmacological perturbations in glial cells, single lab\",\n      \"pmids\": [\"25113558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CXCL12/CXCR4 signaling promotes immunological synapse formation and T cell activation through Gi and JAK1/JAK2 kinase activation, contributing to actin polymerization at the APC contact site and MTOC polarization.\",\n      \"method\": \"CXCR4 blockade/downregulation; pharmacological JAK inhibition; actin polymerization assay; MTOC polarization analysis; T cell activation markers\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition combined with receptor downregulation and multiple cellular readouts, single lab\",\n      \"pmids\": [\"25917087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss-of-function JAK1 mutations in tumor cells result in inability to respond to interferon-gamma (IFN-γ), preventing IFN-γ–induced PD-L1 expression and interferon-stimulated gene induction, thereby mediating primary resistance to PD-1 blockade.\",\n      \"method\": \"Tumor biopsy sequencing; melanoma cell line functional assays; IFN-γ stimulation with PD-L1 expression readout; JAK1/2 mutation characterization\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human tumor samples plus functional cell line validation with mechanistic readout, replicated in two cancer types\",\n      \"pmids\": [\"27903500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Biallelic JAK1 missense mutations (P733L and P832S) cause reduced JAK1 and STAT phosphorylation following cytokine stimulation, reduced interferon-regulated gene induction, and dysregulated cytokine production. The P733L mutation is primarily responsible. Reconstitution experiments revealed a phosphorylation-independent role of JAK1 in signal transduction.\",\n      \"method\": \"Patient-derived cells; exome sequencing; cytokine stimulation assays; STAT phosphorylation; reconstitution experiments in JAK1-deficient cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient-derived cells plus reconstitution experiments with mutation-specific rescue, multiple readouts\",\n      \"pmids\": [\"28008925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AJUBA LIM protein binds specifically to the FERM domain of JAK1 to dissociate JAK1 from the IFN-γ receptor, inhibiting STAT1 phosphorylation and nuclear translocation, thereby suppressing the JAK1-STAT1-IFIT2 network and promoting cancer cell survival.\",\n      \"method\": \"Co-immunoprecipitation; domain mapping; STAT1 phosphorylation assay; IFIT2 expression analysis; cell viability and xenograft assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping and functional readouts, single lab\",\n      \"pmids\": [\"27893714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Conditional Jak1 deletion in hematopoietic stem cells (HSCs) reduces self-renewal, alters lymphoid/myeloid differentiation, decreases competitiveness, prevents cell cycle entry in response to hematopoietic stress, and markedly reduces cytokine sensing including to type I interferons and IL-3. JAK2 constitutive activation cannot fully rescue JAK1 loss in HSCs.\",\n      \"method\": \"Conditional Jak1 knockout mouse model; in vivo transplantation; cell cycle analysis; cytokine stimulation assays; competitive repopulation assay\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic KO in vivo with multiple orthogonal readouts and non-rescue by JAK2, single lab but rigorous\",\n      \"pmids\": [\"28965767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JAK1 phosphorylates SIRT1 at tyrosine residues Y280 and Y301 within the histone deacetylase catalytic domain in response to IL-6 stimulation. This phosphorylation does not alter SIRT1 deacetylase activity but is required for SIRT1 interaction with STAT3, enhancing SIRT1 suppression of STAT3 acetylation and transcriptional activity, constituting a negative feedback of the JAK1-STAT3 pathway.\",\n      \"method\": \"Co-immunoprecipitation; in vitro kinase assay; site-directed mutagenesis (Y280A, Y301A); STAT3 acetylation assay; transcriptional activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis identifying specific phosphorylation sites, plus functional consequence on STAT3, single lab\",\n      \"pmids\": [\"29789426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-6-activated JAK1 directly phosphorylates PD-L1 at Tyr112, which recruits the ER-associated N-glycosyltransferase STT3A to catalyze PD-L1 glycosylation and maintain PD-L1 stability, linking oncogenic IL-6/JAK1 signaling to immune evasion.\",\n      \"method\": \"In vitro kinase assay; phospho-specific antibody; co-immunoprecipitation; glycosylation assay; mutagenesis of PD-L1 Y112; animal models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with site-specific mutagenesis and co-IP demonstrating direct substrate relationship, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31305264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JAK1 (not JAK2) is the STAT3-activating kinase mediating extrinsically activated STAT3 in TKI-treated CML stem cells, driven by IL-6. This was established using selective JAK1/2 inhibitors and genetic inactivation, and combined Bcr-Abl + JAK1 inhibition reduced CML stem cell colony formation and leukemic stem cells.\",\n      \"method\": \"Selective JAK1/2 inhibitors; genetic JAK1 inactivation; IL-6 blocking peptide; CFU assay; transgenic CML mouse model\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological plus genetic approach identifying JAK1 specifically, single lab\",\n      \"pmids\": [\"30842608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Conditional deletion of JAK1 (but not JAK2) in NKp46+ NK cells markedly reduces NK cell numbers in bone marrow, spleen, blood, and liver, impairs NK cell development, and impairs NK cell–mediated tumor surveillance. JAK2 is dispensable for NK cell survival and cannot compensate for JAK1 loss.\",\n      \"method\": \"Conditional NK cell–specific Jak1 knockout (Jak1Ncr1Cre); NK cell number/function assessment; tumor surveillance assay; comparison with JAK2-conditional KO\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with clear phenotypic readouts and JAK2 comparison establishing JAK1-specific function\",\n      \"pmids\": [\"30671064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TROY (orphan TNF receptor) directly interacts with JAK1, increases JAK1 phosphorylation, and promotes STAT3 phosphorylation and transcriptional activity in a JAK1-dependent manner. JAK1 inhibition or knockdown significantly inhibits TROY-induced STAT3 activation, GBM cell migration, and temozolomide resistance.\",\n      \"method\": \"Co-immunoprecipitation; JAK1 phosphorylation assay; STAT3 reporter assay; JAK1 siRNA knockdown; ruxolitinib pharmacological inhibition; migration assay\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional knockdown with multiple readouts, single lab\",\n      \"pmids\": [\"32629176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The JAK1 pseudokinase domain (JH2) has distinct regulatory functions across different receptor complexes: in IL-2 signaling JAK1 is dominant over JAK3 and strictly requires both JH1 and JH2; in IFN-γ signaling both JAK1 and JAK2 are indispensable for STAT1 activation and JAK1 JH2 (rather than kinase activity) is the key requirement. Mutations in the JAK1 JH2 αC-helix (L633) reduce basal and cytokine-induced STAT activation.\",\n      \"method\": \"JAK-deficient cell lines; structure-based mutagenesis; cytokine stimulation assays; STAT phosphorylation analysis\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-guided mutagenesis in defined cell backgrounds, single lab with multiple cytokine systems\",\n      \"pmids\": [\"31892268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRAF6 negatively regulates JAK1 activation in IL-2 signaling by binding to the TRAF6-binding site on the IL-2R β-chain, which overlaps with the JAK1-binding site. A β-chain mutation that inactivates TRAF6 binding while retaining JAK1 binding abrogated TRAF6-dependent reduction in JAK1-Erk pathway activation.\",\n      \"method\": \"Traf6-knockout T cells and MEFs; IL-2 signaling reconstitution; β-chain binding-site mutagenesis; JAK1 phosphorylation and Erk activation assays\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus receptor mutagenesis defining binding competition, single lab\",\n      \"pmids\": [\"21155952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Itaconate and 4-octyl itaconate (OI) directly modify JAK1 at multiple cysteine residues (C715, C816, C943, C1130) and inhibit JAK1 kinase activity and phosphorylation, suppressing M2 macrophage polarization in response to IL-4, IL-13, IFN-β, and IFN-γ in vitro and in vivo.\",\n      \"method\": \"Direct chemical modification identified by mass spectrometry; in vitro kinase activity assay; JAK1 phosphorylation analysis; M2 polarization assays in macrophages and Th2 cells; in vivo OI treatment\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical modification identified by MS plus in vitro kinase assay, multiple cell types, confirmed in vivo\",\n      \"pmids\": [\"35235776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAK1 contains a druggable allosteric cysteine (C817) in its non-catalytic pseudokinase domain (absent from JAK2 and JAK3). Electrophilic compounds targeting C817 block JAK1-dependent trans-phosphorylation and cytokine signaling. Cells expressing a C817A JAK1 mutant are insensitive to these allosteric inhibitors, confirming C817 as the functional engagement site.\",\n      \"method\": \"Chemical proteomics; electrophilic compound library; covalent labeling; C817A mutagenesis; STAT phosphorylation assays; cytokine signaling assays\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — chemical proteomic identification plus mutagenesis confirming functional site, multiple orthogonal assays\",\n      \"pmids\": [\"36097295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Influenza A virus PB2 protein targets mammalian JAK1 at lysine residues K859 and K860 for ubiquitination and proteasomal degradation, suppressing IFN-α/β signaling and STAT1/STAT2 activation as a mechanism of immune evasion.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; site-specific mutagenesis (K859/K860); JAK1 protein level analysis; STAT phosphorylation assay; viral replication assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP plus mutagenesis identifying specific ubiquitination sites with functional consequence on signaling, replicated in multiple IAV subtypes\",\n      \"pmids\": [\"36271046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DPYSL2 (dihydropyrimidinase-like 2) directly interacts with JAK1, and this binding is required for activating STAT3 and subsequent vimentin expression, promoting breast cancer cell migration and metastasis.\",\n      \"method\": \"Co-immunoprecipitation; DPYSL2 knockout; migration/invasion assays; STAT3 phosphorylation analysis; in vivo xenograft\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus genetic KO with mechanistic readout, single lab\",\n      \"pmids\": [\"35575798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAK1 directly interacts with TGF-β receptor I subunit (TβRI). Silencing JAK1 promotes myofibroblast transdifferentiation; this is mediated via constitutive STAT3 activation that requires JAK1. Silencing unphosphorylated STAT3 suppresses TGF-β signaling, SMAD3 activation, and ECM production, revealing a noncanonical JAK1/STAT3 regulatory axis in lung fibroblasts.\",\n      \"method\": \"Co-immunoprecipitation; siRNA silencing; upadacitinib pharmacological inhibition; SMAD3 phosphorylation assay; myofibroblast differentiation assay; in vivo fibrosis model\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus siRNA with multiple signaling readouts, single lab\",\n      \"pmids\": [\"36283961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC1 deacetylates JAK1 at lysine 1109; HDAC inhibition (SAHA) increases JAK1 K1109 acetylation, promoting JAK1 proteasomal degradation and reducing STAT3-driven FGL1 transcription, thereby enhancing CD8+ T cell antitumor activity.\",\n      \"method\": \"Co-immunoprecipitation; mass spectrometry; site-specific mutagenesis; proteasome inhibitor assay; STAT3 activity assay; chromatin immunoprecipitation; in vivo tumor model\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometry identifying specific modification site, co-IP, mutagenesis, and in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39384195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EHBP1L1 interacts with and stabilizes JAK1 protein by competing with SOCS1 for JAK1 binding, thereby protecting JAK1 from proteasomal degradation and maintaining elevated JAK1/STAT1/PD-L1 signaling in renal cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation; EHBP1L1 depletion; protein stability assay; proteasome inhibitor rescue; STAT1/PD-L1 expression analysis; PDX tumor model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with competition assay and protein stability readout, single lab\",\n      \"pmids\": [\"36775874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"JAK1 is palmitoylated endogenously in dorsal root ganglion (DRG) neurons and in HEK293T cells. ZDHHC3 and ZDHHC7 are the dominant protein acyltransferases (PATs) for JAK1. Palmitoylation is critical for JAK1 kinase activity (even in vitro) and facilitates transphosphorylation of key activation loop sites, but minimally affects JAK1 localization in neurons. A leukemia-associated JAK1 mutation overrides palmitoylation-dependence of JAK1 activity. JAK1 palmitoylation is required for neuropoietic cytokine-dependent signaling and neuronal survival.\",\n      \"method\": \"Palmitoylation assay; ZDHHC screening; shRNA knockdown; in vitro kinase assay; neuronal survival assay; cytokine signaling assays; structural modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus genetic identification of PATs with multiple cellular readouts including neuronal survival, single lab with comprehensive approach\",\n      \"pmids\": [\"37356718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL3 deposits m6A on the 3' UTR of JAK1 mRNA to promote JAK1 translation via YTHDF1 recognition, increasing JAK1 protein levels and contributing to STAT3 pathway activation and colorectal cancer progression.\",\n      \"method\": \"m6A-seq; YTHDF1 co-immunoprecipitation; ribosome profiling; JAK1 reporter assay; METTL3 catalytic mutant\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epitranscriptomic mechanism with co-IP and reader protein, single lab\",\n      \"pmids\": [\"38001065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"JAK1 kinase activity is required for HDV replication. JAK1 inhibition modulates ERK1/2 activation and S-HDAg (small hepatitis delta antigen) phosphorylation, which is crucial for viral replication. Co-immunoprecipitation confirmed JAK1 interaction within the HDV replication complex.\",\n      \"method\": \"Loss-of-function (siRNA/JAK1 inhibitors); co-immunoprecipitation; ERK1/2 and S-HDAg phosphorylation assays; HDV replication assay in primary human hepatocytes\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional kinase activity assay with viral readout, single lab\",\n      \"pmids\": [\"37925078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Chemotherapy-induced JAK1 activation occurs through an alternative mechanism: DNA damage induces JAK1-SQ phosphorylation that releases JAK1 pseudokinase domain (JH2) inhibition, allowing JAK1 activation without cytokine receptor engagement. This leads to STAT6 nuclear translocation and GAS6 secretion, activating TAM kinases to confer chemoresistance in Ewing sarcoma.\",\n      \"method\": \"Phospho-profiling; JAK1 inhibition (filgotinib); STAT6 nuclear translocation assay; GAS6 secretion measurement; in vitro and in vivo chemosensitization assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-profiling with pharmacological inhibition and multiple functional readouts, single lab\",\n      \"pmids\": [\"38906855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STING acts downstream of IFN-α/β receptor (IFNAR) in endothelial cells and interacts directly with JAK1 upon IFN-I stimulation, promoting JAK1 phosphorylation. This interaction requires STING palmitoylation at Cysteine 91 but not the STING C-terminal tail (CTT) domain, and drives JAK1-STAT signaling for tumor vessel normalization and CD8+ T cell infiltration.\",\n      \"method\": \"Co-immunoprecipitation; STING palmitoylation-site mutagenesis (C91); IFN-I signaling assays; endothelial-specific STING deletion; JAK1 phosphorylation analysis; in vivo tumor models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with site-specific mutagenesis and genetic deletion, single lab\",\n      \"pmids\": [\"39817453\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JAK1 is a non-receptor tyrosine kinase constitutively associated with diverse cytokine receptors that acts as an obligate signaling hub: it heterodimerizes with TYK2 (IFN-α/β), JAK2 (IFN-γ, gp130 cytokines), or JAK3 (γc-chain cytokines) to enable receptor complex assembly, trans-phosphorylation, and downstream STAT activation; its activity is negatively regulated by receptor-associated phosphatases (TCPTP, receptor PTPs), by SOCS1-mediated proteasomal degradation, by HDAC1-dependent acetylation at K1109, and is positively regulated by palmitoylation (via ZDHHC3/7) which facilitates activation-loop transphosphorylation; JAK1 directly phosphorylates substrates beyond STATs including PERK, SIRT1 (Y280/Y301), and PD-L1 (Y112, initiating glycosylation), and is itself targeted for ubiquitination/degradation by viral proteins (IAV PB2 at K859/K860) or stabilized by scaffold proteins (EHBP1L1 competing with SOCS1); an allosteric cysteine in its pseudokinase domain (C817) provides an isoform-selective regulatory site, and the pseudokinase domain (JH2) exerts regulatory control over the kinase domain (JH1) in a receptor context-dependent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"JAK1 is a non-receptor tyrosine kinase that serves as an obligate signaling hub for cytokine and interferon receptors, coupling receptor engagement to STAT activation across immune, hematopoietic, and developmental programs [#0, #15]. It is mutually dependent on partner kinases for interferon signaling — acting with TYK2 in the IFN-\\u03b1/\\u03b2 pathway and with JAK2 in the IFN-\\u03b3 pathway — where its activity and pseudokinase (JH2) domain are required for correct receptor complex assembly and STAT phosphorylation [#0, #2, #21]. JAK1 function is non-redundant in vivo: conditional deletion impairs hematopoietic stem cell self-renewal, cytokine sensing, and NK cell development, and JAK2 cannot compensate for its loss [#15, #19]. Beyond canonical STAT signaling, JAK1 directly phosphorylates a defined set of substrates: PERK during ER stress to drive a PERK/JAK1/STAT3 axis [#10], SIRT1 at Y280/Y301 to enable SIRT1-STAT3 negative feedback [#16], and PD-L1 at Y112 to recruit STT3A and stabilize PD-L1 glycosylation, linking IL-6/JAK1 signaling to immune evasion [#17]. JAK1 activity is tightly controlled by multiple layers: dephosphorylation by receptor-associated PTPs including TCPTP [#1, #8], proteasomal turnover modulated by SOCS1 competition (antagonized by EHBP1L1) [#29], HDAC1-dependent acetylation at K1109 [#28], and positive regulation by ZDHHC3/7-mediated palmitoylation that facilitates activation-loop transphosphorylation [#30]. Its catalytic state is further shaped by activating hinge mutations that confer drug resistance [#9] and by a JAK1-selective allosteric cysteine (C817) in the pseudokinase domain that is targetable by electrophilic inhibitors [#24]. Loss-of-function JAK1 mutations abrogate IFN-\\u03b3 responsiveness and PD-L1 induction, mediating resistance to PD-1 blockade [#12], while biallelic missense mutations cause a human immune dysregulation phenotype with impaired cytokine signaling [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that JAK1 is an essential, non-redundant component of interferon signaling, defining its core role as a receptor-coupled kinase required for STAT pathway activation.\",\n      \"evidence\": \"Genetic complementation of a JAK1-deficient cell line with loss-of-function and rescue across IFN-\\u03b1/\\u03b2 and IFN-\\u03b3 responses\",\n      \"pmids\": [\"8232552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular basis of receptor complex assembly\", \"Did not establish substrate specificity beyond STATs\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined the kinase hierarchy and constitutive negative regulation of JAK1, showing its kinase activity acts upstream of TYK2 and that receptor-associated PTPs suppress persistent JAK1 activity.\",\n      \"evidence\": \"Dominant-negative kinase-dead mutants for pathway ordering; pervanadate PTP inhibition with JAK1-deficient cell complementation\",\n      \"pmids\": [\"9249040\", \"9238016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the responsible receptor-associated phosphatase not pinned down here\", \"Mechanism of dimerization-independent activation not defined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Extended JAK1 function beyond cytokine signaling to embryonic development, indicating a role in morphogenetic movements and patterning.\",\n      \"evidence\": \"Dominant-negative Jak1 RNA injection in zebrafish with epiboly and goosecoid phenotype readouts\",\n      \"pmids\": [\"9096349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dominant-negative may not phenocopy null\", \"Receptor/ligand upstream of developmental JAK1 not identified\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed viral proteins can hijack JAK1 selectively, with HBx directly binding and activating JAK1 to drive STAT3/STAT5.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, and STAT DNA-binding assays in HBx-expressing cells\",\n      \"pmids\": [\"9738022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface on JAK1 not mapped\", \"Single-lab; physiological relevance to HBV pathogenesis not established here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated a tumor-suppressive function for JAK1 via IFN-\\u03b3-dependent growth arrest, linking JAK1 loss to increased tumorigenicity.\",\n      \"evidence\": \"Jak1-deficient v-abl-transformed pre-B cells with in vivo transplantation and IFN-\\u03b3 response assays\",\n      \"pmids\": [\"12576323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address JAK1 oncogenic gain-of-function contexts\", \"Downstream effectors of growth arrest not fully defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Positioned JAK1 as a proliferation checkpoint in muscle, acting through a LIF/JAK1-STAT1-STAT3 axis to repress premature differentiation.\",\n      \"evidence\": \"siRNA knockdown in primary and immortalized myoblasts with differentiation marker and proliferation readouts\",\n      \"pmids\": [\"17908914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct STAT targets controlling differentiation genes not mapped\", \"Receptor mediating LIF input not specified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified TCPTP as a specific phosphatase dephosphorylating JAK1 during the cell cycle, refining the negative regulatory machinery.\",\n      \"evidence\": \"TCPTP-knockout MEFs and HeLa RNAi with cell cycle analysis\",\n      \"pmids\": [\"18948751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"JAK1/STAT3 signaling dispensable for the observed G1/S phenotype, decoupling phosphatase target from function\", \"Direct dephosphorylation site on JAK1 not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided chemical-biology evidence that small molecules can directly engage and inhibit JAK1, with myricetin binding JAK1 to block its phosphorylation.\",\n      \"evidence\": \"Pull-down/affinity binding assays and phospho-JAK1 western blots with transformation assay\",\n      \"pmids\": [\"18995957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site not localized\", \"Selectivity over other JAKs not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed JAK1 can be oncogenically activated by kinase-domain hinge mutations (F958/P960) that also confer ATP-competitive inhibitor resistance.\",\n      \"evidence\": \"Spontaneous transformation screen in BaF3 cells with mutation sequencing and inhibitor sensitivity assays\",\n      \"pmids\": [\"21393331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of constitutive activation not solved here\", \"Clinical prevalence not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed receptor-level negative regulation through binding-site competition, with TRAF6 occluding the JAK1-binding site on IL-2R\\u03b2.\",\n      \"evidence\": \"Traf6-knockout T cells/MEFs with IL-2R \\u03b2-chain binding-site mutagenesis and JAK1/Erk readouts\",\n      \"pmids\": [\"21155952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality across other cytokine receptors not tested\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a non-canonical activation route in which ER stress activates JAK1 PERK-dependently and JAK1 phosphorylates PERK, defining a PERK/JAK1/STAT3 inflammatory axis.\",\n      \"evidence\": \"ER stress induction with PERK disruption and JAK1 inhibition in astrocytes\",\n      \"pmids\": [\"25113558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PERK phosphosites by JAK1 not mapped\", \"Whether interaction is direct not fully established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected chemokine signaling to cytoskeletal reorganization, showing CXCL12/CXCR4 engages JAK1/JAK2 to support immune synapse formation.\",\n      \"evidence\": \"Pharmacological JAK inhibition and CXCR4 downregulation with actin/MTOC and T cell activation readouts\",\n      \"pmids\": [\"25917087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"JAK1-specific contribution vs JAK2 not separated\", \"Direct substrates in synapse formation unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a scaffold-based off-switch in which AJUBA binds the JAK1 FERM domain to dissociate JAK1 from the IFN-\\u03b3 receptor and suppress STAT1 signaling.\",\n      \"evidence\": \"Co-IP with domain mapping, STAT1 phosphorylation, IFIT2 readouts, and xenografts\",\n      \"pmids\": [\"27893714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry of dissociation not quantified\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established the clinical consequence of JAK1 loss-of-function, showing tumor JAK1 mutations abolish IFN-\\u03b3-induced PD-L1 and ISG induction to drive PD-1 blockade resistance.\",\n      \"evidence\": \"Tumor biopsy sequencing with melanoma cell line IFN-\\u03b3 stimulation and PD-L1 readouts\",\n      \"pmids\": [\"27903500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not enumerate full ISG dependency\", \"Did not address gain-of-function tumor contexts\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked biallelic JAK1 missense mutations to a human immune dysregulation phenotype and uncovered a phosphorylation-independent JAK1 function in signal transduction.\",\n      \"evidence\": \"Patient-derived cells, exome sequencing, and reconstitution in JAK1-deficient cells\",\n      \"pmids\": [\"28008925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the phosphorylation-independent role not defined\", \"Genotype-phenotype across additional families limited\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified SIRT1 as a direct JAK1 substrate (Y280/Y301), revealing a feedback loop where JAK1 phosphorylation licenses SIRT1 to suppress STAT3 acetylation.\",\n      \"evidence\": \"In vitro kinase assay, site-directed mutagenesis, and STAT3 acetylation/transcription assays after IL-6\",\n      \"pmids\": [\"29789426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural consequence of Y280/Y301 phosphorylation not resolved\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a non-redundant role for JAK1 in NK cell development and tumor surveillance that JAK2 cannot substitute for.\",\n      \"evidence\": \"NK-specific conditional Jak1 knockout (Ncr1Cre) with developmental, functional, and tumor surveillance readouts versus JAK2 KO\",\n      \"pmids\": [\"30671064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytokine receptor input(s) driving NK dependence not isolated\", \"Downstream STAT specificity in NK cells not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed JAK1 directly phosphorylates PD-L1 at Y112 to recruit STT3A for glycosylation-dependent stabilization, mechanistically coupling IL-6/JAK1 to immune evasion.\",\n      \"evidence\": \"In vitro kinase assay, phospho-specific antibody, PD-L1 Y112 mutagenesis, glycosylation assay, and animal models\",\n      \"pmids\": [\"31305264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether JAK1-PD-L1 phosphorylation occurs at receptor or ER not localized\", \"Generality across cancer types not fully mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated JAK1-specific (not JAK2) STAT3 activation by extrinsic IL-6 in TKI-treated CML stem cells, nominating JAK1 as a co-target for leukemic stem cell eradication.\",\n      \"evidence\": \"Selective JAK1/2 inhibitors, genetic JAK1 inactivation, IL-6 blocking, CFU assay, and transgenic CML model\",\n      \"pmids\": [\"30842608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect JAK1-STAT3 coupling not dissected\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established JAK1 as essential for hematopoietic stem cell self-renewal, stress response, and cytokine sensing, with constitutively active JAK2 unable to rescue JAK1 loss.\",\n      \"evidence\": \"Conditional Jak1 knockout mice with transplantation, cell cycle, cytokine stimulation, and competitive repopulation assays\",\n      \"pmids\": [\"28965767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific receptors mediating HSC dependence not isolated\", \"Mechanism of JAK2 non-redundancy not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed an orphan TNF receptor (TROY) can directly engage and activate JAK1 to drive STAT3-dependent glioma malignancy, broadening the receptor partners of JAK1.\",\n      \"evidence\": \"Co-IP, JAK1 siRNA/ruxolitinib, STAT3 reporter, and migration assays\",\n      \"pmids\": [\"32629176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding region on JAK1 not mapped\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Dissected the receptor-context-dependent regulatory role of the JAK1 pseudokinase (JH2) domain, showing JH2 (rather than kinase activity) is the key requirement in IFN-\\u03b3 signaling and that JAK1 is dominant in IL-2 signaling.\",\n      \"evidence\": \"JAK-deficient cell lines with structure-based JH2 mutagenesis (L633) and STAT phosphorylation assays across cytokine systems\",\n      \"pmids\": [\"31892268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural mechanism of JH2 regulation not solved\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a JAK1-selective allosteric cysteine (C817) in the pseudokinase domain as a functional, druggable site for isoform-selective inhibition.\",\n      \"evidence\": \"Chemical proteomics, covalent labeling, and C817A mutagenesis with STAT phosphorylation and cytokine signaling assays\",\n      \"pmids\": [\"36097295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How C817 engagement allosterically blocks trans-phosphorylation not structurally resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed an endogenous metabolite (itaconate) directly modifies multiple JAK1 cysteines to inhibit its kinase activity, coupling immunometabolism to JAK1 control.\",\n      \"evidence\": \"Mass spectrometry of cysteine adducts (C715/C816/C943/C1130), in vitro kinase assay, and macrophage polarization assays in vitro/in vivo\",\n      \"pmids\": [\"35235776\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of individual cysteines to inhibition not ranked\", \"Endogenous itaconate concentrations achieving inhibition not benchmarked\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Added a developmental/cancer JAK1 partner with DPYSL2 directly binding JAK1 to enable STAT3-driven migration and metastasis.\",\n      \"evidence\": \"Co-IP, DPYSL2 knockout, migration/invasion assays, and xenograft\",\n      \"pmids\": [\"35575798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether binding alters JAK1 catalytic activity unclear\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a noncanonical JAK1/STAT3 axis controlling TGF-\\u03b2 signaling, with JAK1 binding T\\u03b2RI and unphosphorylated STAT3 modulating SMAD3 and ECM production in fibroblasts.\",\n      \"evidence\": \"Co-IP, siRNA, upadacitinib, SMAD3 phosphorylation, and in vivo fibrosis model\",\n      \"pmids\": [\"36283961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direction of JAK1 effect (suppressive) mechanistically unusual and not fully resolved\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a viral immune-evasion strategy where influenza PB2 ubiquitinates JAK1 at K859/K860 for degradation, blunting type I IFN signaling.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, K859/K860 mutagenesis, and STAT/viral replication readouts across IAV subtypes\",\n      \"pmids\": [\"36271046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Host E3 ligase recruited by PB2 not identified\", \"Whether these lysines are used by endogenous turnover unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established palmitoylation as a positive regulatory modification, with ZDHHC3/7 palmitoylating JAK1 to enable activation-loop transphosphorylation and kinase activity.\",\n      \"evidence\": \"Palmitoylation assays, ZDHHC screening/knockdown, in vitro kinase assay, and neuronal survival/cytokine signaling readouts\",\n      \"pmids\": [\"37356718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Palmitoylated residue(s) not pinpointed in this summary\", \"How leukemic mutation overrides palmitoylation-dependence not detailed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified acetylation as a degradative control point, with HDAC1 deacetylating JAK1 at K1109 to stabilize it and sustain STAT3-driven FGL1 transcription.\",\n      \"evidence\": \"Mass spectrometry, site mutagenesis, proteasome inhibition, ChIP, and in vivo tumor model\",\n      \"pmids\": [\"39384195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetyltransferase opposing HDAC1 not identified\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined SOCS1-antagonizing stabilization, with EHBP1L1 competing with SOCS1 for JAK1 to protect it from degradation and maintain JAK1/STAT1/PD-L1 signaling.\",\n      \"evidence\": \"Co-IP competition, protein stability and proteasome rescue assays, and PDX models\",\n      \"pmids\": [\"36775874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface overlap with SOCS1 not structurally mapped\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Added an epitranscriptomic layer, with METTL3-deposited m6A on JAK1 mRNA promoting JAK1 translation via YTHDF1 to amplify STAT3 signaling.\",\n      \"evidence\": \"m6A-seq, YTHDF1 co-IP, ribosome profiling, and METTL3 catalytic mutant in colorectal cancer\",\n      \"pmids\": [\"38001065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific m6A sites in 3'UTR not functionally validated individually\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed JAK1 kinase activity is co-opted within the HDV replication complex, modulating ERK1/2 and S-HDAg phosphorylation required for replication.\",\n      \"evidence\": \"siRNA/JAK1 inhibitors, co-IP, and HDV replication assays in primary hepatocytes\",\n      \"pmids\": [\"37925078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether JAK1 phosphorylates S-HDAg directly not established\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered a DNA damage-driven, receptor-independent activation mode where JAK1-SQ phosphorylation relieves JH2 autoinhibition to drive STAT6/GAS6/TAM signaling and chemoresistance.\",\n      \"evidence\": \"Phospho-profiling, filgotinib inhibition, STAT6 translocation, GAS6 secretion, and chemosensitization in Ewing sarcoma\",\n      \"pmids\": [\"38906855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for JAK1-SQ phosphorylation not identified\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioned STING as a direct JAK1 partner downstream of IFNAR, with palmitoylated STING (C91) promoting JAK1 phosphorylation to drive tumor vessel normalization.\",\n      \"evidence\": \"Co-IP, STING C91 palmitoylation-site mutagenesis, endothelial STING deletion, and in vivo tumor models\",\n      \"pmids\": [\"39817453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How STING palmitoylation enables JAK1 engagement structurally unclear\", \"Single-lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the full network of post-translational modifications (palmitoylation, acetylation, ubiquitination, cysteine modification) and pseudokinase-domain control are integrated to set JAK1 activity in distinct receptor and cellular contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model linking JH2 regulation to receptor context\", \"Cross-talk and hierarchy among competing JAK1 PTMs not established\", \"Substrate selection rules beyond STATs not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [10, 16, 17, 30]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 16, 17]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [9, 24]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [14, 21, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 14, 22]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 12, 19, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 21]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [16, 17, 28]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [25, 28, 29, 30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 25, 32]}\n    ],\n    \"complexes\": [\"cytokine receptor-JAK signaling complex\"],\n    \"partners\": [\"TYK2\", \"JAK2\", \"STAT3\", \"SIRT1\", \"PERK\", \"TCPTP\", \"AJUBA\", \"STING\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}