Affinage

JAK2

Tyrosine-protein kinase JAK2 · UniProt O60674

Round 2 corrected
Length
1132 aa
Mass
130.7 kDa
Annotated
2026-04-28
130 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

JAK2 is a non-receptor tyrosine kinase that constitutively associates with cytokine receptors via its FERM domain, becomes activated through ligand-induced receptor dimerization and trans-phosphorylation, and propagates signals through phosphorylation of STATs, histone H3Y41, TET2, YBX1, IκBα, and the EGF receptor (PMID:8343951, PMID:30044226, PMID:19783980, PMID:30944118, PMID:33239784, PMID:9363897, PMID:11493922). In the basal state, the pseudokinase domain (JH2) directly inhibits the kinase domain (JH1) through an interdomain interface; the oncogenic V617F mutation disrupts this autoinhibitory interaction, producing constitutive kinase activity that drives myeloproliferative neoplasms including polycythemia vera (PMID:10779328, PMID:24918548, PMID:15793561, PMID:15858187). JAK2 activity is negatively regulated by SH-PTP1 recruitment to receptor phosphotyrosines, PTP1B-mediated dephosphorylation, SOCS1/JAB binding to the kinase domain, Lnk/SH2B3, and autophosphorylation at inhibitory sites Y570 and S523 (PMID:7889566, PMID:11694501, PMID:9202126, PMID:19293402, PMID:15143187, PMID:16705160). Beyond classical cytokine signaling, nuclear JAK2 phosphorylates histone H3Y41 to displace HP1α and regulate chromatin state at specific loci, and JAK2 amplification drives PD-L1/PD-L2 immune-evasion transcription in lymphoma (PMID:19783980, PMID:20628145).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1993 High

    The identity of the kinase coupling cytokine receptors to intracellular tyrosine phosphorylation was unknown; demonstration that JAK2 physically associates with the erythropoietin receptor and is activated upon EPO binding established JAK2 as the proximal signal-transducing kinase for type I cytokine receptors.

    Evidence Co-immunoprecipitation, in vitro kinase assay, and EPOR cytoplasmic domain mutant analysis in cell lines

    PMID:8343951

    Open questions at the time
    • Structural basis for FERM–receptor interaction not resolved
    • Trans-phosphorylation mechanism not directly shown
  2. 1994 High

    Whether JAK2 receptor association was universal or receptor-specific was unclear; showing JAK2 preassociates with prolactin receptor, gp130, and LIF receptor β extended the paradigm to multiple cytokine receptor families and established ligand-induced dimerization as the general trigger for JAK2 activation.

    Evidence Co-immunoprecipitation and kinase activation assays across prolactin receptor, gp130, and LIF receptor systems

    PMID:7508935 PMID:8272873

    Open questions at the time
    • Stoichiometry of JAK2–receptor complexes undefined
    • Mechanism by which dimerization activates kinase unknown
  3. 1997 High

    Negative feedback mechanisms for JAK2 were uncharacterized; identification of SH-PTP1 as a receptor-recruited phosphatase that inactivates JAK2, and SOCS1/JAB as a direct kinase-domain inhibitor, defined two distinct layers of JAK2 signal termination.

    Evidence SH-PTP1 SH2 domain binding to EPOR Y429, EPOR mutant prolonged JAK2 phosphorylation; yeast two-hybrid and co-IP showing SOCS1 binds JH1 and suppresses kinase activity

    PMID:7889566 PMID:9202126

    Open questions at the time
    • Relative contribution of each negative regulator in vivo not quantified
    • Whether SOCS1 acts as pseudosubstrate or allosteric inhibitor unresolved
  4. 1997 High

    Whether JAK2 signals beyond STATs was uncertain; demonstration that JAK2 directly phosphorylates EGFR at Y1068 to recruit Grb2 and activate Ras-MAPK revealed JAK2 as a cross-pathway kinase with substrates beyond the STAT family.

    Evidence EGFR phosphorylation-site mutants, Grb2 association, and MAPK activity assays in GH-stimulated cells

    PMID:9363897

    Open questions at the time
    • Full repertoire of non-STAT JAK2 substrates not mapped
    • Physiological importance of JAK2-EGFR cross-talk in vivo untested
  5. 2000 High

    The function of the pseudokinase domain (JH2) was enigmatic; deletion mutagenesis showed JH2 directly interacts with and inhibits the kinase domain, preventing ligand-independent STAT activation, establishing JH2 as the autoinhibitory module of JAK2.

    Evidence Systematic JH2 deletion and domain interaction studies with STAT5 phosphorylation readouts

    PMID:10779328

    Open questions at the time
    • Atomic-resolution structure of JH2–JH1 interface not available
    • Whether JH2 ATP binding contributes to inhibition unknown
  6. 2001 High

    The phosphatase responsible for direct JAK2 dephosphorylation was debated; PTP1B was shown to dephosphorylate JAK2 via a consensus (E/D)-pY-pY-(R/K) motif, and PTP1B-null cells and mice displayed JAK2 hyperphosphorylation, establishing PTP1B as a physiological JAK2 phosphatase in both interferon and leptin signaling.

    Evidence Substrate-trapping PTP1B mutant co-IP, in vitro dephosphorylation, PTP1B−/− MEFs and mice with hypothalamic STAT3 readout

    PMID:11694501 PMID:11970898

    Open questions at the time
    • Whether PTP1B acts at the receptor complex or after JAK2 dissociation unclear
    • Tissue-specific hierarchy of JAK2-directed phosphatases not defined
  7. 2004 High

    Specific autophosphorylation sites controlling JAK2 activity were unmapped; mass spectrometry and mutagenesis identified Y221 as activating and Y570 as inhibitory, and S523 as an independently inhibitory serine site, revealing a multisite autoregulatory code.

    Evidence Mass spectrometry, 2D peptide mapping, Y→F and S→A mutagenesis with kinase activity assays

    PMID:15143187 PMID:16705160

    Open questions at the time
    • Kinases/phosphatases for S523 not identified
    • Temporal order of autophosphorylation events in vivo unknown
  8. 2005 High

    The genetic basis of myeloproliferative neoplasms was largely unknown; four independent groups identified the somatic JAK2 V617F mutation in the JH2 domain as a constitutively activating kinase mutation causing polycythemia vera and related MPNs, fundamentally reshaping diagnosis and therapy of these disorders.

    Evidence DNA sequencing in patient cohorts, retroviral bone marrow transplantation mouse models, in vitro kinase assays, BaF3 transformation, colony assays

    PMID:15781101 PMID:15793561 PMID:15837627 PMID:15858187 PMID:15863514

    Open questions at the time
    • How V617F disrupts JH2–JH1 interaction at atomic level not yet solved
    • Why V617F causes different MPN phenotypes in different patients unexplained
  9. 2009 High

    Whether JAK2 had nuclear substrates was unknown; demonstration that JAK2 phosphorylates histone H3 at Y41 to exclude HP1α and derepress gene expression (e.g., lmo2) established a direct epigenetic function for JAK2 signaling.

    Evidence Nuclear fractionation, in vitro kinase assay on histone H3, ChIP at the lmo2 promoter, JAK2 inhibitor treatment in leukemic cells

    PMID:19783980

    Open questions at the time
    • Genome-wide map of H3Y41ph limited to few loci
    • How JAK2 is imported into the nucleus mechanistically unclear
  10. 2014 High

    The molecular basis for JH2 autoinhibition lacked structural detail; molecular dynamics simulations combined with mutagenesis showed that nearly all MPN-associated mutations map to the JH2–JH1 interdomain interface, providing a unified structural explanation for how V617F and other mutations relieve autoinhibition.

    Evidence Molecular dynamics simulations, protein-protein docking, site-directed mutagenesis

    PMID:24918548

    Open questions at the time
    • Full-length JAK2 crystal structure not obtained
    • Dynamics of JH2–JH1 transition from inhibited to active state in real time not captured
  11. 2018 High

    How receptor dimerization structurally activates JAK2 was unclear; crystal structures of JAK2 FERM-SH2 domains bound to EPOR and LEPR revealed a 2:2 dimer dependent on a membrane-proximal receptor 'switch' region, demonstrating that receptor-mediated FERM dimerization is the structural trigger for kinase activation.

    Evidence X-ray crystallography of JAK2 FERM-SH2 with two receptors, switch-region mutagenesis, STAT phosphorylation assays

    PMID:30044226

    Open questions at the time
    • Full-length activated JAK2–receptor complex structure lacking
    • Whether all cytokine receptors use the same switch mechanism untested
  12. 2019 High

    JAK2's role in epigenetic regulation beyond histone phosphorylation was unexplored; discovery that JAK2 phosphorylates TET2 to activate its DNA hydroxymethylase activity, and that V617F causes genome-wide hypomethylation through TET2 hyperactivation, linked JAK2 signaling directly to the DNA methylation landscape.

    Evidence Phosphoproteomics, in vitro kinase assay, co-IP, 5hmC/5mC genomic profiling in JAK2V617F patient samples and mouse models

    PMID:30944118

    Open questions at the time
    • Whether TET2 phosphorylation is required for normal hematopoiesis unclear
    • Interplay between JAK2-mediated H3Y41ph and TET2 activation at shared loci not examined
  13. 2020 High

    Splicing-level effectors of oncogenic JAK2 signaling were uncharacterized; phosphoproteome profiling identified YBX1 as a JAK2 substrate whose phosphorylation regulates splicing of ERK signaling transcripts, and combined JAK2 inhibition with YBX1 inactivation achieved molecular remission in MPN models.

    Evidence Phosphoproteomics, JAK2 inhibitor plus YBX1 genetic inactivation, RNA-seq splicing analysis, JAK2V617F mouse and human cell models

    PMID:33239784

    Open questions at the time
    • Full spectrum of YBX1-dependent splice targets regulated by JAK2 unknown
    • Clinical feasibility of dual JAK2/YBX1 targeting untested
  14. 2021 High

    Structural understanding of how approved JAK2 inhibitors bind the kinase was lacking; crystal structures of ruxolitinib and fedratinib bound to the JAK2 kinase domain, and of pseudokinase-domain-selective compounds, defined the ATP-site pharmacophore and JH2-selective binding pocket, informing next-generation drug design.

    Evidence X-ray crystallography of JAK2 JH1 with ruxolitinib/fedratinib and JH2 with five diaminotriazole inhibitors, biochemical kinase assays

    PMID:32329617 PMID:33570945

    Open questions at the time
    • No co-crystal of drug-bound full-length JAK2 in context of receptor
    • Whether JH2-selective compounds can overcome V617F resistance clinically untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A complete structural picture of full-length JAK2 in both its autoinhibited and receptor-activated states, the mechanism of JAK2 nuclear import, and the systems-level integration of its kinase-dependent and scaffolding functions remain unresolved.
  • Full-length JAK2 structure in autoinhibited and active conformations not solved
  • Nuclear import mechanism for JAK2 unknown
  • Quantitative contribution of scaffolding versus kinase activity in vivo not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0060090 molecular adaptor activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1643685 Disease 7 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-4839726 Chromatin organization 2
Partners
EPORPTP1BSH2B3SOCS1STAT3STAT5TET2YBX1

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 JAK2 physically associates with a membrane-proximal region of the erythropoietin receptor (EPOR) cytoplasmic domain required for biological activity; EPO stimulation induces tyrosine phosphorylation and activation of JAK2 in vitro autophosphorylation, coupling EPO binding to tyrosine phosphorylation and mitogenesis. Co-immunoprecipitation, in vitro kinase assay, EPOR mutant analysis Cell High 8343951
1994 JAK2 undergoes rapid and transient tyrosine phosphorylation and kinase activation in response to prolactin receptor engagement; JAK2 is associated with the prolactin receptor before and after ligand binding, indicating preassociation with the receptor that is activated upon ligand binding. Anti-JAK2 and anti-phosphotyrosine immunoprecipitation, in vitro tyrosine kinase assay, phosphoamino acid analysis The Journal of biological chemistry High 7508935
1994 JAK2 (and JAK1) constitutively associate with the beta receptor components gp130 and LIF receptor beta; ligand-induced dimerization of these receptor components activates JAK kinases. Co-immunoprecipitation, kinase activation assays across multiple cytokine receptor systems Science High 8272873
1995 SH-PTP1 (a hematopoietic protein tyrosine phosphatase) associates via its SH2 domains with tyrosine-phosphorylated EPOR at Y429, leading to JAK2 inactivation and termination of proliferative signals; EPOR mutants lacking Y429 display prolonged JAK2 autophosphorylation and EPO hypersensitivity. In vitro binding studies, EPOR mutant analysis, JAK2 phosphorylation assays Cell High 7889566
1997 A new SH2-domain-containing protein JAB (SOCS1) binds specifically to the JAK2 JH1 (kinase) domain and markedly reduces JAK2 (and JAK1, JAK3) tyrosine-kinase activity, suppressing STAT tyrosine-phosphorylation and activation. Yeast two-hybrid, co-immunoprecipitation, kinase activity assays Nature High 9202126
1997 Growth hormone activates JAK2, which directly tyrosine-phosphorylates the EGF receptor (EGFR) at Y1068, creating a docking site for Grb2 and thereby activating the Ras-MAP kinase pathway independently of EGFR's intrinsic kinase activity. EGFR mutant transfection, phosphorylation assays, Grb2 association studies, MAP kinase activity assays Nature High 9363897
1997 Shc mediates IL-6 signaling by associating with phosphorylated gp130 via its SH2 domain and with activated JAK2 via its PTB (phosphotyrosine interaction) domain, linking JAK2 to the Ras/ERK pathway. In vivo and in vitro co-immunoprecipitation, domain-specific binding assays Journal of immunology Medium 9126968
1999 Fyn (but not Src) is required upstream of JAK2 for H2O2-induced JAK2 activation; JAK2 in turn is required for ROS-stimulated Shc tyrosine phosphorylation and rapid Ras/ERK1/2 activation, defining a redox-sensitive Fyn-JAK2-Shc-Ras-ERK pathway. Fyn-/- and Src-/- fibroblasts, JAK2 inhibitor AG-490, kinase activity assays, Ras activation assay The Journal of biological chemistry High 10409649
2000 The JAK2 pseudokinase domain (JH2) negatively regulates JAK2 catalytic activity and JAK2-mediated STAT5 activation through a direct interaction with the kinase domain; deletion of the pseudokinase domain deregulates JAK2 and causes ligand-independent STAT activation. Deletion mutagenesis, kinase activity assays, STAT5 phosphorylation assays, domain interaction studies Molecular and cellular biology High 10779328
2001 PTP1B dephosphorylates JAK2 and TYK2 (but not JAK1) using the consensus motif (E/D)-pY-pY-(R/K); a substrate-trapping PTP1B mutant forms stable complexes with JAK2 and TYK2 in response to interferon stimulation; PTP1B-deficient mouse embryo fibroblasts display hyperphosphorylation of JAK2. Substrate-trapping PTP1B mutant co-immunoprecipitation, in vitro dephosphorylation assays, PTP1B-/- MEFs The Journal of biological chemistry High 11694501
2001 EPO receptor-activated JAK2 phosphorylates IκBα, triggering nuclear translocation of NF-κB and NF-κB-dependent neuroprotective gene transcription; dominant-negative JAK2 blocks EPO-mediated neuroprotection, placing JAK2 upstream of NF-κB in the neuronal EPO signaling cascade. Dominant-negative JAK2 transfection, IκBα super-repressor, neuronal apoptosis assays, NF-κB reporter assays Nature High 11493922
2002 PTP1B dephosphorylates JAK2 associated with the leptin receptor in vivo; PTP1B-/- mice show enhanced leptin-induced hypothalamic STAT3 phosphorylation, demonstrating PTP1B as a physiological negative regulator of leptin/JAK2 signaling. PTP1B-/- mice, hypothalamic STAT3 phosphorylation assays, transfection dephosphorylation assays Developmental cell High 11970898
2004 JAK2 autophosphorylates on Y221, Y570, and Y1007; phosphorylation of Y221 increases kinase activity while phosphorylation of Y570 decreases kinase activity, contributing to rapid termination of ligand-induced JAK2 activation. Mass spectrometry, 2D peptide mapping, Y→F point mutagenesis, kinase activity assays Molecular and cellular biology High 15143187
2005 A somatic V617F mutation in the JAK2 pseudokinase (JH2) domain causes constitutive tyrosine phosphorylation activity, promotes cytokine hypersensitivity, and induces erythrocytosis in a mouse bone marrow transplant model. DNA sequencing, retroviral bone marrow transplantation mouse model, kinase activity assays, colony assays Nature High 15793561
2005 The JAK2 V617F mutant has enhanced kinase activity; when co-expressed with the erythropoietin receptor it causes hyperactivation of EPO-induced cell signaling, explaining cytokine hypersensitivity of PV progenitor cells. Cell transfection, in vitro kinase assays, EPO signaling assays The Journal of biological chemistry High 15863514
2005 JAK2 V617F is a dominant gain-of-function mutation in the JH2 domain present in hematopoietic cells; homozygosity arises via mitotic recombination; functional studies confirm V617F gives proliferative and survival advantages to hematopoietic precursors. DNA sequencing, allele-specific PCR, molecular cytogenetics, SNP arrays, in vitro colony assays The New England journal of medicine High 15858187
2005 JAK2 V617F is a constitutively active tyrosine kinase; in vitro analysis confirmed constitutive kinase activity of the V617F mutant compared to wild-type JAK2. DNA resequencing, in vitro kinase activity assays, BaF3 transformation assays Cancer cell High 15837627
2005 JAK2 V617F is acquired in hematopoietic cells, alters a conserved valine in the negative regulatory JH2 domain, and is predicted to dysregulate kinase activity; the mutation was present in all erythropoietin-independent erythroid colonies, linking it mechanistically to growth factor hypersensitivity. Bidirectional sequencing, allele-specific PCR, molecular cytogenetics, colony assays Lancet High 15781101
2006 Serine phosphorylation of JAK2 at S523 inhibits JAK2 kinase activity and leptin receptor signaling; S523 phosphorylation occurs independently of LRb-JAK2 activation and acts via a mechanism independent of Y570-mediated inhibition. Tandem mass spectrometry, site-directed mutagenesis (S523A), Jak2 signaling assays in HEK293 cells and mouse spleen Molecular and cellular biology High 16705160
2007 JAK2 exon 12 gain-of-function mutations (e.g., K539L) cause increased JAK2 phosphorylation and ERK1/2 phosphorylation in BaF3 cells and induce a myeloproliferative phenotype with erythrocytosis in a murine retroviral bone marrow transplantation model. Sequencing, BaF3 cell transduction, phosphorylation assays, retroviral murine bone marrow transplantation The New England journal of medicine High 17267906
2008 Leptin stimulates JAK2-independent signaling: Src family kinases (including c-Src and Fyn) downstream of LEPRb can phosphorylate STAT3 and ERK1/2 in JAK2-null cells; kinase-inactive JAK2(K882E) can still be phosphorylated by these non-JAK2 kinases, revealing a scaffolding/adaptor role for JAK2 in addition to its catalytic role. JAK2-null cells (human and mouse), kinase-inactive JAK2 mutant, Src family pharmacological inhibitors and dominant-negative constructs, STAT3/ERK phosphorylation assays The Journal of biological chemistry High 18718905
2009 JAK2 phosphorylates histone H3 at tyrosine 41 (H3Y41) in the nucleus of haematopoietic cells; phosphorylation at H3Y41 by JAK2 prevents binding of HP1α (but not HP1β) through its chromo-shadow domain; JAK2 inhibition decreases H3Y41 phosphorylation at the lmo2 promoter and reduces lmo2 expression while increasing HP1α binding. Nuclear fractionation, in vitro kinase assay on histone H3, chromatin immunoprecipitation (ChIP), JAK2 inhibitor treatment in leukaemic cells Nature High 19783980
2009 Lnk (SH2B3) interacts with both wild-type and mutant JAK2 through its SH2 and PH domains, is phosphorylated by JAK2V617F, and potently inhibits JAK2V617F-mediated signaling and transformation; Lnk-deficient murine bone marrow cells are more susceptible to JAK2V617F transformation. Co-immunoprecipitation, CFU assays with Lnk-/- bone marrow, domain-specific interaction studies, phosphorylation assays Journal of leukocyte biology High 19293402
2009 The SH2-pseudokinase domain linker of JAK2 acts as a relay switch: its N-terminal part mediates interaction with the Epo receptor, while C-terminal mutations confer constitutive activation; gain-of-function mutations in this linker and pseudokinase domain hinge region cause activated JAK2 that cannot be further stimulated by Epo, indicating the linker relays receptor engagement to kinase domain release from autoinhibition. Gain-of-function mutant screen, scanning mutagenesis, mouse erythrocytosis model, Epo stimulation assays The Journal of biological chemistry High 19638629
2010 JAK2 amplification at 9p24.1 in Hodgkin lymphoma and primary mediastinal large B-cell lymphoma increases JAK2 protein expression and activity, which specifically induces PD-L1 and PD-L2 transcription; JAK2 thus directly transactivates PD-1 ligand gene expression, defining a disease-specific mechanism of immune evasion. Copy number analysis, JAK2 inhibition, PD-L1/PD-L2 expression assays, laser-capture microdissection of primary tumors Blood High 20628145
2014 Molecular dynamics simulations and mutagenesis experiments reveal that the JAK2 pseudokinase domain stabilizes the kinase domain in an inactive state through a direct interdomain interaction; nearly all disease-associated MPN mutations map to this domain interface, providing a molecular basis for how V617F disrupts pseudokinase-mediated autoinhibition. Molecular dynamics simulations, protein-protein docking, site-directed mutagenesis Nature structural & molecular biology High 24918548
2015 Receptor-mediated dimerization model for JAK2 activation by growth hormone: constitutive receptor dimers undergo ligand-induced conformational change separating transmembrane domains, which repositions the pseudokinase inhibitory domain of one JAK2 away from the kinase domain of the partner JAK2, enabling trans-activation. Biochemical binding assays, molecular dynamics simulations, growth hormone receptor mutant analysis The Biochemical journal Medium 25656053
2018 Crystal structures of JAK2 FERM and SH2 domains bound to leptin receptor (LEPR) and erythropoietin receptor (EPOR) reveal a novel 2:2 JAK2/receptor dimer; a membrane-proximal 'switch' region on the receptor is essential for FERM dimer formation; mutation of the receptor switch region disrupts STAT phosphorylation without affecting JAK2 binding, demonstrating that receptor-mediated JAK2 FERM dimerization is required for kinase activation. X-ray crystallography, mutagenesis, STAT phosphorylation assays eLife High 30044226
2019 Cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines Y1939 and Y1964, activating TET2 DNA hydroxymethylase activity; phosphorylated TET2 interacts with the erythroid transcription factor KLF1 in an EPO-enhanced manner; the JAK2V617F mutation causes increased TET2 activity, genome-wide cytosine hydroxymethylation, and loss of cytosine methylation. Phosphoproteomics, in vitro kinase assays, co-immunoprecipitation, 5hmC/5mC genomic analysis, JAK2V617F patient and mouse model samples Cancer discovery High 30944118
2020 In-depth phosphoproteome profiling identified YBX1 as a post-translationally modified target of mutant JAK2; JAK2 phosphorylates YBX1, and YBX1 inactivation disrupts splicing of ERK signaling transcripts; pharmacological JAK2 inhibition combined with YBX1 inactivation induces apoptosis and molecular remission in JAK2V617F mouse and human cells. Phosphoproteome profiling, JAK2 inhibition, YBX1 genetic inactivation, RNA-seq splicing analysis, in vivo mouse models Nature High 33239784
2021 Crystal structures of JAK2 kinase domain bound to ruxolitinib and fedratinib reveal the structural basis for drug binding at the ATP-binding site and the shape complementarity required for chiral selectivity. X-ray crystallography (first crystal structures of JAK2 bound to approved drugs), biochemical and cellular kinase assays Journal of medicinal chemistry High 33570945
2020 Selective binding compounds (diaminotriazole core) that preferentially bind the JAK2 pseudokinase domain (JH2) ATP-binding site rather than the kinase domain (JH1) were developed; crystal structures of five JH2-inhibitor complexes reveal the JH2 binding pocket; a selective JH2 binder reduces autophosphorylation of wild-type but not V617F JAK2 differently than non-selective binders. X-ray crystallography (five JH2 crystal structures), kinase binding assays, autophosphorylation assays Journal of medicinal chemistry High 32329617
2024 PF4 (platelet factor 4) binds and activates the thrombopoietin receptor c-Mpl on platelets, leading to JAK2 activation and phosphorylation of STAT3 and STAT5, resulting in platelet aggregation; inhibition of the c-Mpl-JAK2 pathway inhibits platelet aggregation to PF4 and VITT sera. Receptor binding assays, JAK2/STAT phosphorylation assays, c-Mpl pathway inhibitor studies, platelet aggregation assays Blood High 37883794
2020 PHB (prohibitin) in spermatocytes regulates STAG3 cohesin complex expression via JAK2-mediated H3Y41 phosphorylation; loss of PHB reduces JAK2-mediated H3Y41 phosphorylation and increases H3K9me3 at the Stag3 locus, dysregulating meiotic cohesin and causing male infertility. Spermatocyte-specific Phb conditional knockout mice, ChIP, histone modification assays, JAK2/STAT pathway analysis Nucleic acids research Medium 32232334
2021 IL-6 via the gp130/JAK2/STAT3 pathway mediates sepsis-induced muscle atrophy; JAK2 inhibition (AG490) reduces STAT3 phosphorylation and attenuates skeletal muscle atrophy in septic mice, with reduction of MuRF1 and Atrogin-1 mRNA/protein. CLP mouse model, gp130 muscle-specific conditional KO, JAK2 inhibitor AG490, STAT3 phosphorylation assays, myotube atrophy model Journal of cachexia, sarcopenia and muscle High 34821076

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2005 A gain-of-function mutation of JAK2 in myeloproliferative disorders. The New England journal of medicine 2901 15858187
2005 A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2799 15793561
2005 Mechanisms of type-I- and type-II-interferon-mediated signalling. Nature reviews. Immunology 2780 15864272
2005 Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet (London, England) 2772 15781101
2005 Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer cell 2393 15837627
2000 Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2125 11114383
2008 Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nature genetics 2108 18587394
2010 Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature genetics 2036 21102463
1996 Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 1854 8608603
1995 Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 1763 7543024
1987 Growth hormone receptor and serum binding protein: purification, cloning and expression. Nature 1488 2825030
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Mutation in TET2 in myeloid cancers. The New England journal of medicine 1469 19474426
2013 Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. The New England journal of medicine 1414 24325359
1997 A new protein containing an SH2 domain that inhibits JAK kinases. Nature 1166 9202126
1993 JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell 1111 8343951
2016 Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations. Cancer discovery 1081 27903500
2011 Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nature genetics 1078 21297633
2002 A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. Journal of immunology (Baltimore, Md. : 1950) 1048 12023369
2010 Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 1037 20628145
2010 Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. The New England journal of medicine 978 20843246
2007 JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. The New England journal of medicine 976 17267906
1994 Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science (New York, N.Y.) 929 8272873
1999 Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Molecular cell 834 10635327
1995 Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell 829 7889566
2006 MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 823 16868251
2001 Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 774 11493922
1993 Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science (New York, N.Y.) 772 8493579
2011 The JAK2/STAT3 signaling pathway is required for growth of CD44⁺CD24⁻ stem cell-like breast cancer cells in human tumors. The Journal of clinical investigation 762 21633165
1993 A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. Science (New York, N.Y.) 744 7690989
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2002 PTP1B regulates leptin signal transduction in vivo. Developmental cell 682 11970898
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2005 Identification of an acquired JAK2 mutation in polycythemia vera. The Journal of biological chemistry 495 15863514
2009 JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature 481 19783980
2007 Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nature reviews. Cancer 450 17721432
2001 TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. The Journal of biological chemistry 380 11694501
1994 Activation of receptor-associated tyrosine kinase JAK2 by prolactin. The Journal of biological chemistry 293 7508935
2000 Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Molecular and cellular biology 285 10779328
1997 Tyrosine phosphorylation of the EGF receptor by the kinase Jak2 is induced by growth hormone. Nature 246 9363897
2018 Macrophage Inflammation, Erythrophagocytosis, and Accelerated Atherosclerosis in Jak2 V617F Mice. Circulation research 223 30571460
2013 Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia 204 23459451
2019 Roles of JAK2 in Aging, Inflammation, Hematopoiesis and Malignant Transformation. Cells 196 31398915
1999 Fyn and JAK2 mediate Ras activation by reactive oxygen species. The Journal of biological chemistry 171 10409649
2021 Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting. Journal of cachexia, sarcopenia and muscle 170 34821076
2018 The JAK2 pathway is activated in idiopathic pulmonary fibrosis. Respiratory research 162 29409529
2014 Molecular basis for pseudokinase-dependent autoinhibition of JAK2 tyrosine kinase. Nature structural & molecular biology 131 24918548
2020 Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms. Nature 127 33239784
2004 Autophosphorylation of JAK2 on tyrosines 221 and 570 regulates its activity. Molecular and cellular biology 118 15143187
2011 The JAK2 exon 12 mutations: a comprehensive review. American journal of hematology 117 21674578
2007 Jak2: normal function and role in hematopoietic disorders. Current opinion in genetics & development 113 17208428
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