ArticleProceedings of the National Academy of Sciences of the United States of America2014
Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 119 papers, 1 of them a synthesis that pooled it.
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Who cites it
119 citing papers in PubMed, 1 synthesis or guideline pooled it, 215 citations in OpenAlex.
- JAK inhibitors and COVID-19.Journal for immunotherapy of cancer · 2022Pooled it
- Large-scale comparative virtual screening identifies novel molecular targets underlying the multi-target activity of quercetin in psoriasis.Inflammopharmacology · 2026Article
- Modulating pseudokinase conformation from the ATP-binding site.Structure (London, England : 1993) · 2026Article
- Powassan Virus NS5 Antagonizes TYK2-Mediated Immune Signaling Pathways.bioRxiv : the preprint server for biology · 2026Article
- Black Sheep: Pseudokinases Bucking the Trend to Reveal Non-Catalytic Kinase Functions.IUBMB life · 2026Review
- PocketMaster provides a flexible and automated tool for analyzing, clustering, and visualizing structural diversity in protein pockets.Scientific reports · 2026Article
- Deep mutational scanning reveals pharmacologically relevant insights into TYK2 signaling and disease.eLife · 2026Article
- Probing Allosteric Kinase Modulators as Next Game-Changers in Fighting Neurodegeneration.Journal of medicinal chemistry · 2026Review
- High-Penetrance Rare Variants Underlying Familial Lung Cancer Risk: Insights From Genetic Epidemiology of Lung Cancer Consortium.Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 2026Article
- JAK/STAT signaling in liver disease: a therapeutic target or a context-dependent double-edged sword?Journal of translational medicine · 2026Review
- From Convenience to Clinical Efficacy: Selective TYK2 Inhibition in Psoriasis and the Evolving Role of Next-Generation Oral Targeted Therapies.Pharmaceutics · 2026Review
- Allosteric PROTACs: Expanding the Horizon of Targeted Protein Degradation.Journal of the American Chemical Society · 2026Review
- In silico modeling guides identification of novel JAK1 variants associated with immune dysregulation.EMBO molecular medicine · 2025Article
- Structural and evolutionary insights into understudied bacterial serine-threonine pseudokinase families.Biochemical Society transactions · 2025Review
- Germline JAK2 R564Q variants presenting as hereditary thrombocytosis: case report.BJC reports · 2025Article
- Molecular Dynamics Simulation Analysis of JAK1 Initial Activation: Phosphorylation-Induced Conformational Dynamics and Domain Interactions.Life (Basel, Switzerland) · 2025Article
- Investigating the Potential Therapeutic Targeting of the JAK-STAT Pathway in Cerebrovascular Diseases: Opportunities and Challenges.Molecular neurobiology · 2025Review
- TYK2 regulates tau levels, phosphorylation and aggregation in a tauopathy mouse model.Nature neuroscience · 2024Article
- Engineered chimeric receptors for dissecting interferon signaling.Journal of virology · 2024Review
- JAK inhibitor selectivity: new opportunities, better drugs?Nature reviews. Rheumatology · 2024Review
59 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
6 authors at 1 institution.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Janus kinases (JAKs) are receptor-associated multidomain tyrosine kinases that act downstream of many cytokines and interferons. JAK kinase activity is regulated by the adjacent pseudokinase domain via an unknown mechanism. Here, we report the 2.8-Å structure of the two-domain pseudokinase-kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudokinase and kinase interact near the kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and "exon 12" JAK2 mutations, results in increased kinase activity in vitro. These data indicate that JAK pseudokinases are autoinhibitory domains that hold the kinase domain inactive until receptor dimerization stimulates transition to an active state.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.