Affinage

ALPK1

Alpha-protein kinase 1 · UniProt Q96QP1

Length
1244 aa
Mass
138.9 kDa
Annotated
2026-04-28
100 papers in source corpus 23 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALPK1 is an atypical alpha-kinase that functions as a cytosolic pattern recognition receptor for bacterial ADP-heptose, coupling microbial detection to NF-κB-driven inflammatory signaling. Upon ADP-heptose binding—enhanced by direct copper co-activation—ALPK1 phosphorylates TIFA at Thr9 and Thr177, recruiting TRAF6, TRAF2/c-IAP1, and LUBAC to generate Lys63- and Met1-linked ubiquitin chains that activate TAK1 and the canonical IKK complex, culminating in NF-κB-dependent expression of inflammatory cytokines, chemokines, and host-defense genes (PMID:32591860, PMID:36098982, PMID:38232278). Gain-of-function mutations in ALPK1 (T237M, Y254C) cause the autoinflammatory ROSAH syndrome by broadening ligand specificity to include endogenous nucleotide sugars such as UDP-mannose and ADP-ribose, resulting in constitutive NF-κB activation (PMID:35868845, PMID:38060563). Beyond innate immunity, ALPK1-dependent NF-κB signaling promotes clonal hematopoietic expansion in pre-leukemic cells exposed to gut-derived ADP-heptose, modulates intestinal barrier gene expression in response to commensal bacteria, and drives PD-L1 upregulation and chemoresistance in colorectal cancer cells colonized by Fusobacterium nucleatum (PMID:40269158, PMID:36036242, PMID:38126163).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2011 Medium

    Before ALPK1's ligand or immune function was known, loss-of-function in mice revealed an unexpected requirement for motor coordination, establishing that ALPK1 has physiological roles beyond any anticipated kinase function.

    Evidence PiggyBac insertional mutagenesis in mice with behavioral rescue by transgenic ALPK1 re-expression

    PMID:21208416

    Open questions at the time
    • Mechanism linking ALPK1 kinase activity to motor coordination is undefined
    • Relevant substrate in the nervous system unknown
    • Not replicated independently
  2. 2016 Medium

    Identification of myosin IIA as an ALPK1 substrate in gout-relevant MSU-stimulated cells established the first substrate–product relationship and linked ALPK1 to Golgi-derived TNF-α trafficking, while a parallel study showed ALPK1 knockdown altered differentiation in triple-negative breast cancer cells.

    Evidence Co-IP, in vitro phosphorylation of myosin IIA, TNF-α secretion assays; shRNA kinase screen with xenograft validation

    PMID:27169898 PMID:27829216

    Open questions at the time
    • Myosin IIA phosphorylation site not mapped
    • Relationship between myosin IIA phosphorylation and TIFA pathway unclear
    • Cancer differentiation phenotype not linked to a defined ALPK1 substrate
  3. 2019 Medium

    Discovery that a recurrent ALPK1 kinase-domain mutation drives NF-κB activation in spiradenomas, and that rare germline variants associate with periodic fever, positioned ALPK1 as a disease-relevant signaling node, though the activating ligand remained unknown for these contexts.

    Evidence Tumor sequencing with NF-κB reporter validation; exome sequencing and segregation analysis in PFAPA families

    PMID:31053777 PMID:31101826

    Open questions at the time
    • Spiradenoma mutation mechanism (ligand broadening) not yet demonstrated
    • PFAPA variants lack functional assay validation in this study
    • Structural basis for gain-of-function unknown
  4. 2020 High

    The central mechanistic advance: ADP-heptose (a Gram-negative LPS biosynthetic intermediate) was identified as the PAMP sensed by ALPK1, and TIFA Thr9 phosphorylation followed by TRAF6 recruitment was established as the core signaling cascade linking ALPK1 to NF-κB activation.

    Evidence ALPK1/TIFA genetic disruption, NF-κB reporters, bacterial gene deletion (hldE), chemical identification of ligand, gastric organoid primary cells

    PMID:32591860 PMID:33037203

    Open questions at the time
    • Structural basis of ADP-heptose recognition not resolved
    • Whether additional PAMPs activate ALPK1 unknown
    • Contribution of Thr177 phosphorylation not yet identified
  5. 2021 High

    Extension of the ADP-heptose/ALPK1 axis to diverse biological contexts—Campylobacter jejuni intestinal epithelial infection and pancreatic beta-cell cytokine sensitization—demonstrated the pathway's broad tissue relevance and showed that ALPK1 activation alone is insufficient for apoptosis but synergizes with inflammatory cytokines.

    Evidence ALPK1 KO intestinal cells with bacterial hldE deletion; ADP-heptose stimulation of MIN6 beta cells with TIFA/TAK1 pathway analysis

    PMID:34339468 PMID:34621265

    Open questions at the time
    • Whether heptose phosphates versus ADP-heptose are the true Campylobacter ligand not fully resolved
    • Beta-cell relevance in vivo not tested
  6. 2022 High

    The ubiquitin signaling logic downstream of ALPK1 was dissected: ALPK1 phosphorylates TIFA at Thr177 in addition to Thr9, and Thr177 phosphorylation selectively blocks TRAF6 but not TRAF2 binding, while parallel TRAF2/c-IAP1 and LUBAC E3 ligase pathways generate distinct ubiquitin chain types to activate TAK1 and IKK respectively.

    Evidence In vitro kinase assays with site-directed mutagenesis, Co-IP, ubiquitin linkage analysis, E3 ligase genetic knockouts

    PMID:36098982

    Open questions at the time
    • Whether Thr177 phosphorylation functions as a negative feedback switch in vivo unknown
    • Kinetics and stoichiometry of dual phosphorylation not measured
    • LUBAC recruitment mechanism not fully defined
  7. 2022 High

    ALPK1 gain-of-function mutations T237M and Y254C were shown to cause ROSAH syndrome through constitutive NF-κB and STAT1/interferon signaling, validated in patient samples and Alpk1 T237M knock-in mice that display subclinical inflammation.

    Evidence Mutant ALPK1 constructs, immunoblotting, cytokine profiling, transcriptomics, knock-in mouse model, patient primary samples

    PMID:35868845

    Open questions at the time
    • Whether STAT1 activation is direct or secondary to NF-κB-driven cytokines unclear
    • Ocular pathogenesis mechanism in ROSAH not defined
    • Therapeutic kinase inhibitor efficacy not demonstrated
  8. 2022 Medium

    Multiple groups showed that commensal (Akkermansia muciniphila) and pathogenic (Fusobacterium nucleatum) gut bacteria exploit the ALPK1/TIFA/NF-κB axis in intestinal epithelial and cancer cells, with downstream consequences including barrier gene induction, PD-L1 upregulation, ICAM1-mediated metastasis, and chemoresistance.

    Evidence ALPK1/TIFA KO cells, ADP-heptose stimulation, NF-κB reporters, adhesion/extravasation assays, chemosensitivity assays

    PMID:35220887 PMID:36036242 PMID:38126163 PMID:39881579

    Open questions at the time
    • Whether ALPK1 activation is protective or pathogenic in CRC requires in vivo longitudinal evidence
    • Exact ADP-heptose-like metabolite from A. muciniphila not structurally resolved
    • Relative contribution of ALPK1 versus TLR pathways in mixed microbial settings unclear
  9. 2023 High

    The structural basis of disease-causing gain-of-function was clarified: ROSAH (T237M) and spiradenoma (V1092A) mutations expand ALPK1 ligand specificity to endogenous nucleotide sugars (UDP-mannose, ADP-ribose, cyclic ADP-ribose), explaining constitutive activation without exogenous bacterial ligand.

    Evidence NF-κB/AP-1 reporters with WT and mutant ALPK1, nucleotide sugar panels, binding-site mutagenesis

    PMID:38060563

    Open questions at the time
    • Co-crystal structure of mutant ALPK1 with endogenous ligands not available
    • Whether endogenous nucleotide sugar concentrations in vivo reach activating thresholds not measured
    • No therapeutic strategy to selectively block mutant but not WT ALPK1
  10. 2024 High

    Copper was identified as a direct cofactor for ALPK1 kinase activity: copper binding enhances ADP-heptose sensitivity, and infection-induced cytosolic copper accumulation amplifies ALPK1-dependent innate defense, adding a metal-dependent regulatory layer to the pathway.

    Evidence Direct copper-ALPK1 binding assays, in vitro kinase activity, ALPK1-dependent signaling in KO cells, zebrafish in vivo infection model

    PMID:38232278

    Open questions at the time
    • Copper binding site on ALPK1 not structurally mapped
    • Whether copper dysregulation contributes to ROSAH or spiradenoma pathogenesis unknown
    • Specificity for copper versus other divalent metals not comprehensively tested
  11. 2025 High

    Gut-derived ADP-heptose was shown to reach hematopoietic progenitors and activate ALPK1/NF-κB, conferring a proliferative advantage to pre-leukemic CHIP clones—extending ALPK1 function from local mucosal immunity to systemic clonal hematopoiesis.

    Evidence ADP-heptose detection in human serum, ALPK1-dependent signaling in pre-leukemic cells, competitive repopulation assays, transcriptomics

    PMID:40269158

    Open questions at the time
    • Whether ALPK1 inhibition could prevent CHIP progression not tested
    • Source specificity of circulating ADP-heptose (which bacteria) not defined
    • Interaction between ALPK1 and other CHIP driver mutations not explored

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic structure of ALPK1 bound to ADP-heptose or endogenous ligands, the precise copper-binding site, whether Thr177 phosphorylation of TIFA serves as a physiological negative feedback mechanism, and whether selective pharmacological inhibition of gain-of-function mutants is feasible for ROSAH syndrome therapy.
  • No crystal or cryo-EM structure of ALPK1
  • Thr177 phosphorylation role in vivo undetermined
  • No selective ALPK1 inhibitor validated for disease models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0140299 molecular sensor activity 4
Localization
GO:0005829 cytosol 3
Pathway
R-HSA-1643685 Disease 6 R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 5
Partners
BIRC2MYH9TIFATRAF2TRAF6

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 ALPK1 functions as a cytosolic pattern recognition receptor (PRR) that detects the bacterial lipopolysaccharide biosynthetic intermediate ADP-heptose (β-ADP-heptose), triggering phosphorylation of TIFA and downstream NF-κB activation, leading to inflammatory cytokine production. H. pylori-induced NF-κB/NF-κB-driven R-loop formation and replication stress are dependent on this ALPK1/TIFA signaling pathway. Genetic disruption of ALPK1 and TIFA, chemical inhibition, cell-based reporter assays, replication fork assays, S-phase analysis, gastric organoid primary cells Nature communications High 33037203
2020 ADP-heptose (a soluble intermediate of the LPS biosynthetic pathway in Gram-negative bacteria) is the PAMP recognized by ALPK1; upon binding, ALPK1 phosphorylates TIFA at Thr9, leading to TRAF6 recruitment and NF-κB activation with secretion of inflammatory cytokines. Review/synthesis of biochemical and genetic evidence from multiple studies; TIFA phosphorylation assays, NF-κB reporter assays, genetic epistasis with ALPK1/TIFA knockouts Cellular and molecular life sciences : CMLS High 32591860
2022 ALPK1 directly phosphorylates TIFA at Thr177 (in addition to Thr9) in vitro; Thr177 is located within the TRAF6-binding motif and its phosphomimetic mutation (T177D) prevents TRAF6 but not TRAF2 binding, restricting ADP-heptose signaling. ADP-heptose stimulation also induces TRAF2/c-IAP1-dependent Lys63-linked and LUBAC-dependent Met1-linked ubiquitin chains to activate TAK1 and canonical IKK complexes, respectively. c-IAP1 is recruited to TIFA via TRAF2. In vitro kinase assay, site-directed mutagenesis, Co-immunoprecipitation, ubiquitin chain analysis, genetic knockouts of E3 ligases The Biochemical journal High 36098982
2023 Disease-causing ALPK1 mutants (T237M for ROSAH syndrome; V1092A for spiradenoma) can be activated by endogenous human nucleotide sugars (UDP-mannose, ADP-ribose, cyclic ADP-ribose, and for V1092A also GDP-mannose) that do not activate wild-type ALPK1, explaining constitutive NF-κB activation; mutations in the ADP-heptose binding site prevent activation of both wild-type and mutant ALPK1. NF-κB/AP-1 reporter gene assays with wild-type and mutant ALPK1 constructs, binding-site mutagenesis, nucleotide sugar stimulation assays Proceedings of the National Academy of Sciences of the United States of America High 38060563
2022 ALPK1 gain-of-function mutations (T237M, Y254C) cause the autoinflammatory ROSAH syndrome by constitutively increasing NF-κB signaling, STAT1 phosphorylation, and interferon gene expression; knock-in mice carrying Alpk1 T237M show subclinical inflammation. In vitro assays with mutated ALPK1 constructs, immunoblotting, cytokine profiling, transcriptomics, knock-in mouse model, patient primary samples Annals of the rheumatic diseases High 35868845
2019 A recurrent missense mutation in the kinase domain of ALPK1 (identified in spiradenomas and spiradenocarcinomas) can activate the NF-κB pathway in reporter assays, establishing it as a gain-of-function driver mutation. Genomic sequencing, NF-κB reporter assays with ALPK1 mutant constructs Nature communications Medium 31101826
2016 ALPK1 phosphorylates myosin IIA; in monosodium urate (MSU)-stimulated cells, ALPK1 forms a protein complex with myosin IIA, calmodulin, and F-actin at the N-terminal domain, and MSU-induced ALPK1 activity phosphorylates myosin IIA, which is required for Golgi-derived TNF-α trafficking and secretion. Bioinformatics, proteomics, Co-immunoprecipitation, ALPK1/myosin IIA knockdown, in vitro phosphorylation assays, TNF-α secretion assays, human patient samples Scientific reports Medium 27169898
2024 Copper binds directly to ALPK1 and is essential for its kinase activity; copper binding enhances ALPK1 sensitivity to ADP-heptose and amplifies the innate immune response. In response to bacterial infection, host cells actively accumulate cytosolic copper, which promotes ALPK1-dependent host defense. Direct binding assays (copper-ALPK1 interaction), in vitro kinase activity assays, ALPK1-dependent cell signaling (knockdown/KO), zebrafish in vivo infection model Proceedings of the National Academy of Sciences of the United States of America High 38232278
2025 ADP-heptose (from gut Gram-negative bacteria) binds to ALPK1 in hematopoietic progenitor cells, triggering NF-κB activation and transcriptional reprogramming that confers a proliferative competitive advantage to pre-leukemic (CHIP) cells, driving clonal expansion. ADP-heptose detection in human serum, ALPK1-dependent signaling in pre-leukemic cells, genetic models, transcriptomic analysis, competitive repopulation assays Nature High 40269158
2021 The ALPK1 pathway drives the NF-κB-mediated pro-inflammatory response (CXCL8, CXCL2, TNFAIP2, PTGS2) to Campylobacter jejuni in human intestinal epithelial cells; ADP-heptose and/or related heptose phosphates (not requiring T3SS or T4SS injection) are the released virulence factor activating ALPK1, identified by hldE gene deletion and chemical characterization. ALPK1 knockout cells, chemical characterization of released factor, bacterial gene deletion (hldE), NF-κB reporter assays, independent of TLR/NLR signaling (epistasis) PLoS pathogens High 34339468
2022 Akkermansia muciniphila releases ADP-heptose-like metabolites that enter intestinal epithelial cells and activate NF-κB via ALPK1/TIFA/TRAF6, inducing expression of barrier-function genes (MUC2, BIRC3, TNFAIP3) in a TIFA-dependent manner. Pharmacological inhibitors, gene editing (ALPK1/TIFA/TRAF6 knockouts), chemical characterization of released metabolite, NF-κB reporter assays Gut microbes High 36036242
2022 Fusobacterium nucleatum activates ALPK1, which then signals through NF-κB to upregulate ICAM1 expression on colorectal cancer cells, enhancing adhesion to endothelial cells and promoting extravasation and metastasis. ALPK1 knockdown/overexpression, NF-κB reporter assays, adhesion and extravasation assays, ICAM1 expression studies, patient tissue correlation Gut microbes Medium 35220887
2022 ALPK1 exacerbates condylar cartilage degradation in TMJOA by activating NF-κB signaling (upregulating MMP13, COX2) and suppressing ERK1/2 signaling (downregulating aggrecan); ALPK1 knockout mice show attenuated cartilage/bone damage. ALPK1 KO mouse model (MIA-induced TMJOA), intra-articular recombinant ALPK1 administration, ex vivo chondrocyte studies, NF-κB and ERK1/2 pathway analysis Journal of dental research Medium 35689396
2022 ALPK1 accelerates osteoarthritis pathogenesis by activating NF-κB signaling, which upregulates NLRP3 inflammasome in chondrocytes, driving IL-1β-mediated inflammation; ALPK1 KO reverses OA pathogenesis and NLRP3 is a downstream target of NF-κB in ALPK1-activated chondrocytes. ALPK1 KO and intra-articular recombinant ALPK1 in DMM and CIOA mouse models, selective NF-κB and NLRP3 inhibition, in vitro chondrocyte studies Journal of bone and mineral research Medium 36053817
2021 ALPK1 sensitizes pancreatic beta cells to cytokine-induced apoptosis by potentiating TNF-α and Fas expression through enhanced activation of the TIFA/TAK1/NF-κB signaling axis; ADP-heptose activation of ALPK1 alone is insufficient to induce apoptosis but synergizes with cytokines. ADP-heptose stimulation in MIN6 cells, ALPK1 activation assays, TIFA/TAK1/NF-κB pathway analysis, apoptosis assays, GLP-1 receptor agonist rescue Frontiers in immunology Medium 34621265
2011 Disruption of ALPK1 (via piggyBac transposon insertion into intron 1) in mice causes severe motor coordination deficits, which are rescued by transgenic re-expression of full-length ALPK1, establishing ALPK1 as functionally required for motor coordination. PiggyBac transposon insertional mutagenesis in mice, behavioral analysis (rotarod, hanging wire, dowel, footprint tests), transgenic rescue with full-length Alpk1 BMC neuroscience Medium 21208416
2017 ALPK1 overexpression decreases URAT1 (urate transporter 1, SLC22A12) protein levels in vivo in transgenic mice and in vitro in kidney cells; MSU crystal stimulation upregulates ALPK1, which in turn inhibits URAT1, suggesting ALPK1 acts as a negative regulator of urate reuptake. ALPK1 transgenic mice (URAT1 protein measurement), ALPK1 siRNA knockdown in HK-2 cells, MSU crystal stimulation, immunohistochemistry of renal proximal tubule cells Rheumatology (Oxford, England) Medium 28039413
2022 ALPK1 promotes TMJ synovitis by promoting nuclear translocation of PKM2 and M1 macrophage polarization; LMW-HA upregulates ALPK1 while HMW-HA suppresses it, and rhALPK1 promotes M1 polarization-associated gene expression and nuclear PKM2. ALPK1 KO mice (CFA-induced TMJ synovitis), recombinant ALPK1 stimulation, macrophage polarization assays, PKM2 nuclear translocation assays, patient synovial tissue analysis Journal of cellular and molecular medicine Medium 38494837
2019 ALPK1 is the kinase phosphorylated by/activates upon ADP-heptose bisphosphate recognition, phosphorylating TIFA to trigger the immediate innate immune response to Gram-negative bacterial invasion; rare ALPK1 variants (S924P, D342H, T237M) predispose to periodic fever (PFAPA) syndrome. Exome sequencing, Sanger sequencing, segregation analysis in PFAPA families European journal of human genetics : EJHG Low 31053777
2022 ALPK1 acts as a cytosolic PRR for ADP-heptose released by F. nucleatum, and ALPK1/TIFA/TRAF6 pathway activation promotes expression of inflammatory cytokine IL-8 and anti-apoptotic genes BIRC3 and TNFAIP3, enhancing CRC cell survival and reducing 5-fluorouracil chemosensitivity. ALPK1/TIFA pathway knockouts, ADP-heptose stimulation, gene expression assays, cell survival and chemosensitivity assays Gut microbes Medium 38126163
2022 F. nucleatum activates ALPK1 in intestinal cancer cells in an ADP-heptose-dependent manner, leading to NF-κB pathway activation and ALPK1-dependent upregulation of PD-L1; this mechanism is conserved across multiple Fusobacterium species. ALPK1-dependent reporter assays in HEK293 and HT-29 cells, transcriptional analysis, ADP-heptose stimulation, F. nucleatum conditioned medium experiments Gut microbes Medium 39881579
2016 Knockdown of ALPK1 in triple-negative breast cancer cells (MDA-MB-468) induces loss of the myoepithelial marker keratin 5, increased β-casein production, decreased proliferation, reduced clonogenicity, and reduced tumorigenicity in vivo, establishing ALPK1 as a regulator of cancer cell differentiation state. Kinase knockdown screen (420 kinases), shRNA knockdown, spheroid and anchorage-independent growth assays, in vivo xenograft Oncotarget Medium 27829216
2022 DF-006 (an ALPK1 agonist) activates the NF-κB pathway via ALPK1 and stimulates innate immunity, demonstrating that pharmacological agonism of ALPK1 is sufficient to drive antiviral gene expression and reduce HBV viral markers in mouse and primary human hepatocyte models. AAV-HBV mouse models, primary human hepatocytes, NF-κB target gene upregulation, antiviral efficacy assays, liver localization of DF-006 Hepatology (Baltimore, Md.) Medium 35699669

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1989 Intratumoral LAK cell and interleukin-2 therapy of human gliomas. Journal of neurosurgery 226 2643685
2022 Fusobacterium nucleatum promotes colorectal cancer cells adhesion to endothelial cells and facilitates extravasation and metastasis by inducing ALPK1/NF-κB/ICAM1 axis. Gut microbes 167 35220887
1985 Lymphokine-activated killer (LAK) cells. Analysis of factors relevant to the immunotherapy of human cancer. Cancer 124 3871657
1987 Human lymphokine-activated killer (LAK) cells: identification of two types of effector cells. Journal of immunology (Baltimore, Md. : 1950) 122 3100627
1988 Intralesional infusion of lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) for the treatment of patients with malignant brain tumor. Neurosurgery 97 2851116
2020 The ALPK1/TIFA/NF-κB axis links a bacterial carcinogen to R-loop-induced replication stress. Nature communications 89 33037203
1986 Human lymphokine-activated killer cells (LAK cells) as a potential immunotherapeutic modality. Biochimica et biophysica acta 81 3539198
1989 Interleukin-2 with or without LAK cells in metastatic renal cell carcinoma: a report of a European multicentre study. European journal of cancer & clinical oncology 77 2697575
1990 An explanation of the variable clinical response to interleukin 2 and LAK cells. Immunology today 74 2187466
2018 T-LAK cell-originated protein kinase (TOPK): an emerging target for cancer-specific therapeutics. Cell death & disease 68 30356039
2019 ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma. Nature communications 65 31101826
2022 Akkermansia muciniphila upregulates genes involved in maintaining the intestinal barrier function via ADP-heptose-dependent activation of the ALPK1/TIFA pathway. Gut microbes 62 36036242
2022 Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome. Annals of the rheumatic diseases 56 35868845
2011 Motor coordination deficits in Alpk1 mutant mice with the inserted piggyBac transposon. BMC neuroscience 54 21208416
1996 Lymphocyte, NK and LAK cell responses to maximal exercise. International journal of sports medicine 53 8775578
1990 Diminished A-LAK cytotoxicity and proliferation accompany disease progression in chronic myelogenous leukemia. Blood 53 1695114
1987 Lymphokine activated killer (LAK) cells in patients with gastrointestinal cancer. Gut 52 3501386
1986 Lymphokine-activated killer (LAK) cells. I. Differential recovery of LAK, natural killer cells, and cytotoxic T lymphocytes after a sublethal dose of cyclophosphamide. Journal of immunology (Baltimore, Md. : 1950) 51 3489763
2024 Copper regulates the host innate immune response against bacterial infection via activation of ALPK1 kinase. Proceedings of the National Academy of Sciences of the United States of America 49 38232278
2013 Identification of chromosome 3q28 and ALPK1 as susceptibility loci for chronic kidney disease in Japanese individuals by a genome-wide association study. Journal of medical genetics 49 23539754
2002 Dendritic cells for NK/LAK activation: rationale for multicellular immunotherapy in neuroblastoma patients. Blood 46 12239169
2023 Fusobacterium nucleatum promotes inflammatory and anti-apoptotic responses in colorectal cancer cells via ADP-heptose release and ALPK1/TIFA axis activation. Gut microbes 43 38126163
1994 pH-dependent LAK cell cytotoxicity. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 40 7991991
2017 The T-LAK Cell-originated Protein Kinase Signal Pathway Promotes Colorectal Cancer Metastasis. EBioMedicine 39 28412249
2013 ALPK1 genetic regulation and risk in relation to gout. International journal of epidemiology 39 23569188
1989 Lymphokine-activated killer (LAK) and monocyte-mediated cytotoxicity on tumor cell lines resistant to antitumor agents. Cellular immunology 39 2784721
1996 Age-associated decline in IL-2 and IL-12 induction of LAK cell activity of human PBMC samples. Mechanisms of ageing and development 38 8898314
1988 Interleukin-3 and interleukin-4 each strongly inhibit the induction and function of human LAK cells. Clinical and experimental immunology 38 3265653
1988 Heterogeneity of human lymphokine (IL-2)-activated killer (LAK) precursors and regulation of their LAK induction by blood monocytes. International journal of cancer 37 3262092
1988 Fractionated extract of Astragalus membranaceus, a Chinese medicinal herb, potentiates LAK cell cytotoxicity generated by a low dose of recombinant interleukin-2. Journal of clinical & laboratory immunology 37 3264344
1994 CEA expression of colorectal adenocarcinomas is correlated with their resistance against LAK-cell lysis. International journal of cancer 35 8168994
1989 Interleukin-2 with and without LAK cells in metastatic renal cell carcinoma: the Lyon first-year experience in 20 patients. Cancer treatment reviews 35 2788510
2003 A highly effective and stable bispecific diabody for cancer immunotherapy: cure of xenografted tumors by bispecific diabody and T-LAK cells. Cancer immunology, immunotherapy : CII 33 14648071
1987 Lymphokine-activated killer (LAK) cells. III. Characterization of LAK precursors and susceptible target cells within the murine thymus. Journal of immunology (Baltimore, Md. : 1950) 33 3500221
1996 ICAM-1 expression by lung cancer cell lines: effects of upregulation by cytokines on the interaction with LAK cells. The European respiratory journal 32 8880099
1993 Effect of IFN-gamma and IFN-alpha on killing of human trophoblast by decidual LAK cells. Journal of reproductive immunology 32 8429524
1990 NK and LAK activities from human marrow progenitors. I. The effects of interleukin-2 and interleukin-1. Cellular immunology 32 1689220
2022 Optimizing NK-92 serial killers: gamma irradiation, CD95/Fas-ligation, and NK or LAK attack limit cytotoxic efficacy. Journal of translational medicine 31 35366943
2020 ADP-heptose: a bacterial PAMP detected by the host sensor ALPK1. Cellular and molecular life sciences : CMLS 31 32591860
1994 Swainsonine, a glycosylation inhibitor, enhances both lymphocyte efficacy and tumour susceptibility in LAK and NK cytotoxicity. Immunopharmacology 30 7516929
2022 ALPK1 Aggravates TMJOA Cartilage Degradation via NF-κB and ERK1/2 Signaling. Journal of dental research 29 35689396
2021 The ALPK1 pathway drives the inflammatory response to Campylobacter jejuni in human intestinal epithelial cells. PLoS pathogens 28 34339468
1989 Interferon is able to reduce tumor cell susceptibility to human lymphokine-activated killer (LAK) cells. Cellular immunology 28 2463094
1993 Time-dependent changes of LAK cell phenotypes correlate with the secretion of different cytotoxic proteins. Immunology letters 27 8258456
1990 Role of CD18 in lymphokine activated killer (LAK) cell-mediated lysis of human monocytes: comparison with other LAK targets. International journal of cancer 27 1968054
1986 Interleukin-2 and lymphokine activated killer (LAK) cells in the treatment of malignant glioma: clinical and experimental studies. Neurological research 27 2875409
2019 Rare missense variants in the ALPK1 gene may predispose to periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. European journal of human genetics : EJHG 26 31053777
1991 Evaluation of NK and LAK cell activities in neoplastic patients during treatment with morphine. The International journal of neuroscience 26 1774133
2025 Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1. Nature 25 40269158
1990 Effects of heat shock on cytolysis mediated by NK cells, LAK cells, activated monocytes and TNFs alpha and beta. Scandinavian journal of immunology 25 2309100
1988 Role of proliferation in LAK cell development. Cancer immunology, immunotherapy : CII 25 3129192
1993 Analysis of the relationship between stage of differentiation and NK/LAK susceptibility of colon carcinoma cells. International journal of cancer 24 8428794
1990 Morphologic analysis of human lymphokine-activated killer (LAK) cells. International journal of cancer 24 2157676
2016 ALPK1 phosphorylates myosin IIA modulating TNF-α trafficking in gout flares. Scientific reports 23 27169898
1999 Postoperative adjuvant adoptive immunotherapy with lymph node-LAK cells and IL-2 for pathologic stage I non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 22 10598924
1991 Human small-cell lung-cancer cells are cytokine-resistant but NK/LAK-sensitive. International journal of cancer 22 1850388
2020 Juvenile Onset Splenomegaly and Oculopathy Due to Germline Mutation in ALPK1. Journal of clinical immunology 21 31939038
2016 ERN1 and ALPK1 inhibit differentiation of bi-potential tumor-initiating cells in human breast cancer. Oncotarget 21 27829216
1999 Suppression of TGF-beta1 in human gliomas by retroviral gene transfection enhances susceptibility to LAK cells. Journal of neuro-oncology 21 10448868
2025 Fusobacterium nucleatum upregulates the immune inhibitory receptor PD-L1 in colorectal cancer cells via the activation of ALPK1. Gut microbes 20 39881579
2019 ALPK1 regulates streptozotocin-induced nephropathy through CCL2 and CCL5 expressions. Journal of cellular and molecular medicine 20 31557402
2015 ALPK1 affects testosterone mediated regulation of proinflammatory cytokines production. The Journal of steroid biochemistry and molecular biology 20 26275947
1991 Up-regulation of induction of lymphokine (IL-2)-activated killer (LAK) cell activity by FK-565 and cisplatin. Immunology letters 20 2060971
1990 Reduced LAK cytotoxicity of peripheral blood mononuclear cells in patients with bladder cancer: decreased LAK cytotoxicity caused by a low incidence of CD56+ and CD57+ mononuclear blood cells. Journal of clinical immunology 20 1707414
2019 Role of NOD1 and ALPK1/TIFA Signalling in Innate Immunity Against Helicobacter pylori Infection. Current topics in microbiology and immunology 19 31123889
2022 Co-ordinated control of the ADP-heptose/ALPK1 signalling network by the E3 ligases TRAF6, TRAF2/c-IAP1 and LUBAC. The Biochemical journal 18 36098982
1992 Cytotoxicity of interleukin 2-induced lymphokine-activated killer (LAK) cells against human leukemia and augmentation of killing by interferons and tumor necrosis factor. Leukemia research 18 1560676
1989 Interleukin-2 modulates the expression of lymphocyte function-associated antigen-one (LFA-1) and p150,95 during the generation of lymphokine-activated killer (LAK) cells. Immunology 18 15493273
1989 A functional and phenotypic comparison of murine natural killer (NK) cells and lymphokine-activated killer (LAK) cells. International journal of cancer 18 2469657
1987 Lymphokine-activated killer (LAK) cells: I. Age-dependent decline of LAK cell-mediated cytotoxicity. Immunology letters 18 3428933
1989 Interferon-gamma-treated K562 target cells distinguish functional NK cells from lymphokine-activated killer (LAK) cells. Cellular immunology 17 2491960
2022 ALPK1 Accelerates the Pathogenesis of Osteoarthritis by Activating NLRP3 Signaling. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 16 36053817
2017 URAT1 inhibition by ALPK1 is associated with uric acid homeostasis. Rheumatology (Oxford, England) 16 28039413
2016 Down-regulated and Commonly mutated ALPK1 in Lung and Colorectal Cancers. Scientific reports 16 27283888
1991 Resistance of leukemic blasts to lymphokine activated killer (LAK)-mediated cytotoxicity is not related to their adhesion properties. European journal of haematology 16 1716215
1989 Therapeutic uses of interleukin-2 and lymphokine-activated killer (LAK) cells. Blood reviews 16 2673443
1988 Comparison of in vitro glioma cell cytotoxicity of LAK cells from glioma patients and healthy subjects. Journal of neurosurgery 16 3260622
2021 Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway. Frontiers in immunology 15 34621265
2001 Measurement of cytotoxic activity of NK/LAK cells. Current protocols in immunology 15 18432832
1994 Identification of a mannose-acetate-specific 87-kDa receptor responsible for human NK and LAK activity. Immunology letters 15 7829133
1988 Anti-tumor reactivity of human lymphokine activated killer (LAK) cells against fresh and cultured preparations of renal cell cancer. The Journal of urology 15 3257274
2024 The relationship of ALPK1, hyaluronic acid and M1 macrophage polarization in the temporomandibular joint synovitis. Journal of cellular and molecular medicine 14 38494837
2004 Mycophenolate mofetil does not suppress the graft-versus-leukemia effect or the activity of lymphokine-activated killer (LAK) cells in a murine model. Cancer immunology, immunotherapy : CII 14 15692848
1994 A novel role for MHC class II antigens: evidence implicating a protective effect on tumour cells against cytotoxicity by NK and LAK cells. Immunology 14 7835941
1993 Effect of GVHD on the recovery of NK cell activity and LAK precursors following BMT. Bone marrow transplantation 14 8241989
1989 Lymphokine-activated killer (LAK) cell activity in tumor-infiltrating lymphocytes from non-small cell lung cancer. American journal of clinical pathology 14 2552792
1989 Target cell-directed inactivation and IL-2-dependent reactivation of LAK cells. Cellular immunology 14 2788512
1989 Treatment of patients with advanced cancer using multiple long-term cultured lymphokine-activated killer (LAK) cell infusions and recombinant human interleukin-2. Journal of biological response modifiers 14 2795092
2024 Decoding huge phage diversity: a taxonomic classification of Lak megaphages. The Journal of general virology 13 38814706
2023 ALPK1 mutants causing ROSAH syndrome or Spiradenoma are activated by human nucleotide sugars. Proceedings of the National Academy of Sciences of the United States of America 13 38060563
2022 Alpha-kinase 1 (ALPK1) agonist DF-006 demonstrates potent efficacy in mouse and primary human hepatocyte (PHH) models of hepatitis B. Hepatology (Baltimore, Md.) 13 35699669
2022 Anticancer activity of D-LAK-120A, an antimicrobial peptide, in non-small cell lung cancer (NSCLC). Biochimie 13 35764196
2018 ALPK1 Expression Is Associated with Lymph Node Metastasis and Tumor Growth in Oral Squamous Cell Carcinoma Patients. The American journal of pathology 13 30315765
1995 Enhanced expression of novel CD57+CD8+ LAK cells from cats infected with feline immunodeficiency virus. Journal of leukocyte biology 13 7561518
1994 Bispecific anti-CD22/anti-CD3-ricin A chain immunotoxin is cytotoxic to Daudi lymphoma cells but not T cells in vitro and shows both A-chain-mediated and LAK-T-mediated killing. Journal of immunology (Baltimore, Md. : 1950) 13 8133047
1993 Expression of adhesion molecules on acute leukemic blast cells and sensitivity to normal LAK activity. Annals of hematology 13 7694662
1988 Soluble glucan and lymphokine-activated killer (LAK) cells in the therapy of experimental hepatic metastases. Journal of biological response modifiers 13 3283299
2018 Molecular epidemiology analysis of enterovirus 71 strains isolated in Dak Lak, Vietnam, 2011-2016. Journal of medical virology 12 30132913
2008 Melanoma and lymphoma rejection associated with eosinophil infiltration upon intratumoral injection of dendritic and NK/LAK cells. Journal of immunotherapy (Hagerstown, Md. : 1997) 12 18463539
1996 Anti-candidial activity of natural killer (NK) and lymphokine activated killer (LAK) lymphocytes in vitro. Immunobiology 12 8877398