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Showing MAP3K20 — ZAK is a alias.

MAP3K20

Mitogen-activated protein kinase kinase kinase 20 · UniProt Q9NYL2

Length
800 aa
Mass
91.2 kDa
Annotated
2026-06-10
66 papers in source corpus 34 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP3K20 (ZAK/MLTK) is a MAP kinase kinase kinase that operates as the central sensor of ribotoxic stress, transducing damage at the ribosome to stress-activated MAPK output (PMID:18331592). The protein is expressed as two alternatively spliced isoforms (ZAKα/MLTKα and ZAKβ/MLTKβ) that activate JNK/SAPK, p38, ERK and NF-κB and are activated by osmotic shock through autophosphorylation (PMID:11042189, PMID:10924358). Its architecture—kinase domain, leucine zipper required for full catalytic activity, and a sterile-alpha (SAM) domain mediating homo-oligomerization—defines its activation logic (PMID:10924358, PMID:14521931). ZAKα is constitutively recruited to elongating ribosomes through interactions with RACK1, RPS27 and 18S rRNA, monitoring the mRNA exit channel; ribosome collisions promote SAM-domain dimerization at the collision interface, trans-autophosphorylation, and ribotoxic stress response activation, a step negatively regulated by SERBP1, while pathogenic SAM-domain variants bypass the ribosome requirement (PMID:41261136). Downstream, ZAK preferentially routes JNK activation through MKK7 and simultaneously activates p38 in vivo, driving proinflammatory cytokine production (IL-8, IL-1β, IL-6, CXCL1), apoptosis, and cell-cycle arrest in response to ribotoxic insults including Shiga toxin, ricin and doxorubicin (PMID:12220515, PMID:15350844, PMID:18331592, PMID:23114643, PMID:27598200). Beyond stress sensing, ZAK acts as a positive mediator of cardiac hypertrophy and fibrosis via p38/JNK→GATA4/c-Jun (PMID:15465036, PMID:15350844, PMID:25869677), is essential for chondrogenesis through Sox9-dependent Sox6 induction (PMID:22764049), promotes cancer cell migration, EMT and invasion (PMID:26522728, PMID:29396440), and participates in canonical TGF-β/SMAD signaling by complexing with Smad2/3 and TβRI (PMID:27783979, PMID:35276386). The ZAKβ isoform is the mechanosensitive species in skeletal muscle, activated by contraction and compression and required for adaptive turnover of Filamin C with BAG3 and SYNPO2 under mechanical stress (PMID:37427997). Loss-of-function SAM-domain mutations cause human split-foot/limb defects, placing ZAK upstream of Trp63 in limb patterning (PMID:26755636).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2000 Medium

    Establishing that MAP3K20 is a genuine MAP3K answered whether a new node feeds the stress MAPK network; it defined two isoforms and their upstream-kinase behavior.

    Evidence cloning, overexpression with kinase-dead mutants, and pharmacological p38 inhibition in mammalian cells

    PMID:10924358 PMID:11042189

    Open questions at the time
    • Activation relied on overexpression, not endogenous stimuli
    • Physiological activating signals beyond osmotic shock unknown
    • Isoform-specific functions not resolved
  2. 2002 Medium

    Defining the immediate downstream MAPKK answered how ZAK channels JNK activation and linked it to cell-cycle control.

    Evidence dominant-negative MKK7 vs MKK4 epistasis, kinase-dead mutant, flow cytometry and cyclin E blots

    PMID:12220515

    Open questions at the time
    • MKK7 specificity tested only by dominant-negative, not direct phosphorylation
    • Mechanism of G2/M arrest not defined
  3. 2003 High

    Identifying PKNα as a direct activator/scaffold addressed how ZAK kinase activity is itself regulated upstream.

    Evidence in vitro kinase assay, kinase-negative PKNα, and co-IP of MLTKα/MKK6/p38γ

    PMID:12761180 PMID:14521931

    Open questions at the time
    • Whether PKNα regulation operates at endogenous levels untested
    • Relationship of PKNα input to ribotoxic activation unknown
  4. 2008 High

    Placing ZAK as the MAP3K of the ribotoxic stress response answered what kinase couples damaged ribosomes to SAPK and cytokine output—its defining role.

    Evidence ZAK-specific inhibitor and siRNA after Shiga toxin/ricin, with SAPK and IL-8 readouts

    PMID:18331592

    Open questions at the time
    • How damaged ribosomes are physically sensed not yet defined
    • Direct ribosome interaction not shown at this stage
  5. 2010 Medium

    Extending ribotoxic stress to chemotherapy and context dependence clarified when ZAK governs apoptosis versus proliferation.

    Evidence siRNA and multiple inhibitors in keratinocytes vs HeLa; ERK/JNK/AP-1 readouts and xenografts in lung cancer cells

    PMID:20331627 PMID:20559024

    Open questions at the time
    • Cell-type basis of opposing outcomes unexplained
    • Direct substrates of ERK vs JNK branches not mapped
  6. 2015 High

    Defining the cardiac and migration outputs answered what physiological processes ZAK MAPK signaling drives beyond stress.

    Evidence inducible WT/dominant-negative ZAK, kinase-dead mutants, pathway inhibitors, transgenic and H9c2 systems

    PMID:15350844 PMID:15465036 PMID:25869677 PMID:26522728

    Open questions at the time
    • Mechanistic link between ribotoxic sensing and cardiac/migration roles unclear
    • Endogenous activating signal in cardiomyocytes undefined
  7. 2016 High

    Structural and genetic work answered both the catalytic basis of ZAK substrate selection and its in vivo developmental requirement.

    Evidence kinase-domain crystal structure with peptide-library specificity profiling, and CRISPR SAM-deletion mice with human SHFM family genetics linking ZAK upstream of Trp63

    PMID:22764049 PMID:26755636 PMID:26999302 PMID:27598200

    Open questions at the time
    • Physiological substrates matching the histidine-preference motif not identified
    • How SAM-domain loss perturbs limb patterning at the signaling level unresolved
  8. 2018 Medium

    Resolving isoform divergence and EMT control answered why ZAKα and ZAKβ can produce opposing tumor phenotypes.

    Evidence isoform-specific overexpression, soft-agar growth, ZEB1/ESRP/CD44 isoform analysis, and ERβ co-IP/SUMO-1 modulation of nuclear translocation

    PMID:29374956 PMID:29396440 PMID:29932238

    Open questions at the time
    • Molecular determinant of ZAKα vs ZAKβ output not defined
    • Direct effectors of EMT splicing switch unknown
  9. 2022 High

    Linking ZAKα to ribosome-stress-driven stem cell plasticity and TGF-β fibrosis expanded the downstream physiology of the ribotoxic sensor.

    Evidence intestinal organoids/conditional KO with ZAKα→SRC→YAP epistasis, and ZAK–Smad2/3–TβRI co-IP with UUO mouse model

    PMID:35276386 PMID:35918345

    Open questions at the time
    • How ribosome stress is decoded into a YAP versus MAPK output unclear
    • Direct phosphorylation events in the SMAD complex not mapped
  10. 2023 Medium

    Defining ZAKβ as the muscle mechanosensor answered the distinct physiological function of the second isoform.

    Evidence phosphoproteomics identifying SYNPO2/BAG3/FLNC, ZAK-deficient mice and zebrafish, and human biopsy immunofluorescence with overloading

    PMID:37427997

    Open questions at the time
    • Direct phosphorylation of FLNC not biochemically confirmed
    • How mechanical force activates ZAKβ mechanistically unknown
  11. 2025 High

    Cryo-EM and channel-monitoring models answered the long-standing question of how ZAKα physically senses ribosome collisions and mRNA stasis to trigger activation.

    Evidence cryo-EM, biochemical reconstitution and SAM mutagenesis (RACK1/SERBP1); plus CLIP and AlphaFold3 mapping of RACK1/RPS27/18S helix-26 contacts (preprint)

    PMID:41261136

    Open questions at the time
    • How collision-driven dimerization is timed and reversed not fully defined
    • Quantitative threshold of collisions required for activation unknown
  12. 2026 High

    Connecting oncogene inhibition to ribosome collisions and clarifying inhibitor off-target effects refined the therapeutic logic of ZAK targeting.

    Evidence ZAK loss-of-function with ribosome collision assays in CML cells defining mTOR-EEF2K-EEF2→collision→ZAK→p38; biochemical and structural demonstration that GCN2iB directly inhibits ZAK

    PMID:41912913 PMID:42031169

    Open questions at the time
    • Generality of collision-driven ZAK cytotoxicity across drug classes untested
    • Selectivity of clinical ZAK inhibitors incompletely characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the same ribosome-collision-activated kinase is wired to such divergent outputs—cytokine/apoptosis, cardiac hypertrophy, chondrogenesis, EMT, stem-cell identity, and muscle mechanostructural turnover—remains the central open question.
  • Physiological direct substrates beyond MAPKKs largely unidentified
  • Determinants selecting downstream output by cell type and isoform unknown
  • Activation mechanism of ZAKβ mechanosensing not structurally defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 4 GO:0140098 catalytic activity, acting on RNA 3 GO:0140299 molecular sensor activity 3 GO:0140657 ATP-dependent activity 1
Localization
GO:0005829 cytosol 2 GO:0005840 ribosome 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1266738 Developmental Biology 2
Partners
ESR2FLNCMKK7PKNΑRACK1RPS27SERBP1SMAD2/3
Complex memberships
ZAK-Smad2/3-TβRI complexribosome (ZAKα-RACK1-RPS27)

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 MLTK (MAP3K20) was identified as a novel MAPKKK with two alternatively spliced isoforms, MLTKα and MLTKβ. Both isoforms activate ERK, JNK/SAPK, p38, and ERK5 pathways when overexpressed. Both are activated by osmotic shock via autophosphorylation. MLTKα (but not MLTKβ) expression disrupts actin stress fibers and causes morphological changes; a kinase-dead MLTKα does not, and p38 inhibition blocks these effects, placing p38 downstream of MLTKα in actin regulation. Overexpression in cells, kinase-dead mutant analysis, pharmacological p38 inhibition, SDS-PAGE mobility shift assays The Journal of biological chemistry Medium 11042189
2000 ZAK protein contains a kinase catalytic domain, a leucine-zipper, and a sterile-alpha motif (SAM), forms homodimers or oligomers in mammalian cells, and specifically activates the JNK/SAPK pathway and NF-κB transcription factor upon overexpression. Overexpression induces apoptosis in hepatoma cells. Cloning, overexpression in mammalian cells, Western blot for homodimerization/oligomerization, reporter assays for NF-κB and JNK/SAPK Biochemical and biophysical research communications Medium 10924358
2002 ZAK activates JNK/SAPK via MKK7 but not MKK4: co-expression of dominant-negative MKK7 (but not dominant-negative MKK4) significantly attenuates ZAK-induced JNK/SAPK activation. ZAK expression (but not kinase-dead ZAK) disrupts actin stress fibers. ZAK expression increases the G2/M cell population and decreases cyclin E levels. Dominant-negative co-expression, kinase-dead mutant, Western blot for cyclin E, flow cytometry for cell cycle Biochemical and biophysical research communications Medium 12220515
2003 PKNα phosphorylates MLTKα (MAP3K20) in vitro and this phosphorylation enhances MLTKα kinase activity. A kinase-negative PKNα mutant inhibits osmotic shock-induced MLTKα mobility shift. PKNα physically associates with MLTKα, MKK6, and p38γ, suggesting PKNα functions as both an upstream activator of MLTKα and a scaffold for the p38γ MAPK signaling pathway. In vitro kinase assay, kinase-negative mutant expression, co-immunoprecipitation, SDS-PAGE mobility shift Journal of biochemistry High 12761180
2003 ZAK interacts with the novel zinc finger protein ZZaPK (identified by yeast two-hybrid). ZZaPK overexpression promotes cell re-entry into the cell cycle by increasing E2F expression and cyclin E/CDK2 activity, counteracting ZAK-mediated cell cycle arrest. ZAK is proposed to suppress ZZaPK function upstream. Yeast two-hybrid, co-expression studies, Western blot for E2F and cyclin E Biochemical and biophysical research communications Low 12535642
2003 The leucine zipper domain of MLK7 (MAP3K20) is required for full catalytic activity and is necessary for full pathway (JNK) activation: C-terminal deletion mutants lacking the leucine zipper retain only ~25% catalytic activity. However, sequence in residues 322–436 (beyond the leucine zipper) is necessary for full JNK pathway activation, as deletion of this region abolishes JNK activation. C-terminal deletion mutants, in vitro kinase assay for specific activity, co-transfection with JNK Biochemical and biophysical research communications Medium 14521931
2004 ZAK overexpression in H9c2 cardiomyoblast cells induces hypertrophic growth features including increased cell size, elevated atrial natriuretic factor (ANF) expression, and increased actin fiber organization, establishing ZAK as a positive mediator of cardiac hypertrophy. Overexpression in H9c2 cells, cell size measurement, ANF reporter/expression, actin staining Biochemical and biophysical research communications Medium 15485649
2004 TGF-β induces cardiac hypertrophy via a ZAK→MKK7→ANF signaling axis. Dominant-negative ZAK inhibits TGF-β-induced hypertrophic features (cell size, ANF expression, actin organization). Dominant-negative MKK7 blocks both TGF-β- and ZAK-induced ANF expression. JNK inhibitor SP600125 had little effect, distinguishing a JNK-independent MKK7-mediated pathway downstream of ZAK. Dominant-negative ZAK and MKK7 constructs, pharmacological JNK inhibitor, ANF expression assay, cell size measurement Biochemical and biophysical research communications Medium 15465036
2004 Transgenic mice with cardiac-specific overexpression of MLK7 (MAP3K20) develop myocardial fibrosis, hypertrophy, impaired systolic function, diastolic dysfunction, and increased mortality upon isoproterenol administration. Isoproterenol-induced activation of JNK and p38 (but not ERK) is significantly greater in MLK7 Tg mice, establishing that MLK7 simultaneously activates JNK and p38 in vivo in cardiac stress. Transgenic mouse generation, hemodynamic analysis, histology, Western blot for MAPK phosphorylation, isoproterenol challenge Journal of molecular and cellular cardiology High 15350844
2008 ZAK (a ZAK isoform) is the MAP3K that transduces the ribotoxic stress response (RSR) from intoxicated ribosomes to SAPKinase activation following Shiga toxin 2 and ricin treatment. A ZAK-specific inhibitor (DHP-2) and siRNA knockdown of ZAK both diminish Stx2/ricin-induced SAPKinase activation and block upregulation of proinflammatory cytokine IL-8. ZAK-specific small molecule inhibitor (DHP-2), siRNA knockdown, Western blot for SAPK phosphorylation, IL-8 cytokine measurement Cellular microbiology High 18331592
2009 RhoGDIβ physically interacts with ZAK and is phosphorylated by ZAK in vitro. This phosphorylation negatively regulates RhoGDIβ functions. Conversely, the ZAK–RhoGDIβ interaction maintains ZAK in an inactive hypophosphorylated form, revealing mutual negative regulation. ZAK knockdown in ZAK/RhoGDIβ co-expressing cells restores full RhoGDIβ function. Co-immunoprecipitation, in vitro kinase/phosphorylation assay, siRNA knockdown, Western blot Journal of biomedical science Medium 19272173
2009 ZAK overexpression in H9c2 cells increases MMP-2 activity via JNK1/2 and p38 signaling, and reduces MMP-9 activity by increasing TIMP-1/2 expression, potentially contributing to cardiac fibrosis. Overexpression in H9c2 cells, zymography for MMP-2/9 activity, Western blot for TIMP-1/2, pathway inhibitor studies Molecular and cellular biochemistry Medium 19184368
2010 ZAK is required for doxorubicin-induced SAPK activation and apoptosis in HaCaT keratinocytes (but not HeLa cells). siRNA-mediated knockdown of ZAK or ZAK inhibitors (sorafenib, nilotinib) block doxorubicin-induced proinflammatory and apoptotic responses, establishing ZAK as the upstream MAP3K in doxorubicin-triggered ribotoxic stress response. siRNA knockdown, pharmacological inhibition (sorafenib, nilotinib), Western blot for SAPK/ZAK, cell viability/apoptosis assays Cancer biology & therapy High 20559024
2010 ZAK overexpression in lung cancer cells suppresses proliferation via ERK and JNK pathway activation in an AP-1-dependent manner. ZAK silencing reduces phospho-ERK and phospho-JNK without affecting p38. c-Jun RNAi reverses ZAK-mediated growth suppression and AP-1 activity. ZAK activates JNK→c-Jun and ERK→c-Fos to regulate AP-1. Overexpression, siRNA knockdown, ERK/JNK pathway inhibitors, AP-1 reporter (SEAP assay), c-Jun RNAi, Western blot, in vivo tumor xenograft Cancer science Medium 20331627
2012 MLTK (MAP3K20) plays an essential role in chondrogenesis by triggering Sox9-dependent induction of Sox6 expression. Knockdown of MLTK in Xenopus embryos causes loss of craniofacial cartilages without defects in neural crest development. Sox6 knockdown phenocopies MLTK knockdown. Ectopic MLTK expression induces Sox6 in a Sox9-dependent manner. p38 and JNK pathways function downstream of MLTK during chondrogenesis. Morpholino knockdown in Xenopus, ectopic expression, in situ hybridization, pharmacological p38/JNK inhibition Development (Cambridge, England) High 22764049
2012 ZAK is required for doxorubicin-induced activation of JNK and p38 MAPK in mouse primary macrophages. Using ZAK-deficient mouse macrophages, ZAK deficiency prevents doxorubicin-mediated phosphorylation of JNK and p38 and blocks expression of IL-1β, IL-6 and CXCL1. Nilotinib, ponatinib, and sorafenib suppress these effects pharmacologically. ZAK-deficient mouse macrophages (genetic KO), pharmacological inhibitors, Western blot for MAPK phosphorylation, qRT-PCR and ELISA for cytokines, in vivo co-administration in mice Cancer biology & therapy High 23114643
2013 Sorafenib suppresses UV-induced apoptosis in cells by off-target inhibition of ZAK, thereby preventing ZAK-mediated JNK activation. This JNK suppression is independent of the ERK pathway, identifying ZAK inhibition as a mechanism of sorafenib adverse effects (cutaneous SCC development). Pharmacological inhibition, Western blot for JNK phosphorylation, apoptosis assays, comparison with ERK pathway Molecular cancer therapeutics Medium 24170769
2013 ZAK activates MKK4 at the MAPKK level and is upstream of a ZAK→MKK4→JNK→TGFβ2 signaling cascade activated by the anticancer compound BA-TPQ in cancer cells but not normal cells. Phosphorylation analysis, pathway inhibitors (SP600125 for JNK, SD-208 for TGFβ), Western blot, mRNA quantification Current cancer drug targets Low 23607596
2015 ZAK-mediated cardiomyocyte hypertrophy requires p38 and JNK pathway activation and nuclear translocation of GATA4 and c-Jun transcription factors, without involvement of ERK or NFATc3. A dominant-negative ZAK shows no effect on p38/JNK signaling. JNK1/2 and p38 inhibitors significantly suppress ZAK-induced BNP expression. Doxycycline-inducible Tet-on ZAK WT and DN expression systems, pathway inhibitors, Western blot for MAPK and transcription factors, nuclear translocation imaging Molecular and cellular biochemistry Medium 25869677
2015 ZAK (both isoforms ZAKα and ZAKβ) is a key factor in cancer cell migration. ZAK depletion reduces cell motility; overexpression activates ERK, JNK, and p38 and increases cell motion. Kinase-dead mutants ZAKα K45M and ZAKβ K45M act as dominant negatives, suppressing MAPK activation and migration. ZAK constitutes an essential element of the EGF/ERK-dependent cell migration pathway. siRNA knockdown, kinase-dead mutant overexpression, ZAK inhibitor (nilotinib), migration assays, Western blot for MAPK phosphorylation Oncogene Medium 26522728
2016 Crystal structure of ZAK kinase domain in complex with vemurafenib was solved, revealing a highly distorted P-loop conformation. Positional scanning peptide library analysis revealed unique substrate specificity with unprecedented preferences for histidine residues at positions -1 and +2 relative to the phosphoacceptor site. X-ray crystallography (co-crystal structure), positional scanning peptide library, clinical kinase inhibitor library screen ACS chemical biology High 26999302
2016 Loss-of-function mutations in the SAM domain of ZAK cause split-foot defects in humans. CRISPR/Cas9-mediated knockout of both Zak isoforms is embryonically lethal in mice, while SAM domain deletion induces complex hindlimb defects associated with down-regulation of Trp63 (a known SHFM disease gene), placing ZAK upstream of Trp63 in limb patterning. Human genetic analysis, CRISPR/Cas9 knockout/deletion in mouse, in situ hybridization for Zak expression in limbs, transcriptome analysis for Trp63 Genome research High 26755636
2016 In a novel ZAK knockout mouse, ricin-intoxicated macrophages from zak-/- mice fail to activate p38 and JNK1/2 and show decreased c-jun and cxcl-1 expression compared to wild-type. zak-/- mice show decreased duodenal damage following in vivo ricin challenge, confirming ZAK's essential role in the ribotoxic stress response in vivo. ZAK knockout mouse, Western blot for p38/JNK activation, qRT-PCR, blinded histopathology of duodenal tissue Toxins High 27598200
2016 ZAK (MRK) protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. siRNA depletion of ZAK sensitizes medulloblastoma cells to radiation. A ZAK-specific irreversible small molecule inhibitor (M443) inhibits radiation-induced activation of p38 and Chk2 (downstream of ZAK) and radiosensitizes tumor cells but not normal brain cells. siRNA knockdown, small molecule ZAK inhibitor (M443, irreversible), Western blot for p38/Chk2, cell viability, orthotopic animal model Molecular cancer therapeutics Medium 27207779
2016 ZAK kinase activity is required for canonical TGF-β/SMAD-dependent signaling: siRNA depletion of ZAK strongly inhibits TGF-β-dependent SMAD2/3 phosphorylation and SMAD binding element-driven luciferase activity. A ZAK inhibitor (DHP-2) dose-dependently activates a TGFβR-kinase activity reporter, blocks TGF-β-induced SMAD2/3 phosphorylation, and inhibits cancer cell invasion. siRNA knockdown, pharmacological ZAK inhibitor (DHP-2), bioluminescent kinase reporter (BTR), SMAD2/3 phosphorylation assay, SBE4-Luc reporter, invasion assay Translational oncology Medium 27783979
2018 ZAK-mediated EMT is associated with activation of ZEB1, suppression of epithelial splicing regulatory proteins (ESRPs), and a switch in CD44 isoform expression from epithelial CD44v8-9 to mesenchymal CD44s. ZAK depletion in mesenchymal cancer cells reverses EMT, increases drug sensitivity, and attenuates bone metastasis. cDNA overexpression screen, ZAK depletion (siRNA/shRNA), Western blot for EMT markers, CD44 isoform analysis, bone metastasis assay, transcriptomics Cell death & disease Medium 29396440
2018 ERβ directly binds ZAK under normal conditions (interaction shown by co-IP). ZAK overexpression reduces ZAK-ERβ association. ERβ overexpression blocks ZAK nuclear translocation via inhibition of SUMO-1 modification of ZAK, and suppresses ZAK-induced p-JNK, p-p38, c-Jun, and GATA-4 upregulation. Co-immunoprecipitation, transient transfection, Western blot for SUMO-1 modification, nuclear fractionation/localization assay Journal of cellular biochemistry Medium 29932238
2018 ZAKβ isoform has antitumorigenic properties opposite to ZAKα. High ZAKβ:ZAKα ratio activates cAMP/CREB1 signaling, reduces cyclooxygenase 2 and β-catenin, and inhibits anchorage-independent growth. Doxorubicin treatment switches endogenous expression from ZAKα to ZAKβ. Isoform-specific overexpression, soft agar anchorage-independent growth assay, Western blot, cAMP reporter assay, doxorubicin treatment The Chinese journal of physiology Medium 29374956
2022 Upon ribosome impairment (Rptor deletion, amino acid starvation, or low-dose cycloheximide), intestinal stem cells gain an Lgr5-negative fetal-like identity requiring ZAKα activation. Mechanistically, ZAKα activates YAP via SRC kinase to mediate this stem cell identity switch. ZAKα is thus identified as a critical mediator of ISC plasticity downstream of ribosome stress. Mouse intestinal organoids, conditional mouse knockouts, pharmacological ribosome impairment, Western blot for ZAKα/YAP/SRC, ISC identity markers (Lgr5, fetal markers), metabolic profiling Nature communications High 35918345
2022 ZAK overexpression in fibrotic kidney is in complex with Smad2/3 and TGF-β receptor I (TβRI). Silencing ZAK reduces Smad2/3 recruitment to TβRI and attenuates p38 MAPK and Smad signaling, reducing tubulointerstitial fibrosis in vivo. Co-immunoprecipitation of ZAK-Smad2/3-TβRI complex, ZAK siRNA knockdown, UUO mouse model, Western blot, pharmacological ZAK inhibitor (6p) Translational research : the journal of laboratory and clinical medicine Medium 35276386
2023 ZAKβ isoform is the only isoform expressed in skeletal muscle and is activated by muscle contraction and cellular compression. Phosphoproteomics identified SYNPO2, BAG3, and Filamin C (FLNC) as ZAKβ substrates/interactors. ZAK deficiency leads to accumulation of mislocalized FLNC and BAG3 in muscle fibers, with exacerbation by endogenous muscle overloading, establishing ZAKβ as necessary for adaptive turnover of FLNC in response to mechanical stress. Phosphoproteomics, ZAK-deficient mice and zebrafish, immunofluorescence of human biopsy and mouse muscle, overloading model, histopathology Human molecular genetics Medium 37427997
2025 Cryo-EM and biochemistry revealed that ZAK is constitutively recruited to ribosomes and, upon ribosome collisions, interactions between ZAK and ribosomal protein RACK1 enable activation by dimerization of its SAM domains at the collision interface. SERBP1, a ribosome-binding protein, negatively regulates ZAK by preventing constitutive activation. SAM domain variants (including a known pathogenic variant) can bypass the ribosome requirement for ZAK activation, confirming the SAM domain's key role in regulating kinase activity on and off the ribosome. Cryo-electron microscopy, biochemical reconstitution, SAM domain mutagenesis, co-immunoprecipitation for RACK1 and SERBP1 interactions Nature High 41261136
2026 BCR::ABL1 inhibition in CML cells induces ribosome collisions, generating collided ribosomes that trigger ZAK-dependent p38 activation and apoptosis. Mechanistically, BCR::ABL1 inhibition activates the mTOR-EEF2K pathway to phosphorylate EEF2, slowing translation elongation and generating nuclease-resistant collided ribosomes upstream of ZAK. Loss of ZAK function reduces the cytotoxic effects of BCR::ABL1 inhibitors. ZAK loss-of-function (siRNA/CRISPR), ribosome profiling/nuclease protection assay for collided ribosomes, Western blot for p38/EEF2 phosphorylation, primary CML patient cells, pharmacological translation modulation Leukemia High 41912913
2026 GCN2iB, widely used as a GCN2/ISR inhibitor, is a direct inhibitor of ZAK kinase. Biochemical measurements, cell-based assays, and structural modeling demonstrate that GCN2iB inhibits ZAK, dampening stress-induced JNK and p38 activation. This off-target ZAK inhibition masks cytotoxic consequences normally associated with GCN2 inhibition. Biochemical kinase assay, cell-based MAPK phosphorylation assays, structural modeling The Journal of biological chemistry Medium 42031169
2025 ZAKα dynamically monitors the mRNA exit channel of elongating ribosomes for mRNA stasis via direct interactions with ribosomal proteins RACK1 and RPS27 and with 18S rRNA helix-26. Four mRNA-binding peptides in ZAKα span across the path of ribosome-exiting mRNA. Progressive elongation threads ZAKα off the ribosome, while mRNA stasis stabilizes the interaction. Prolonged binding is associated with sequestration of the inhibitory SAM domain on RACK1, allowing transient ZAKα dimerization, activation loop trans-autophosphorylation, and RSR activation. AlphaFold3 structural prediction, RNA crosslinking and immunoprecipitation (CLIP), biochemical interaction mapping, mutagenesis bioRxivpreprint Medium

Source papers

Stage 0 corpus · 66 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Identification and characterization of a novel MAP kinase kinase kinase, MLTK. The Journal of biological chemistry 97 11042189
2014 Long non-coding RNA URHC regulates cell proliferation and apoptosis via ZAK through the ERK/MAPK signaling pathway in hepatocellular carcinoma. International journal of biological sciences 94 25013376
2000 Cloning and expression of ZAK, a mixed lineage kinase-like protein containing a leucine-zipper and a sterile-alpha motif. Biochemical and biophysical research communications 88 10924358
2008 ZAK: a MAP3Kinase that transduces Shiga toxin- and ricin-induced proinflammatory cytokine expression. Cellular microbiology 87 18331592
2014 Integrated exome and transcriptome sequencing reveals ZAK isoform usage in gastric cancer. Nature communications 76 24807215
2018 Long noncoding RNA MLK7-AS1 promotes ovarian cancer cells progression by modulating miR-375/YAP1 axis. Journal of experimental & clinical cancer research : CR 61 30249278
2016 Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice. Genome research 52 26755636
2012 Small molecule kinase inhibitors block the ZAK-dependent inflammatory effects of doxorubicin. Cancer biology & therapy 51 23114643
2010 ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells. Cancer biology & therapy 49 20559024
2002 Mixed lineage kinase ZAK utilizing MKK7 and not MKK4 to activate the c-Jun N-terminal kinase and playing a role in the cell arrest. Biochemical and biophysical research communications 36 12220515
2010 ZAK inhibits human lung cancer cell growth via ERK and JNK activation in an AP-1-dependent manner. Cancer science 34 20331627
2015 The MAP3K ZAK, a novel modulator of ERK-dependent migration, is upregulated in colorectal cancer. Oncogene 32 26522728
2019 Network pharmacology modeling identifies synergistic Aurora B and ZAK interaction in triple-negative breast cancer. NPJ systems biology and applications 30 31312514
2004 ZAK re-programs atrial natriuretic factor expression and induces hypertrophic growth in H9c2 cardiomyoblast cells. Biochemical and biophysical research communications 29 15485649
2016 Recessive mutations in the kinase ZAK cause a congenital myopathy with fibre type disproportion. Brain : a journal of neurology 27 27816943
2015 ZAK induces cardiomyocyte hypertrophy and brain natriuretic peptide expression via p38/JNK signaling and GATA4/c-Jun transcriptional factor activation. Molecular and cellular biochemistry 27 25869677
2009 Molecular mapping of a stripe rust resistance gene in spring wheat cultivar Zak. Phytopathology 27 19740035
2022 Ribosome impairment regulates intestinal stem cell identity via ZAKɑ activation. Nature communications 26 35918345
2013 Sorafenib suppresses JNK-dependent apoptosis through inhibition of ZAK. Molecular cancer therapeutics 26 24170769
2004 Transforming growth factor-beta induces the expression of ANF and hypertrophic growth in cultured cardiomyoblast cells through ZAK. Biochemical and biophysical research communications 26 15465036
2003 Regulation of a mitogen-activated protein kinase kinase kinase, MLTK by PKN. Journal of biochemistry 26 12761180
2012 Shiga toxin 2-induced intestinal pathology in infant rabbits is A-subunit dependent and responsive to the tyrosine kinase and potential ZAK inhibitor imatinib. Frontiers in cellular and infection microbiology 25 23162799
2018 Knockdown of long non-coding RNA MAP3K20 antisense RNA 1 inhibits gastric cancer growth through epigenetically regulating miR-375. Biochemical and biophysical research communications 24 29428732
2019 Fisetin activates Hippo pathway and JNK/ERK/AP-1 signaling to inhibit proliferation and induce apoptosis of human osteosarcoma cells via ZAK overexpression. Environmental toxicology 23 31044527
2017 Structure Based Design of N-(3-((1H-Pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamides as Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) Inhibitors. Journal of medicinal chemistry 23 28586211
2009 ZAK induces MMP-2 activity via JNK/p38 signals and reduces MMP-9 activity by increasing TIMP-1/2 expression in H9c2 cardiomyoblast cells. Molecular and cellular biochemistry 23 19184368
2016 Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib. ACS chemical biology 22 26999302
2019 Design, Synthesis, and Structure-Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) Inhibitors. Journal of medicinal chemistry 21 31244114
2003 A novel zinc finger protein, ZZaPK, interacts with ZAK and stimulates the ZAK-expressing cells re-entering the cell cycle. Biochemical and biophysical research communications 19 12535642
2018 Mixed lineage kinase ZAK promotes epithelial-mesenchymal transition in cancer progression. Cell death & disease 18 29396440
2012 Increased ABA sensitivity results in higher seed dormancy in soft white spring wheat cultivar 'Zak'. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 17 23212773
2004 Transgenic mice with cardiac-specific over-expression of MLK7 have increased mortality when exposed to chronic beta-adrenergic stimulation. Journal of molecular and cellular cardiology 14 15350844
2020 Long-range ballistic transport of Brown-Zak fermions in graphene superlattices. Nature communications 13 33188210
2012 The protein kinase MLTK regulates chondrogenesis by inducing the transcription factor Sox6. Development (Cambridge, England) 12 22764049
2018 ERβ targets ZAK and attenuates cellular hypertrophy via SUMO-1 modification in H9c2 cells. Journal of cellular biochemistry 11 29932238
2009 ZAK negatively regulates RhoGDIbeta-induced Rac1-mediated hypertrophic growth and cell migration. Journal of biomedical science 11 19538723
2025 ZAK activation at the collided ribosome. Nature 10 41261136
2018 Long non‑coding RNA MLK7‑AS1 promotes proliferation in human colorectal cancer via downregulation of p21 expression. Molecular medicine reports 10 30535460
2020 ZAK Inhibitor PLX4720 Promotes Extrusion of Transformed Cells via Cell Competition. iScience 9 32688284
2017 Novel genetic variants in the P38MAPK pathway gene ZAK and susceptibility to lung cancer. Molecular carcinogenesis 9 29071797
2016 Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma. Molecular cancer therapeutics 9 27207779
2016 A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response. Toxins 9 27598200
2022 Targeted inhibition of ZAK ameliorates renal interstitial fibrosis. Translational research : the journal of laboratory and clinical medicine 8 35276386
2016 Leucine-zipper and Sterile-α Motif Kinase (ZAK): A Potential Target for Drug Discovery. Current medicinal chemistry 8 27655071
2024 Heterozygous MAP3K20 variants cause ectodermal dysplasia, craniosynostosis, sensorineural hearing loss, and limb anomalies. Human genetics 7 38451290
2018 Antitumorigenic Effects of ZAKβ, an Alternative Splicing Isoform of ZAK. The Chinese journal of physiology 7 29374956
2013 Identification of the ZAK-MKK4-JNK-TGFβ signaling pathway as a molecular target for novel synthetic iminoquinone anticancer compound BA-TPQ. Current cancer drug targets 7 23607596
2009 RhoGDIbeta-induced hypertrophic growth in H9c2 cells is negatively regulated by ZAK. Journal of biomedical science 7 19272173
2023 Two antisense RNAs-AFAP1-AS1 and MLK7-AS1-promote colorectal cancer progression by sponging miR-149-5p and miR-485-5p. Molecular therapy. Nucleic acids 6 37547289
2021 Long Noncoding RNA MLK7-AS1 Promotes Non-Small-Cell Lung Cancer Migration and Invasion via the miR-375-3p/YWHAZ Axis. Frontiers in oncology 6 33968726
2016 A Prospective Observational Study of Adoptive Immunotherapy for Cancer Using Zoledronate-Activated Killer (ZAK) Cells - An Analysis for Patients with Incurable Pancreatic Cancer. Anticancer research 6 27127137
2020 Selective Activation of ZAK β Expression by 3-Hydroxy-2-Phenylchromone Inhibits Human Osteosarcoma Cells and Triggers Apoptosis via JNK Activation. International journal of molecular sciences 5 32397561
2017 Zak phase induced multiband waveguide by two-dimensional photonic crystals. Optics letters 5 28809879
2016 A Requirement for ZAK Kinase Activity in Canonical TGF-β Signaling. Translational oncology 5 27783979
2003 Effect of C-terminal truncations on MLK7 catalytic activity and JNK activation. Biochemical and biophysical research communications 5 14521931
2011 Transient global cerebral ischemia induces up-regulation of MLTKα in hippocampal CA1 neurons. Journal of molecular histology 4 22146853
2023 Myofibrillar myopathy hallmarks associated with ZAK deficiency. Human molecular genetics 3 37427997
2020 Rare missense variant p.Ala505Ser in the ZAK protein observed in a patient with split-hand/foot malformation from a non-consanguineous pedigree. The Journal of international medical research 3 32266845
2022 Republication: A Prospective Observational Study of Adoptive Immunotherapy for Cancer Using Zoledronate-Activated Killer (ZAK) Cells - An Analysis for Patients With Incurable Pancreatic Cancer. Anticancer research 2 35093924
2020 Retraction Note: Long noncoding RNA MLK7-AS1 promotes ovarian cancer cells progression by modulating miR-375/YAP1 axis. Journal of experimental & clinical cancer research : CR 2 33153490
2019 Studies of pharmacokinetics in beagle dogs and drug-drug interaction potential of a novel selective ZAK inhibitor 3h for hypertrophic cardiomyopathy treatment. Journal of pharmaceutical and biomedical analysis 2 31060033
2025 Polypharmacology-Driven Discovery of ZAK-I-57: A Potent Multi-Targeted Benzoxazinone Small Molecule for Hepatocellular Carcinoma Therapy. MedComm 1 40727254
2026 BCR::ABL1 tyrosine kinase inhibitors induce ribosome collisions to activate ZAK-dependent ribotoxic stress and apoptosis in chronic myeloid leukemia. Leukemia 0 41912913
2026 An inhibitor of GCN2 and the integrated stress response directly targets ZAK protein kinase to limit cytotoxicity. The Journal of biological chemistry 0 42031169
2025 Confirmation of the Hotspot Variant in MAP3K20 Responsible for Deafness, Ectodermal Dysplasia, Craniosynostosis, Ectrodactyly, and Skeletal Anomaly Spectrum. Molecular syndromology 0 41064052
2025 Inhibition the MAP3K20-mediated ribotoxic stress response pathway downregulates M1 macrophage polarization in ulcerative colitis. International immunopharmacology 0 41192115

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