Affinage

DAPK1

Death-associated protein kinase 1 · UniProt P53355

Length
1430 aa
Mass
160.0 kDa
Annotated
2026-06-09
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DAPK1 is a Ca2+/calmodulin-regulated serine/threonine kinase that functions as a central executioner of apoptotic, necrotic, and autophagic death programs and as a tumor and migration suppressor, integrating signals through both its catalytic domain and a protein-interaction death domain (PMID:20141836, PMID:24806680, PMID:16476779). In neuronal injury, DAPK1 is recruited into the NMDA receptor GluN2B (NR2B) complex during ischemia, where it binds the NR2B C-terminal tail and phosphorylates Ser-1303 to amplify channel conductance and injurious Ca2+ influx; uncoupling DAPK1 from NR2B or deleting DAPK1 is neuroprotective (PMID:20141836), and a distinct extra-synaptic GluN2B pool engages DAPK1 separately from the synaptic CaMKII pool that drives ischemic death (PMID:28614711, PMID:31914378). DAPK1 propagates death signaling by phosphorylating substrates through its death domain, including p53 at Ser-23 to drive parallel nuclear-apoptotic and mitochondrial-necrotic pathways (PMID:24806680), and by phosphorylating TSC2 to dissociate the TSC1-TSC2 complex and activate mTORC1 downstream of growth-factor and TCR/calcineurin signals (PMID:18974095, PMID:31541182). Beyond canonical death substrates, the death domain serves as a non-catalytic activator of MARK1/2 kinases, driving tau and MAP2/4 phosphorylation and microtubule destabilization (PMID:21311567). DAPK1 catalytic output is held in check by a multilayered regulatory system: dephosphorylation of the inhibitory Ser-308 permits calmodulin binding and activation (PMID:17056602), an intrinsic ROC GTPase domain promotes inhibitory Ser-308 autophosphorylation (PMID:22988864), reciprocal Src (inhibitory Y491/492) and LAR phosphatase (activating) control its anti-migratory and proapoptotic activity (PMID:17803936), and ERK phosphorylates DAPK1 at Ser-735 in a positive-feedback loop that amplifies death signaling in apoptosis and seizure-induced neuronal death (PMID:15616583, PMID:35742817). DAPK1 abundance is set by ubiquitin-proteasome turnover via the KLHL20-CUL3-ROC1 E3 ligase, which recognizes an LPDLV motif buried in the death domain (PMID:20389280, PMID:31279627), and via the E3 ligase DIP-1 (PMID:12351649). Functionally, DAPK1 suppresses cell migration and rigidity-dependent survival by blocking talin-integrin association and the integrin-Cdc42 polarity pathway (PMID:16476779, PMID:35927990), promotes autophagy through MAP1B and BECLIN1-complex remodeling (PMID:18195017, PMID:30136419), and acts as a tumor suppressor that restrains PD-L1-mediated immune evasion (PMID:35114597).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2002 High

    Establishing that DAPK protein levels are actively controlled answered how its proapoptotic potential is restrained, identifying ubiquitin-mediated turnover as a brake.

    Evidence Yeast two-hybrid, in vitro and in vivo ubiquitination, and apoptosis assays identifying the E3 ligase DIP-1

    PMID:12351649

    Open questions at the time
    • Physiological signals controlling DIP-1 activity unresolved
    • Relationship to other DAPK1 E3 ligases not addressed
  2. 2004 High

    Linking DAPK to ERK answered how upstream MAPK signaling tunes DAPK activity, revealing a bidirectional feedback loop that amplifies apoptosis.

    Evidence In vitro kinase assay with Ser-735 mutagenesis, reciprocal co-IP, and subcellular fractionation

    PMID:15616583

    Open questions at the time
    • In vivo physiological contexts of the loop not defined at this stage
    • Structural basis of the death-domain ERK docking site unknown
  3. 2006 Medium

    Defining Ser-308 dephosphorylation as an activation switch and mapping DAPK's block of talin-integrin coupling answered how DAPK is rapidly activated and how it suppresses migration independent of apoptosis.

    Evidence Ser-308 mutagenesis with TNF/ceramide time course; talin-integrin co-IP and migration/polarization assays

    PMID:16476779 PMID:17056602

    Open questions at the time
    • Phosphatase responsible for Ser-308 dephosphorylation not identified here
    • Direct kinase substrate among adhesion components not defined in the migration study
  4. 2007 High

    Identifying Src/LAR tyrosine control at Y491/492 and a cathepsin B survival complex answered how DAPK is reversibly inactivated and protected from degradation, connecting it to EGF-driven tumor cell migration.

    Evidence In vitro kinase/phosphatase assays with Y491/492 mutagenesis, co-IP, migration assays, and human cancer staining; co-IP domain mapping with cathepsin B and dominant-negative miniprotein

    PMID:17324927 PMID:17803936

    Open questions at the time
    • Mechanism by which Y491/492 phosphorylation drives intramolecular inactivation only inferred
    • Cathepsin B interaction is Medium-confidence single-lab
  5. 2008 High

    Mapping DAPK death-domain interactions to TSC2 and MAP1B answered how DAPK couples to mTORC1 signaling and to the autophagy machinery, revealing roles beyond classical apoptosis.

    Evidence Peptide aptamer/library screens, in vitro kinase assays, death-domain miniproteins, siRNA, and DAPK+/- MEF analysis

    PMID:18195017 PMID:18974095

    Open questions at the time
    • TSC2 phosphosite(s) not precisely mapped
    • MAP1B finding is Medium-confidence single-lab
    • How DAPK switches between proautophagic and promTORC1 outputs unclear
  6. 2009 Medium

    Identifying a kinase-deficient splice variant answered whether the DAPK1 locus encodes endogenous negative regulators of the full-length protein.

    Evidence Transfection of s-DAPK-1 variants, domain mapping, proteasome inhibitor and pulse-chase stability assays

    PMID:19267229

    Open questions at the time
    • Mechanism of proteasome-independent destabilization undefined
    • Physiological abundance/relevance of s-DAPK-1 not established
  7. 2010 High

    Demonstrating that DAPK1 binds and phosphorylates GluN2B at Ser-1303 and that KLHL20-CUL3-ROC1 degrades it answered, respectively, the molecular cause of excitotoxic Ca2+ influx in stroke and how interferon stabilizes DAPK1 to license death.

    Evidence Co-IP, direct binding, constitutively active DAPK1, knockout mice, in vivo NR2B uncoupling peptide and electrophysiology; reciprocal co-IP, in vitro/in vivo ubiquitination, and PML body localization for KLHL20

    PMID:20141836 PMID:20389280

    Open questions at the time
    • Whether the NR2B and degradation pathways intersect not addressed
    • Kinetics of DAPK1 recruitment to GluN2B during ischemia partially defined
  8. 2011 High

    Showing that the death domain (not the catalytic domain) activates MARK1/2 answered how DAPK1 destabilizes microtubules and drives tau phosphorylation, defining a non-catalytic effector mechanism.

    Evidence Co-IP, domain-specific mutagenesis, in vitro kinase assay, DAPK-/- mouse brain biochemistry, and a Drosophila tauopathy model

    PMID:21311567

    Open questions at the time
    • Structural basis for MARK spacer-region engagement not resolved
    • Direct tauopathy relevance in mammals via this axis not established
  9. 2012 Medium

    Identifying an intrinsic ROC GTPase domain answered how DAPK1 catalytic activity is regulated in cis, linking GTP binding to inhibitory Ser-308 autophosphorylation.

    Evidence In vitro GTP binding/hydrolysis assays, autophosphorylation at Ser-308, and domain mutagenesis

    PMID:22988864

    Open questions at the time
    • Cellular GTP/GDP states governing this switch not measured
    • Limited experimental detail; single-lab summary
  10. 2013 Medium

    Establishing DAPK as a scaffold for LIMK/cofilin answered how DAPK links TNF signaling to cytoskeletal reorganization during apoptotic morphology changes.

    Evidence Peptide array binding, DAPK inhibitor and siRNA, immunofluorescence redistribution, and structural modeling

    PMID:23702034

    Open questions at the time
    • No in vitro reconstitution of the ternary complex
    • Whether DAPK directly phosphorylates LIMK or cofilin not demonstrated
  11. 2014 High

    Identifying p53 Ser-23 phosphorylation and an HSF1 feedback loop answered how DAPK1 commits neurons to dual apoptotic/necrotic death and how it transcriptionally amplifies its own expression.

    Evidence Death-domain p53 binding/kinase assays with in vivo Tat-peptide uncoupling and ischemia model; DAPK-HSF1 co-IP, ChIP on DAPK promoter, and inhibitor/siRNA

    PMID:24806680 PMID:25380824

    Open questions at the time
    • HSF1 study is Medium-confidence single-lab
    • Determinants partitioning p53 to nuclear versus mitochondrial fates only partially defined
  12. 2016 High

    Linking ATF6/ER stress to DAPK1 transcription and identifying PTRN-1/microtubule control in C. elegans answered how DAPK1 is induced under stress to drive autophagosome formation and how it maintains cytoskeletal/epidermal integrity.

    Evidence Stable shRNA knockdowns with LC3/MRLC readouts; C. elegans suppressor screen, co-IP with PTRN-1, and pharmacological MT modulation

    PMID:27085326 PMID:27661253

    Open questions at the time
    • ATF6-DAPK1 axis is Medium-confidence single-lab
    • Whether mammalian DAPK1 engages CAMSAP analogously not tested
  13. 2017 High

    Defining DAPK1's competitive block of CaMKII-GluN2B binding and a Bik-DAPK1-Bak ER-mitochondria complex answered how DAPK1 mediates synaptic LTD and how it facilitates ER-to-mitochondrial Ca2+ transfer.

    Evidence Pharmacogenetic dissection with LTP/LTD electrophysiology and binding competition; co-IP domain mapping, Ca2+ imaging, and ER-mito contact measurements

    PMID:28614711 PMID:28986568

    Open questions at the time
    • Bik-DAPK1-Bak study is Medium-confidence single-lab
    • How Ca2+/CaM dynamically gates DAPK1/GluN2B during LTP versus LTD not fully resolved
  14. 2019 High

    Resolving the KLHL20 Kelch-DAPK1 LPDLV interface, the DAPK1-TSC2-mTORC1 axis in T cells, the DAPK1-Pellino1 inflammatory pathway, and a DAPK1-ZEB1 tumor axis expanded DAPK1's mechanistic and disease reach in degradation, immunity, and cancer.

    Evidence 1.1 Å crystal structure with motif mutagenesis; TCR/calcineurin co-IP, domain analysis and LCMV model; in vitro Pellino1 Ser39 kinase assay with DAPK1-/- septic AKI model; DAPK1-ZEB1 co-IP and xenograft

    PMID:31279627 PMID:31541182 PMID:33052227 PMID:34289746

    Open questions at the time
    • ZEB1 finding is Low-confidence single co-IP
    • Whether the TSC2 axis operates identically in neurons and T cells unclear
  15. 2020 High

    Genetic separation of synaptic CaMKII from extra-synaptic DAPK1 GluN2B pools, plus identification of caytaxin as a presynaptic DAPK1 inhibitor, refined which GluN2B-associated kinase drives ischemic death and how DAPK1 is restrained in injury.

    Evidence GluN2B L1298A/R1300Q knock-in with cardiac-arrest model and fractionation; caytaxin co-IP, in vitro kinase assay, and MCAO model

    PMID:31914378 PMID:32277960

    Open questions at the time
    • Caytaxin study is Medium-confidence single-lab
    • Functional role of the extra-synaptic DAPK1-GluN2B pool not fully defined
  16. 2022 Medium

    Defining DAPK1 rigidity-sensing substrates (tropomyosin1.1, talin1 head), the ERK-DAPK1 epilepsy axis, and a DAPK1-IKKβ-CSN5-PD-L1 immune-evasion pathway extended DAPK1 mechanism into mechanotransduction, seizure-induced neuronal death, and anti-tumor immunity.

    Evidence Phosphorylation/anoikis rigidity assays with Src and PTPN12; ERK inhibitors, DAPK1 KO and phospho-deficient knock-in with EEG/seizure model; DAPK1-IKKβ-CSN5-PD-L1 binding, NK killing and xenograft assays

    PMID:35114597 PMID:35742817 PMID:35927990

    Open questions at the time
    • Rigidity-sensing and PD-L1 axes are single-lab
    • Direct versus indirect DAPK1 regulation of IKKβ/CSN5 not fully dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DAPK1's many context-specific outputs (excitotoxicity, mTORC1 activation, autophagy, migration suppression, immune regulation) are selected by upstream signals and substrate availability in a single cell remains unresolved.
  • No unified model integrating catalytic versus death-domain effector branches
  • Tissue-specific substrate repertoire incompletely mapped
  • Relative in vivo contribution of competing E3 ligases (KLHL20 vs DIP-1) unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016740 transferase activity 5 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2 GO:0003924 GTPase activity 1 GO:0060089 molecular transducer activity 1
Localization
GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9612973 Autophagy 3 R-HSA-168256 Immune System 2
Partners
GRIN2BKLHL20MAP1BMAPK1MARK1SRCTP53TSC2
Complex memberships
Bik-DAPK1-ERK1/2-Bak complexKLHL20-CUL3-ROC1 E3 ligaseNMDA receptor GluN2B complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 During cerebral ischemia, DAPK1 is recruited into the NMDA receptor NR2B protein complex in cortical neurons. DAPK1 directly binds the NR2B C-terminal tail (amino acids 1292–1304). A constitutively active DAPK1 phosphorylates NR2B at Ser-1303, enhancing NR1/NR2B receptor channel conductance and injurious Ca2+ influx. Genetic deletion of DAPK1 or peptide uncoupling of DAPK1 from NR2B blocks this Ca2+ influx and protects neurons against ischemic injury. Co-immunoprecipitation, direct binding assays, constitutively active DAPK1 overexpression, genetic knockout mice, in vivo peptide uncoupling (NR2B CT peptide), electrophysiology Cell High 20141836
2004 DAPK interacts with ERK through a docking sequence within its death domain. ERK phosphorylates DAPK at Ser-735, increasing DAPK catalytic activity both in vitro and in vivo. Conversely, DAPK promotes cytoplasmic retention of ERK, inhibiting ERK nuclear signaling. This bidirectional regulation forms a positive feedback loop that promotes DAPK apoptotic activity. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, siRNA knockdown, subcellular fractionation The EMBO journal High 15616583
2010 The BTB-Kelch protein KLHL20 binds DAPK via its Kelch-repeat domain and assembles with Cullin 3 (Cul3) and ROC1 to form an E3 ligase complex that promotes DAPK polyubiquitination and proteasomal degradation. IFN-α/γ sequesters KLHL20 into PML nuclear bodies, separating it from DAPK and stabilizing DAPK. This mechanism controls IFN-induced apoptosis and autophagy. Co-immunoprecipitation, ubiquitination assay in vitro and in vivo, siRNA depletion, immunofluorescence localization, functional cell death assays The EMBO journal High 20389280
2014 DAPK1 directly binds the DNA-binding motif of p53 via its death domain (DAPK1DD), and phosphorylates p53 at Ser-23. This phosphorylation creates a functional form of p53 that drives both apoptotic (nuclear, inducing Bax expression) and necrotic (mitochondrial matrix, via CypD interaction) neuronal death pathways. Deletion of DAPK1DD or a Tat-p53DM uncoupling peptide blocks both pathways in cortical neurons and in vivo. Co-immunoprecipitation, in vitro kinase assay, deletion mutant analysis, Tat-peptide uncoupling in vivo, primary cortical neuron culture assays, mouse ischemia model The Journal of neuroscience High 24806680
2007 The tyrosine phosphatase LAR dephosphorylates DAPK at pY491/492, stimulating DAPK catalytic, proapoptotic, and anti-adhesion/migration activities. Conversely, Src phosphorylates DAPK at Y491/492, inducing DAPK intramolecular/intermolecular interaction and inactivation. EGF stimulation activates Src and downregulates LAR synergistically to inactivate DAPK, facilitating tumor cell migration. In vitro kinase/phosphatase assay, site-directed mutagenesis at Y491/492, co-immunoprecipitation, cell migration assays, immunostaining of human cancer samples Molecular cell High 17803936
2006 DAPK inhibits cell migration and polarization by blocking the association of the talin head domain with integrin, thereby suppressing the integrin-Cdc42 polarity pathway. This anti-migratory effect is apoptosis-independent and contributes to DAPK tumor suppression. Cell migration assays, cell polarization assays, co-immunoprecipitation of talin-integrin, overexpression and knockdown of DAPK, invasion assays with adenocarcinoma cell lines The Journal of cell biology High 16476779
2008 DAPK-1 binds to the microtubule-associated protein MAP1B via a linear peptide motif in the MAP1B N-terminal domain (residues 1–126). Amino acid starvation induces formation of the endogenous DAPK-1/MAP1B complex. MAP1B is required for DAPK-1-stimulated autophagy and membrane blebbing; siRNA knockdown of MAP1B attenuates both activities. Peptide combinatorial library screening, co-immunoprecipitation, siRNA knockdown, clonogenic assay, confocal co-localization, autophagy inhibitor (3-MA) treatment The Journal of biological chemistry Medium 18195017
2008 DAPK's death domain binds the tumor suppressor TSC2 (tuberin). Recombinant DAPK phosphorylates TSC2 in vitro, and DAPK kinase activity (stimulated by growth factors) promotes TSC2 phosphorylation in vivo, leading to TSC1-TSC2 complex dissociation. DAPK thereby acts as a positive regulator of mTORC1 signaling downstream of RAS-MEK-ERK and PI3K-AKT pathways. DAPK+/- MEFs show attenuated mTORC1 signaling. Peptide aptamer library, in vitro binding with death domain miniproteins, in vitro kinase assay, co-immunoprecipitation, siRNA knockdown, DAPK+/- MEF analysis, epistasis with pathway inhibitors The Journal of biological chemistry High 18974095
2011 DAPK activates MARK1/2 kinases through its death domain (not its catalytic domain) by binding the MARK1/2 spacer region, disrupting an inhibitory intramolecular interaction in MARK. This leads to MARK-dependent phosphorylation of tau and MAP2/4, destabilizing microtubules. DAPK-/- mouse brains show reduced tau phosphorylation. In a Drosophila tauopathy model, DAPK enhances tau toxicity via PAR-1 (MARK ortholog) in a phosphorylation-dependent manner. Co-immunoprecipitation, deletion mutagenesis (catalytic vs. death domain), in vitro kinase assay, DAPK-/- mouse brain biochemistry, Drosophila genetic model, neuronal differentiation assays Cell death and differentiation High 21311567
2002 DIP-1, a multi-RING finger protein, binds DAPK and acts as an E3 ubiquitin ligase that ubiquitinates DAPK in vitro and in vivo, targeting DAPK for proteasomal degradation. DIP-1 expression antagonizes the anti-apoptotic function of DAPK and promotes caspase-dependent apoptosis. Yeast two-hybrid and co-immunoprecipitation (binding), in vitro ubiquitination assay, in vivo ubiquitination, transient transfection apoptosis assay The Journal of biological chemistry High 12351649
2006 DAPK activity is controlled by phosphorylation status: dephosphorylation at Ser-308 activates DAPK by allowing calcium/calmodulin association. TNF or ceramide treatment induces rapid Ser-308 dephosphorylation and transient kinase activation, followed by proteasome-dependent DAPK degradation. Dephosphorylation and activation temporally precede degradation. In vitro kinase assay, phosphorylation site mutagenesis (Ser-308), proteasome inhibitor treatment, TNF/ceramide stimulation time course, Western blot The Journal of biological chemistry Medium 17056602
2017 DAPK1 mediates long-term depression (LTD) by competitively blocking CaMKII binding to GluN2B. During LTD, calcineurin-dependent DAPK1 activation suppresses CaMKII synaptic accumulation. Ca2+/CaM negatively regulates DAPK1/GluN2B binding, causing DAPK1 removal from synapses during LTP but retention during LTD. A pharmacogenetic approach confirmed that DAPK1 suppression of CaMKII/GluN2B binding is required for LTD. Pharmacogenetic (chemical-genetic) approach, biochemical binding assays, synaptic fractionation, LTP/LTD electrophysiology, DAPK1 inhibition and knockdown Cell reports High 28614711
2020 In ischemic neuronal death following cardiac arrest/resuscitation, a GluN2B mutation (L1298A/R1300Q) that selectively abolishes CaMKII—but not DAPK1—binding to GluN2B is neuroprotective. CaMKII accumulates at synaptic GluN2B during ischemia; extra-synaptic GluN2B decreases but its relative association with DAPK1 increases. This demonstrates that ischemic neuronal death requires CaMKII binding to synaptic GluN2B, while DAPK1 binding is restricted to a distinct extra-synaptic GluN2B population. GluN2B knock-in mutation (L1298A/R1300Q), cardiac arrest/resuscitation mouse model, synaptic fractionation, co-immunoprecipitation, cell death quantification Cell reports High 31914378
2019 A crystal structure (1.1 Å) of the KLHL20 Kelch domain bound to a DAPK1 death domain peptide reveals an 'LPDLV' motif in the DAPK1 death domain that inserts as a loose helical turn deeply into the central pocket of the KLHL20 β-propeller, contacting all six blades and forming salt-bridge and hydrophobic interactions. This structural basis determines DAPK1 recruitment and ubiquitination by the KLHL20-CUL3-ROC1 E3 ligase. X-ray crystallography (1.1 Å resolution), peptide binding assays, mutagenesis of LPDLV motif Structure High 31279627
2007 DAPK-1 forms a multiprotein survival complex with cathepsin B. TNFR-1 activation induces complex formation between DAPK-1 and cathepsin B. The minimal DAPK-1 binding region for cathepsin B was mapped to amino acids 836–947. A DAPK-1(836–947) miniprotein acts as a dominant negative, promoting endogenous DAPK-1 degradation in a TNFR-1-dependent manner. Cathepsin B depletion by siRNA stimulates TNFR-1-dependent apoptosis. Co-immunoprecipitation, domain mapping with miniproteins, siRNA knockdown, dominant-negative transfection, apoptosis assay The Journal of biological chemistry Medium 17324927
2013 DAPK acts as a scaffold protein for the LIMK/cofilin complex during TNF-induced apoptosis. TNF treatment enhances LIMK phosphorylation at Thr508 and cofilin phosphorylation at Ser3, both dependent on DAPK activity and expression. DAPK, LIMK, and cofilin redistribute to the perinuclear compartment upon TNF stimulation. Phospho-cofilin(Ser3) accumulates in cells with apoptotic morphology. Peptide array screen (binding identification), DAPK inhibitor treatment, siRNA knockdown, overexpression, immunofluorescence, 3D structural modeling The international journal of biochemistry & cell biology Medium 23702034
2014 DAPK phosphorylates HSF1 at Ser230 in response to low-concentration TNF. DAPK and HSF1 physically interact both in vitro and in vivo. HSF1 binds the DAPK promoter and transient HSF1 overexpression increases DAPK mRNA and apoptosis levels, defining a DAPK-HSF1 positive-feedback loop in TNF-induced apoptosis. In vitro binding assay, co-immunoprecipitation in vivo, ChIP (HSF1 on DAPK promoter), DAPK inhibitor treatment, siRNA knockdown, overexpression, immunohistochemistry on colorectal carcinoma Journal of cell science Medium 25380824
2012 DAPK possesses a ROC (Ras of complex proteins) domain that binds and hydrolyzes GTP. GTP binding regulates DAPK catalytic activity by enhancing autophosphorylation at the inhibitory Ser308, thereby promoting the kinase 'off' state. This represents a novel in cis regulatory mechanism of DAPK kinase activity by its distal ROC domain. GTP binding assay, GTPase activity assay, autophosphorylation assay at Ser308, domain mutagenesis Biochemical Society transactions Medium 22988864
2017 Bik dissociates the Bak/Bcl-2 complex, enriching ER-associated Bak, and interacts with the kinase domain of DAPK1 to form a Bik-DAPK1-ERK1/2-Bak complex. ER-associated Bak interacts with kinase and calmodulin domains of DAPK1 to increase ER-mitochondria contact sites, facilitating mitochondrial Ca2+ uptake from the ER. Reduced Bak levels block Bik-induced mitochondrial Ca2+ uptake. Co-immunoprecipitation, domain interaction mapping (kinase/calmodulin domains), siRNA knockdown of Bak, Ca2+ imaging, ER-mitochondria contact site measurement, in vivo mouse airway model Nature communications Medium 28986568
2016 In C. elegans, DAPK-1 maintains epidermal integrity through regulation of the microtubule (MT) cytoskeleton. DAPK-1 physically interacts with PTRN-1 (Patronin/CAMSAP), a MT minus-end binding protein. Loss of ptrn-1 suppresses dapk-1 epidermal and innate immunity phenotypes; overexpression of the PTRN-1 CKK domain mimics dapk-1 mutant phenotypes. PTRN-1 localization is regulated by DAPK-1, and DAPK-1 itself undergoes MT-dependent transport. Genetic suppressor screen, co-immunoprecipitation, pharmacological MT destabilization/stabilization, overexpression of CKK domain, confocal localization, C. elegans genetic epistasis eLife High 27661253
2019 DAPK1 directly binds to and phosphorylates Pellino1 at Ser39, leading to Pellino1 poly-ubiquitination and proteasomal turnover. This DAPK1-mediated phosphorylation of Pellino1 couples MyD88-dependent inflammatory signaling to tubular cell damage during septic acute kidney injury under hypoxia. DAPK1 kinase activity is essential for this process; pharmacological or genetic ablation of DAPK1 protects against septic AKI. In vitro protein kinase assay, co-immunoprecipitation, GST-pulldown, ubiquitination assay, immunofluorescence, CRISPR-based gene ablation, DAPK1-/- mouse model (CLP), pharmacological DAPK1 inhibition Theranostics High 33052227
2019 TCR-induced calcineurin activation leads to DAPK1 activation, which then interacts with TSC2 via its death domain and phosphorylates TSC2, mediating mTORC1 activation in CD8+ T cells. Both the kinase domain and death domain of DAPK1 are required for maximal mTOR activation and CD8+ T-cell antiviral function. Co-immunoprecipitation, domain deletion analysis (kinase vs. death domain), in vitro phosphorylation of TSC2, LCMV infection model (in vivo), calcineurin pharmacological activation Cellular & molecular immunology Medium 31541182
2020 Caytaxin (a brain-specific BNIP-2 family member) interacts with DAPK1 at the presynaptic site and inhibits DAPK1 catalytic activity. Caytaxin levels increase as early as 2 hours after MCAO in the penumbra. Silencing Caytaxin enhances DAPK1 activity and worsens neuronal apoptosis and brain injury both in vitro and in vivo. Co-immunoprecipitation, in vitro kinase activity assay, shRNA knockdown, mouse MCAO model, in vitro neuronal apoptosis assay Experimental neurology Medium 32277960
2022 DAPK1 catalyzes matrix adhesion assembly on rigid surfaces and triggers anoikis on soft matrices through rigidity sensing. DAPK1 phosphorylates tropomyosin1.1 and the talin1 head domain, and is itself tyrosine-phosphorylated by Src. On soft surfaces, PTPN12 activity and talin1 head promote DAPK1 dissociation from adhesion complexes and activation of apoptosis. Inhibition of DAPK1 activity transforms cells for growth on soft matrices. DAPK1 kinase inhibition, phosphorylation assays (tropomyosin1.1, talin1), Src tyrosine phosphorylation of DAPK1, PTPN12 activity assay, rigidity-sensing matrix assays, anoikis assays Frontiers in cell and developmental biology Medium 35927990
2009 An alternatively spliced product of the DAPK1 locus (s-DAPK-1), which lacks the kinase domain but contains part of the ankyrin-repeat region, destabilizes full-length DAPK-1 protein in a proteasome-independent manner. The core ankyrin-repeat region of s-DAPK-1 is sufficient for this effect; the target minimal domain on full-length DAPK-1 is the kinase domain. s-DAPK-1 itself is rapidly degraded by a proteasome-dependent pathway. Transfection of s-DAPK-1 variants, domain mapping, proteasome inhibitor treatment, pulse-chase protein stability assays Molecular and cellular biochemistry Medium 19267229
2021 DAPK1 negatively regulates IKKβ; loss of DAPK1 allows IKKβ to activate CSN5, which upregulates PD-L1 expression, enabling immune evasion of gastric cancer cells. DAPK1 overexpression restores NK cell killing ability and reduces PD-L1-mediated immune evasion. Binding affinity among DAPK1, IKKβ, CSN5, and PD-L1 was characterized in vitro and in vivo. Co-immunoprecipitation/binding assays among DAPK1-IKKβ-CSN5-PD-L1, siRNA and overexpression in GC cell lines, NK cell co-culture killing assay, in vivo xenograft model Cellular immunology Medium 35114597
2022 ERK phosphorylates and activates DAPK1 in epilepsy (kainic acid model). DAPK1 activation increases seizure severity and neuronal death. Selective ERK antagonism, DAPK1 gene ablation, ERK-DAPK1 uncoupling peptides, or a DAPK1 phosphorylation-deficient mutant each exert anti-seizure and anti-apoptotic effects in vitro and in vivo. ERK inhibitors, DAPK1 KO mice, uncoupling peptides, DAPK1 phosphorylation-deficient knock-in mutant, EEG, KA-induced seizure model, neuronal cell death assays International journal of molecular sciences Medium 35742817
2016 ATF6 cleavage during ER stress upregulates DAPK1 transcription. DAPK1 then promotes MRLC (myosin regulatory light chain) phosphorylation, stimulating mAtg9a trafficking that is critical for autophagosome formation. Stable ATF6 and DAPK1 knockdown cell lines show decreased LC3 conversion in response to quinocetone. Western blotting, RT-PCR, GFP-LC3 transfection, immunofluorescence, stable shRNA knockdown cell lines, ER stress inhibitor treatments Cell biology and toxicology Medium 27085326
2018 DHA (dihydroartemisinin) induces DAPK1 expression in cholangiocarcinoma cells, which reduces the interaction of BECLIN1 with BCL-2 and promotes BECLIN1 interaction with PI3KC3, triggering autophagy-dependent cell death. Genetic silencing of DAPK1 prevents DHA-induced autophagy, establishing DAPK1-BECLIN1 as a functional signaling pathway. DAPK1 siRNA knockdown, co-immunoprecipitation (BECLIN1/BCL-2, BECLIN1/PI3KC3), pharmacological autophagy inhibition, cell death assays in multiple CCA cell lines Molecular carcinogenesis Medium 30136419
2019 DAPK1 interacts with ZEB1 and represses ZEB1 expression in prostate cancer CD133+ stem-like cells. DAPK1 suppresses the Hippo/YAP signaling pathway through this ZEB1 interaction. DAPK1 knockdown promotes stem cell-like characteristics, sphere formation, and migration/invasion, all reversed by ZEB1 knockdown. Co-immunoprecipitation (DAPK1-ZEB1), siRNA knockdown and overexpression, sphere formation assay, tumor xenograft model, flow cytometry for stem cell markers Stem cells and development Low 34289746

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. Cell 420 20141836
2007 Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell 282 17540169
2004 Bidirectional signals transduced by DAPK-ERK interaction promote the apoptotic effect of DAPK. The EMBO journal 195 15616583
2006 DAPk protein family and cancer. Autophagy 177 17139808
2016 Death Associated Protein Kinase 1 (DAPK1): A Regulator of Apoptosis and Autophagy. Frontiers in molecular neuroscience 175 27445685
2008 DAPK-1 binding to a linear peptide motif in MAP1B stimulates autophagy and membrane blebbing. The Journal of biological chemistry 115 18195017
2006 DAPK1 variants are associated with Alzheimer's disease and allele-specific expression. Human molecular genetics 114 16847012
2020 Dapk1 improves inflammation, oxidative stress and autophagy in LPS-induced acute lung injury via p38MAPK/NF-κB signaling pathway. Molecular immunology 109 32045770
2014 DAPK1-p53 interaction converges necrotic and apoptotic pathways of ischemic neuronal death. The Journal of neuroscience : the official journal of the Society for Neuroscience 108 24806680
2010 The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquitination to control interferon responses. The EMBO journal 104 20389280
2014 The DAPK family: a structure-function analysis. Apoptosis : an international journal on programmed cell death 100 24220854
2006 The tumor suppressor DAPK inhibits cell motility by blocking the integrin-mediated polarity pathway. The Journal of cell biology 96 16476779
2018 Death-associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes. Medicinal research reviews 93 29949198
2009 Death-associated protein kinase (DAPK) and signal transduction: regulation in cancer. The FEBS journal 93 19878310
2002 A death-associated protein kinase (DAPK)-interacting protein, DIP-1, is an E3 ubiquitin ligase that promotes tumor necrosis factor-induced apoptosis and regulates the cellular levels of DAPK. The Journal of biological chemistry 91 12351649
2017 Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects. Molecular psychiatry 88 28439098
2006 Methylation of tumour suppressor genes APAF-1 and DAPK-1 and in vitro effects of demethylating agents in bladder and kidney cancer. British journal of cancer 79 17133271
2009 Death-associated protein kinase (DAPK) and signal transduction: additional roles beyond cell death. The FEBS journal 77 19878313
2017 DAPK1 Mediates LTD by Making CaMKII/GluN2B Binding LTP Specific. Cell reports 74 28614711
2011 DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity. Cell death and differentiation 73 21311567
2008 Peptide combinatorial libraries identify TSC2 as a death-associated protein kinase (DAPK) death domain-binding protein and reveal a stimulatory role for DAPK in mTORC1 signaling. The Journal of biological chemistry 72 18974095
2016 DAPK1 Signaling Pathways in Stroke: from Mechanisms to Therapies. Molecular neurobiology 68 27447806
2018 LncRNA MIR22HG negatively regulates miR-141-3p to enhance DAPK1 expression and inhibits endometrial carcinoma cells proliferation. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 65 29775889
2007 The tumor suppressor DAPK is reciprocally regulated by tyrosine kinase Src and phosphatase LAR. Molecular cell 63 17803936
2012 DAPk1 inhibits NF-κB activation through TNF-α and INF-γ-induced apoptosis. Cellular signalling 60 22465880
2009 Death-associated protein kinase (DAPK) and signal transduction: blebbing in programmed cell death. The FEBS journal 60 19878312
2020 LncRNA MALAT1 targeting miR-124-3p regulates DAPK1 expression contributes to cell apoptosis in Parkinson's Disease. Journal of cellular biochemistry 55 32277510
2019 DAPK1 loss triggers tumor invasion in colorectal tumor cells. Cell death & disease 55 31772156
2018 Dihydroartemisinin induces apoptosis and autophagy-dependent cell death in cholangiocarcinoma through a DAPK1-BECLIN1 pathway. Molecular carcinogenesis 50 30136419
2006 Control of death-associated protein kinase (DAPK) activity by phosphorylation and proteasomal degradation. The Journal of biological chemistry 50 17056602
2014 The functions and regulations of DAPK in cancer metastasis. Apoptosis : an international journal on programmed cell death 48 24166138
2020 CaMKII versus DAPK1 Binding to GluN2B in Ischemic Neuronal Cell Death after Resuscitation from Cardiac Arrest. Cell reports 47 31914378
2015 CYP1B1 promotes tumorigenesis via altered expression of CDC20 and DAPK1 genes in renal cell carcinoma. BMC cancer 44 26626260
2014 Evaluating DAPK as a therapeutic target. Apoptosis : an international journal on programmed cell death 43 24305735
2019 miR-483-5p decreases the radiosensitivity of nasopharyngeal carcinoma cells by targeting DAPK1. Laboratory investigation; a journal of technical methods and pathology 41 30664712
2017 MicroRNA-141-3p targets DAPK1 and inhibits apoptosis in rat ovarian granulosa cells. Cell biochemistry and function 41 28543175
2014 Regulation of inflammation by DAPK. Apoptosis : an international journal on programmed cell death 41 24185831
2011 Sodium butyrate-induced DAPK-mediated apoptosis in human gastric cancer cells. Oncology reports 40 22160140
2013 Structural and functional diversity in the activity and regulation of DAPK-related protein kinases. The FEBS journal 39 23745726
2008 Aberrant methylation of the death-associated protein kinase 1 (DAPK1) CpG island in chronic myeloid leukemia. European journal of haematology 38 19018866
2016 Silencing DNA methyltransferase 1 (DNMT1) inhibits proliferation, metastasis and invasion in ESCC by suppressing methylation of RASSF1A and DAPK. Oncotarget 37 27286455
2014 Role of DAPK in neuronal cell death. Apoptosis : an international journal on programmed cell death 36 24114363
2011 Hypermethylation of p16 and DAPK promoter gene regions in patients with non-invasive urinary bladder cancer. Archives of medical science : AMS 36 22295037
2009 Methylated DAPK and APC promoter DNA detection in peripheral blood is significantly associated with apparent residual tumor and outcome. Journal of cancer research and clinical oncology 34 19259700
2007 Identification of a dominant negative functional domain on DAPK-1 that degrades DAPK-1 protein and stimulates TNFR-1-mediated apoptosis. The Journal of biological chemistry 34 17324927
2019 Structural Basis for Recruitment of DAPK1 to the KLHL20 E3 Ligase. Structure (London, England : 1993) 33 31279627
2018 DAPK1-ERK signal mediates oxygen glucose deprivation reperfusion induced apoptosis in mouse N2a cells. Journal of the neurological sciences 33 29571866
2018 DAPK1: a Novel Pathology and Treatment Target for Alzheimer's Disease. Molecular neurobiology 33 30062675
2017 Correlation of DAPK1 methylation and the risk of gastrointestinal cancer: A systematic review and meta-analysis. PloS one 32 28934284
2014 Transcription control of DAPK. Apoptosis : an international journal on programmed cell death 32 24217921
2009 Sodium arsenite-induced DAPK promoter hypermethylation and autophagy via ERK1/2 phosphorylation in human uroepithelial cells. Chemico-biological interactions 32 19577553
2015 DAPK1 Promoter Methylation and Cervical Cancer Risk: A Systematic Review and a Meta-Analysis. PloS one 31 26267895
2019 The lncRNA DAPK-IT1 regulates cholesterol metabolism and inflammatory response in macrophages and promotes atherogenesis. Biochemical and biophysical research communications 30 31300197
2014 Promoter hypermethylation patterns of P16, DAPK and MGMT in oral squamous cell carcinoma: a systematic review and meta-analysis. Indian journal of dental research : official publication of Indian Society for Dental Research 30 25728117
2010 Promoter hypermethylation of CDH13, DAPK1 and TWIST1 genes in precancerous and cancerous lesions of the uterine cervix. Pathology, research and practice 30 21129853
2013 Investigation of MGMT and DAPK1 methylation patterns in diffuse large B-cell lymphoma using allelic MSP-pyrosequencing. Scientific reports 29 24071855
2018 First-in-class DAPK1/CSF1R dual inhibitors: Discovery of 3,5-dimethoxy-N-(4-(4-methoxyphenoxy)-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-5-yl)benzamide as a potential anti-tauopathies agent. European journal of medicinal chemistry 28 30445265
2019 Gliotoxin Enhances Autophagic Cell Death via the DAPK1-TAp63 Signaling Pathway in Paclitaxel-Resistant Ovarian Cancer Cells. Marine drugs 27 31336860
2018 MicroRNA-98 attenuates cardiac ischemia-reperfusion injury through inhibiting DAPK1 expression. IUBMB life 27 30419147
2016 Quinocetone triggered ER stress-induced autophagy via ATF6/DAPK1-modulated mAtg9a trafficking. Cell biology and toxicology 27 27085326
2021 Overexpression of DAPK1-mediated inhibition of IKKβ/CSN5/PD-L1 axis enhances natural killer cell killing ability and inhibits tumor immune evasion in gastric cancer. Cellular immunology 26 35114597
2010 Promoter methylation of DAPK1, E-cadherin and thrombospondin-1 in de novo and therapy-related myeloid neoplasms. Blood cells, molecules & diseases 26 20655775
2021 Rapamycin Inhibits Glioma Cells Growth and Promotes Autophagy by miR-26a-5p/DAPK1 Axis. Cancer management and research 25 33790644
2017 Bik reduces hyperplastic cells by increasing Bak and activating DAPk1 to juxtapose ER and mitochondria. Nature communications 25 28986568
2015 DAPK1, MGMT and RARB promoter methylation as biomarkers for high-grade cervical lesions. International journal of clinical and experimental pathology 25 26823825
2014 DAPK and cytoskeleton-associated functions. Apoptosis : an international journal on programmed cell death 25 24166137
2014 Association between DAPK1 promoter methylation and cervical cancer: a meta-analysis. PloS one 25 25268905
2020 Redox DAPK1 destabilizes Pellino1 to govern inflammation-coupling tubular damage during septic AKI. Theranostics 24 33052227
2016 DAPK interacts with Patronin and the microtubule cytoskeleton in epidermal development and wound repair. eLife 24 27661253
2009 Death-associated protein kinase (DAPK) promoter methylation and response to neoadjuvant radiochemotherapy in esophageal cancer. Annals of surgical oncology 24 19224282
2009 The alternative splice variant of DAPK-1, s-DAPK-1, induces proteasome-independent DAPK-1 destabilization. Molecular and cellular biochemistry 23 19267229
2022 Circular RNA circTLK1 regulates dopaminergic neuron injury during Parkinson's disease by targeting miR-26a-5p/DAPK1. Neuroscience letters 22 35447224
2019 Role of DAPK1 in neuronal cell death, survival and diseases in the nervous system. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 22 30763607
2018 Prediction of GluN2B-CT1290-1310/DAPK1 Interaction by Protein⁻Peptide Docking and Molecular Dynamics Simulation. Molecules (Basel, Switzerland) 21 30463177
2018 Methylation status of SFRP1, SFRP2, RASSF1A, RARβ and DAPK1 genes in patients with oral squamous cell carcinoma. Archives of oral biology 21 30576962
2013 Identification of DAPK as a scaffold protein for the LIMK/cofilin complex in TNF-induced apoptosis. The international journal of biochemistry & cell biology 21 23702034
2020 Presynaptic Caytaxin prevents apoptosis via deactivating DAPK1 in the acute phase of cerebral ischemic stroke. Experimental neurology 20 32277960
2017 Association between promoter methylation of DAPK gene and HNSCC: A meta-analysis. PloS one 20 28249042
2014 DAPK-HSF1 interaction as a positive-feedback mechanism stimulating TNF-induced apoptosis in colorectal cancer cells. Journal of cell science 20 25380824
2009 Death-associated protein kinase (DAPK1) in cerebral cortex of late-onset Alzheimer's disease patients and aged controls. Neuropathology and applied neurobiology 20 19627511
2009 Death-associated protein kinase (DAPK) and signal transduction: fine-tuning of autophagy in Caenorhabditis elegans homeostasis. The FEBS journal 20 19878311
2022 The impact of DAPK1 and mTORC1 signaling association on autophagy in cancer. Molecular biology reports 19 35083613
2022 Bone mesenchymal stem cell-derived extracellular vesicles inhibit DAPK1-mediated inflammation by delivering miR-191 to macrophages. Biochemical and biophysical research communications 19 35151201
2020 H19/miR-130a-3p/DAPK1 axis regulates the pathophysiology of neonatal hypoxic-ischemia encephalopathy. Neuroscience research 19 32173462
2015 Clinical significance of DAPK promoter hypermethylation in lung cancer: a meta-analysis. Drug design, development and therapy 19 25848215
2022 Blocking ERK-DAPK1 Axis Attenuates Glutamate Excitotoxicity in Epilepsy. International journal of molecular sciences 17 35742817
2022 High DAPK1 Expression Promotes Tumor Metastasis of Gastric Cancer. Biology 17 36290392
2015 Death Associated Protein Kinase (DAPK) -mediated neurodegenerative mechanisms in nematode excitotoxicity. BMC neuroscience 17 25899010
2012 Biochemical and functional characterization of the ROC domain of DAPK establishes a new paradigm of GTP regulation in ROCO proteins. Biochemical Society transactions 17 22988864
2010 Gene methylation of SFRP2, P16, DAPK1, HIC1, and MGMT and KRAS mutations in sporadic colorectal cancer. Cancer genetics and cytogenetics 17 20682398
2022 Tumor Suppressor DAPK1 Catalyzes Adhesion Assembly on Rigid but Anoikis on Soft Matrices. Frontiers in cell and developmental biology 16 35927990
2019 DAPK1 (death associated protein kinase 1) mediates mTORC1 activation and antiviral activities in CD8+ T cells. Cellular & molecular immunology 16 31541182
2019 CD93 hematopoietic stem cells improve diabetic wound healing by VEGF activation and downregulation of DAPK-1. Journal of cellular physiology 16 31549396
2016 DAPK Promoter Methylation and Bladder Cancer Risk: A Systematic Review and Meta-Analysis. PloS one 16 27907054
2013 Suppression of VEGF expression through interruption of the HIF‑1α and Akt signaling cascade modulates the anti‑angiogenic activity of DAPK in ovarian carcinoma cells. Oncology reports 16 24337450
2023 Aerobic exercise mitigates hippocampal neuronal apoptosis by regulating DAPK1/CDKN2A/REDD1/FoXO1/FasL signaling pathway in D-galactose-induced aging mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15 37768886
2022 Neurodegenerative effect of DAPK1 after cerebral hypoxia-ischemia is associated with its post-transcriptional and signal transduction regulations: A systematic review and meta-analysis. Ageing research reviews 15 35202858
2003 Promoter methylation and down-regulation of DAPK is associated with gastric atrophy. International journal of molecular medicine 15 14612952
2021 Reduced DAPK1 Expression Promotes Stem Cell-Like Characteristics of Prostate Cancer Cells by Activating ZEB1 via Hippo/YAP Signaling Pathway. Stem cells and development 14 34289746
2014 Effect of DAPK1 gene on proliferation, migration, and invasion of carcinoma of pancreas BxPC-3 cell line. International journal of clinical and experimental pathology 14 25550789

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