Affinage

DAPK3

Death-associated protein kinase 3 · UniProt O43293

Length
454 aa
Mass
52.5 kDa
Annotated
2026-06-09
46 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DAPK3 (ZIPK) is a Ca²⁺-independent serine/threonine kinase that converges on the actomyosin contractile machinery: it directly phosphorylates myosin regulatory light chain—sequentially at Ser-19 then Thr-18 in smooth muscle myosin, and at Ser-15 in cardiac myocytes—to drive smooth muscle, cardiac, non-muscle, and endothelial contractility, and is required for endothelial barrier function in vivo [PMID:20038585, PMID:31180722, PMID:bio_10.1101_2025.08.15.670483]. Substrate targeting and force generation depend on Par-4/PAWR, which localizes ZIPK to actin filaments (PMID:18505470), and additional smooth muscle output flows through nonmuscle myosin II isoforms (NMIIA/NMIIB) controlling vascular smooth muscle migration and contraction (PMID:24633547); ATP-competitive inhibitors that block ZIPK reduce RLC and MYPT1 phosphorylation and contractile force, and dual Pim/DAPK3 inhibition lowers blood pressure in hypertensive mice (PMID:24070067, PMID:30033129). Beyond contractility, DAPK3 promotes autophagy as an activating kinase for Beclin 1 (Ser-90) and ULK1 (Ser-556) and supports autophagosome–lysosome fusion through the STX17–SNAP29–VAMP8 SNARE complex; its kinase activity toward Beclin 1 is gated by PP2A, which both dephosphorylates the Beclin 1 site and dephosphorylates DAPK3 itself to activate it (PMID:26994142, PMID:33037394, PMID:31811899, PMID:38038430). In innate immunity DAPK3 coordinates STING regulation, restraining K48-linked degradative ubiquitination at rest and enabling cGAMP-induced K63-linked ubiquitination and STING–TBK1 association in part by phosphorylating the E3 ligase LMO7 (PMID:33767426). Its localization is species-dependent—cytoplasmic in human cells and nuclear in rodents—governed by phosphorylation of T299 adjacent to an NLS, with T299 dephosphorylation permitting nuclear import and Rho signaling promoting cytoplasmic retention (PMID:17953487, PMID:20854903). Cancer-associated mutations (T112M, D161N, P216S) abolish kinase activity, act dominant-negatively, and cause cytokinesis failure and multinucleation through reduced MRLC phosphorylation at the contractile ring (PMID:21487036, PMID:33032825).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 2007 High

    Established that ZIPK subcellular distribution differs between species and is controlled by a phosphosite-bearing region, framing where the kinase acts and how its compartmentalization is encoded.

    Evidence Sequence alignment, T299 mutagenesis, ectopic expression imaging, and PAR-4 Co-IP comparing human, murine, and rat ZIPK

    PMID:17953487

    Open questions at the time
    • Functional consequence of human cytoplasmic vs rodent nuclear localization not resolved in physiology
    • Did not define the kinase regulating T299 in vivo
  2. 2008 Medium

    Showed how ZIPK reaches its contractile substrates by demonstrating Par-4/PAWR targets it to actin filaments, answering how a soluble kinase couples to the myofilament.

    Evidence Immunofluorescence co-localization, decoy peptide, antisense knockdown, and contractility/phosphorylation assays in vascular smooth muscle

    PMID:18505470

    Open questions at the time
    • Structural basis of Par-4–ZIPK–actin interaction not defined
    • Single lab; reciprocal validation limited
  3. 2009 High

    Identified cardiac RLC Ser-15 as a direct ZIPK substrate, extending the contractile role of the kinase beyond smooth muscle into cardiac myocytes.

    Evidence In vitro kinase assay on heart homogenates, MS substrate identification, siRNA knockdown in cardiac myocytes

    PMID:20038585

    Open questions at the time
    • Physiological impact on cardiac function not tested
    • Upstream activation of ZIPK in heart not addressed
  4. 2010 Medium

    Defined the molecular switch for ZIPK nucleocytoplasmic shuttling, showing T299 phosphorylation masks an adjacent NLS and Rho signaling biases cytoplasmic retention.

    Evidence Mutational analysis, constitutively active Rho, leptomycin B export block, fractionation/imaging

    PMID:20854903

    Open questions at the time
    • Identity of the T299 kinase/phosphatase not established
    • Nuclear vs cytoplasmic substrate repertoire not distinguished
  5. 2011 High

    Linked DAPK3 loss-of-function to cancer by showing recurrent mutations abolish kinase activity, act dominant-negatively, and impair cell cycle/survival control.

    Evidence Kinase assays, dominant-negative co-expression, viability assays, and WT reconstitution in an NSCLC mutant line

    PMID:21487036

    Open questions at the time
    • Substrate(s) responsible for the growth phenotype not defined here
    • Mechanism of dominant-negativity not structurally explained
  6. 2011 Medium

    Connected ZIPK to canonical Wnt/β-catenin signaling via NLK, indicating a transcriptional regulatory role distinct from contractility.

    Evidence Co-IP of NLK–ZIPK, siRNA knockdown, β-catenin/TCF reporter and growth assays in colon carcinoma cells

    PMID:21454679

    Open questions at the time
    • Whether ZIPK phosphorylates NLK or TCF4 not shown
    • Single Co-IP without reciprocal/in vitro confirmation
  7. 2013 High

    Provided a chemical-biology toolkit (HS38) defining ZIPK as an ATP-competitive target whose inhibition lowers RLC20/MYPT1 phosphorylation and contractile force.

    Evidence Biochemical inhibition (FLECS), cellular phosphorylation, ex vivo smooth muscle contractility, structural analogue control

    PMID:24070067

    Open questions at the time
    • Selectivity over related kinases incomplete at this stage
    • In vivo efficacy not yet tested
  8. 2014 Medium

    Resolved downstream effectors of ZIPK in vascular smooth muscle motility, identifying NMIIA/NMIIB as mediators of migration and gel contraction.

    Evidence shRNA knockdown with 3D migration and collagen gel contraction assays

    PMID:24633547

    Open questions at the time
    • Direct phosphorylation of NMII by ZIPK not demonstrated
    • Single lab
  9. 2014 Medium

    Placed DAPK3 upstream of mTORC1 as a suppressor of proliferation, establishing a growth-control axis and the essentiality of the gene in development.

    Evidence shRNA in 3D acinar morphogenesis, RAPTOR epistasis, rapamycin sensitivity, constitutive knockout mice

    PMID:25304685

    Open questions at the time
    • Molecular link between DAPK3 and mTORC1 not defined
    • Embryonic lethality cause not pinpointed
  10. 2015 Medium

    Defined DAPK3 as a p53-activating kinase under miR-17/20a control that guards genome stability, expanding its tumor-suppressive role.

    Evidence miRNA target validation, DAPK3 KD/OE, p53 reporter, genome instability assay

    PMID:26117336

    Open questions at the time
    • Direct DAPK3 substrate in the p53 axis not identified
    • Single lab
  11. 2016 High

    Identified Beclin 1 Ser-90 as a direct DAPK3 substrate gated by PP2A, providing a mechanistic entry point for DAPK3 into autophagy induction.

    Evidence In vitro kinase assay, Co-IP, S90A phospho-mutant rescue, okadaic acid, mouse starvation model

    PMID:26994142

    Open questions at the time
    • Upstream signal activating DAPK3 toward Beclin 1 not fully defined
    • Interplay with other autophagy regulators not mapped
  12. 2018 High

    Delivered a co-crystal structure and demonstrated that dual Pim/DAPK3 inhibition, not DAPK3 alone, controls contractility and lowers blood pressure, refining therapeutic targeting.

    Evidence Co-crystal of DAPK3–HS38, in vitro kinase assays, ex vivo contractility, hypertensive mouse model

    PMID:30033129

    Open questions at the time
    • Relative contribution of Pim vs DAPK3 in vivo not fully separated
    • Off-target effects of dual inhibitors not excluded
  13. 2019 High

    Demonstrated ZIPK's physiological role in endothelial contractility and barrier integrity, with genetic deletion causing embryonic lethality and protecting against stroke-induced BBB dysfunction.

    Evidence Inhibition, siRNA, endothelium-specific and inducible KO mice, MCAO stroke model

    PMID:31180722

    Open questions at the time
    • Endothelial substrate beyond MLC not specified
    • Mechanism of embryonic lethality not dissected
  14. 2019 Medium

    Extended DAPK3's autophagy role to flux by showing it supports STX17–SNAP29–VAMP8 SNARE assembly for autophagosome–lysosome fusion.

    Evidence siRNA knockdown, autophagy flux assay, SNARE complex Co-IP in trophoblast cells

    PMID:31811899

    Open questions at the time
    • Whether SNAP29 is a direct phospho-substrate not shown
    • Single lab/cell type
  15. 2020 High

    Identified ULK1 Ser-556 as a direct DAPK3 substrate, positioning the kinase at the initiation step of autophagy upstream of VPS34.

    Evidence MS, in vitro kinase assay, Co-IP, phospho-mutant functional analysis

    PMID:33037394

    Open questions at the time
    • Coordination with Beclin 1 Ser-90 phosphorylation not integrated
    • Upstream control of DAPK3 in starvation not fully defined
  16. 2020 Medium

    Established a nuclear, transcription-associated role: DAPK3 is recruited to Pol II upon BCR activation and phosphorylates histone H3 Thr-6/Thr-11 at immediate early genes, affecting mRNA processing.

    Evidence ChIP recruitment, DAPK inhibition, ibrutinib comparison, histone phospho and mRNA assays in CLL cells

    PMID:32306542

    Open questions at the time
    • Mechanism of Pol II recruitment unknown
    • Direct histone phosphorylation in vitro not shown here
  17. 2020 Medium

    Connected cancer-associated DAPK3 mutations mechanistically to cytokinesis failure via reduced contractile-ring MRLC phosphorylation, explaining a genome-destabilizing phenotype.

    Evidence EGFP-DAPK3 mutant expression, cytokinesis quantification, phospho-MRLC immunofluorescence at the contractile ring

    PMID:33032825

    Open questions at the time
    • Spatiotemporal regulation of DAPK3 at the ring not defined
    • Single lab
  18. 2021 High

    Defined DAPK3 as a coordinator of STING ubiquitination state, restraining K48 degradation at rest and enabling K63 ubiquitination and STING–TBK1 coupling after cGAMP via LMO7 phosphorylation.

    Evidence Loss-of-function screen, phospho-proteomics, Co-IP, ubiquitination and kinase assays with in vivo validation

    PMID:33767426

    Open questions at the time
    • Direct STING phosphosite vs LMO7-mediated effect not fully separated
    • How DAPK3 senses stimulation state not defined
  19. 2021 Medium

    Placed ZIPK upstream of NF-κB in endothelial inflammation, driving TNF-α-induced adhesion molecule expression and monocyte adhesion.

    Evidence Tc-DAPK6 inhibition, siRNA, NF-κB activation, adhesion molecule and monocyte adhesion assays

    PMID:33710297

    Open questions at the time
    • Direct substrate in the NF-κB pathway not identified
    • Single lab
  20. 2022 Medium

    Showed ZIPK suppresses HIV-1 by inhibiting LTR-driven expression and phosphorylating STAT3 Ser-727, with viral Nef counteracting via ZIPK proteasomal degradation, revealing a host-restriction role and a degradation regulatory input.

    Evidence LTR reporter, Nef–ZIPK Co-IP, proteasome inhibitor rescue, phospho-STAT3 Ser-727 assay

    PMID:35961135

    Open questions at the time
    • Direct in vitro STAT3 phosphorylation not shown
    • E3 ligase mediating Nef-induced degradation unknown
  21. 2022 Medium

    Implicated DAPK3 in renal cancer protein homeostasis by modulating UBE3A ligase activity and PBRM1 stability downstream of RBPJ.

    Evidence PBRM1 interactome MS, Co-IP, ubiquitination assay, epistasis in RCC cells

    PMID:35368029

    Open questions at the time
    • Whether DAPK3 phosphorylates UBE3A directly not established
    • Single lab
  22. 2022 Low

    Reported a nuclear ZIPK–STAT5A interaction required for high-glucose-induced p53 and ROS, extending ZIPK into diabetic vascular signaling.

    Evidence Co-IP, siRNA, overexpression, TC-DAPK6 in a diabetic rat model

    PMID:39030705

    Open questions at the time
    • No in vitro kinase assay for direct STAT5A phosphorylation
    • Single Co-IP without reciprocal validation
  23. 2023 Medium

    Integrated PP2A regulation by showing a viral protein (CSFV NS5A) redirects PP2A to dephosphorylate and activate DAPK3, which then phosphorylates Beclin 1 to induce autophagy.

    Evidence Co-IP interaction mapping, kinase activity assay, autophagy flux in viral infection

    PMID:38038430

    Open questions at the time
    • DAPK3 dephosphosite targeted by PP2A not mapped
    • Generality beyond viral context untested
  24. 2024 Low

    Linked ZIPK to FAK signaling in VSMC migration through a ZIPK–CDC14A partnership controlling FAK-pY397 and nuclear translocation.

    Evidence HS38 inhibition, siRNA, proximity ligation assay, immunofluorescence, phospho-westerns (preprint)

    PMID:38496458

    Open questions at the time
    • No direct kinase assay for ZIPK→CDC14A phosphorylation
    • Preprint, single lab
  25. 2024 Low

    Implicated DAPK3 in endothelial senescence via PGC1α inactivation and impaired mitochondrial gene expression.

    Evidence siRNA, DAPK3-P216S dominant-negative, senescence assays, phospho-PGC1α western (Series A)

    PMID:38563090

    Open questions at the time
    • No in vitro kinase assay for DAPK3→PGC1α
    • AKT involvement correlative
  26. 2026 Medium

    Identified Insig1 as a direct DAPK3 interactor that stabilizes the kinase, with both implicated in acute kidney injury, revealing a stability-based regulatory input with therapeutic relevance.

    Evidence Insig1 interactome proteomics, conditional KO mice, siRNA, cisplatin injury, HS148 inhibition in vivo

    PMID:42144057

    Open questions at the time
    • Mechanism of Insig1-mediated stabilization not defined
    • DAPK3 substrate driving AKI not identified
  27. 2026 Medium

    Connected DAPK3 to microglial pyroptosis after stroke through a UNC5B-promoted DAPK3–MVK complex and MVK phosphorylation.

    Evidence DAPK3–MVK Co-IP, UNC5B/MVK knockdown, DAPK3 inhibition, pyroptosis assays, photothrombosis model

    PMID:41498970

    Open questions at the time
    • MVK phosphosite not mapped
    • New interaction, single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DAPK3's distinct activities—contractility, autophagy, innate immunity, and transcription—are partitioned by localization, stability inputs (PP2A, Insig1, Nef), and substrate selection within a single cell remains unresolved.
  • No unified model linking T299-controlled localization to substrate choice
  • Upstream activators in each pathway incompletely defined
  • Direct kinase relationships for several reported substrates unconfirmed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 6 GO:0140096 catalytic activity, acting on a protein 6 GO:0140657 ATP-dependent activity 2 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-397014 Muscle contraction 4 R-HSA-9612973 Autophagy 4 R-HSA-1640170 Cell Cycle 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
BECN1INSIG1LMO7NLKPAWRSTAT3STING1ULK1

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 DAPK3 coordinates post-translational modification of STING: in unstimulated cells DAPK3 inhibits STING K48-linked poly-ubiquitination and proteasome-mediated degradation; after cGAMP stimulation DAPK3 is required for STING K63-linked poly-ubiquitination and STING–TBK1 interaction. DAPK3 also phosphorylates the E3 ligase LMO7, which is critical for LMO7–STING interaction and STING K63-linked poly-ubiquitination. Loss-of-function screen, phospho-proteomics (mass spectrometry), co-immunoprecipitation, ubiquitination assays, kinase activity assays Nature immunology High 33767426
2016 DAPK3 directly phosphorylates Beclin 1 at Ser-90 to promote autophagy; PP2A (B55α subunit) associates with Beclin 1 and dephosphorylates this site, with starvation causing PP2A dissociation and allowing DAPK3-mediated phosphorylation. In vitro kinase assay, co-immunoprecipitation, phospho-mutant (S90A) functional assay, okadaic acid treatment, mouse starvation model The Journal of biological chemistry High 26994142
2020 DAPK3 directly phosphorylates ULK1 at Ser-556, increasing ULK1 activity, facilitating ULK1 complex formation, VPS34 complex activation, and autophagy induction upon starvation. Mass spectrometry, in vitro kinase assay, immunoprecipitation, phospho-mutant functional analysis Cell death and differentiation High 33037394
2011 Cancer-associated DAPK3 point mutations (T112M, D161N, P216S) decrease or abolish kinase activity, dominantly inhibit wild-type DAPK3 function, and impair regulation of cell cycle and cell survival; reconstitution of DAPK3-P216S lung cancer cells with wild-type DAPK3 decreased cellular aggregation and increased chemotherapy sensitivity. Kinase activity assays, co-expression dominant-negative analysis, cell viability/proliferation assays, reconstitution in NSCLC cell line Cancer research High 21487036
2009 ZIPK/DAPK3 phosphorylates cardiac myosin regulatory light chain (RLC) at Ser-15 in vitro and in ventricular cardiac myocytes; siRNA knockdown of ZIPK significantly decreased RLC Ser-15 phosphorylation in cardiac myocytes. In vitro kinase assay with purified ZIPK on heart homogenates, mass spectrometry substrate identification, siRNA knockdown with biochemical readout The Journal of biological chemistry High 20038585
2019 ZIPK/DAPK3 phosphorylates myosin light chain (MLC) and is required for endothelial cell contraction and paracellular permeability; endothelium-specific deletion of Zipk caused embryonic lethality in mice, and induced adult deletion reduced ischemia-reperfusion-induced blood-brain barrier dysfunction and neuronal injury. Pharmacological inhibition, siRNA knockdown, conditional knockout mice (endothelium-specific and tamoxifen-inducible), in vivo stroke model (MCAO) FASEB journal High 31180722
2013 DAPK3/ZIPK inhibits DAPK1 and ZIPK in an ATP-competitive manner; selective inhibitor HS38 decreased RLC20 phosphorylation in cells and reduced contractile force in smooth muscle via decreased RLC20 and MYPT1 phosphorylation. Biochemical kinase inhibition assay (FLECS), cellular RLC20 phosphorylation assay, ex vivo smooth muscle contractility assay, close structural analogue control (HS43) ACS chemical biology High 24070067
2018 A co-crystal structure of DAPK3 with lead inhibitor HS38 was determined; Pim kinases directly phosphorylate smooth muscle targets, and dual Pim/DAPK3 inhibition but not selective DAPK3 inhibition alone significantly reduces contractility; HS56 (dual Pim/DAPK3 inhibitor) decreased blood pressure in spontaneously hypertensive mice. Co-crystal structure, in vitro kinase assays, ex vivo smooth muscle contractility assays, in vivo hypertension model Cell chemical biology High 30033129
2008 Par-4 (PAWR) co-localizes with ZIPK on actin filaments in vascular smooth muscle; Par-4 decoy peptide inhibits ZIPK targeting to actin filaments upon PGF-2α stimulation, and Par-4 knockdown reduces contractility and myosin light chain/MYPT phosphorylation, indicating Par-4 facilitates ZIPK-mediated contraction by targeting it to its substrates. Immunofluorescence co-localization, cell-permeant decoy peptide, antisense morpholino knockdown, contractility assay, phosphorylation biochemistry Journal of cellular and molecular medicine Medium 18505470
2007 Human ZIPK localizes to the cytoplasm and induces membrane blebbing, while murine ZIPK localizes to the nucleus (PML bodies); this species difference is linked to absence of a conserved phosphorylation site (T299) in murine ZIPK. Human ZIPK fails to bind PAR-4, while rat ZIPK binds PAR-4 efficiently, and co-expression of PAR-4 with rat ZIPK causes nuclear-to-cytoplasm translocation and blebbing. Sequence alignment, site-directed mutagenesis, ectopic expression with fluorescence microscopy, co-immunoprecipitation (PAR-4 interaction), membrane blebbing assay PLoS genetics High 17953487
2010 Phosphorylation of T299 in human ZIPK controls its nuclear import by masking an adjacent nuclear localization sequence; constitutively active Rho promotes cytoplasmic retention of a human ZIPK mutant that would otherwise be nuclear; endogenous hZIPK shuttles between cytoplasm and nucleus in a leptomycin B-sensitive manner dependent on T299 dephosphorylation. Mutational analysis, constitutively active Rho expression, leptomycin B nuclear export inhibition, subcellular fractionation/imaging Cellular signalling Medium 20854903
2011 ZIPK interacts with Nemo-like kinase (NLK) and regulates NLK-mediated repression of canonical Wnt/β-catenin signaling; ZIPK affects NLK–TCF4 complex formation; siRNA knockdown of ZIPK reduces β-catenin/TCF-mediated gene expression and cell growth in colon carcinoma cells. Co-immunoprecipitation (NLK-ZIPK interaction), siRNA knockdown, reporter gene assay (β-catenin/TCF), cell growth assay The Journal of biological chemistry Medium 21454679
2014 ZIPK depletion by shRNA impairs VSMC migration and substantially decreases VSMC-mediated collagen gel contraction; NMIIA and NMIIB (nonmuscle myosin II isoforms) are downstream effectors of ZIPK in controlling VSMC motility and contractility. shRNA knockdown, 3D collagen matrix migration assay, collagen gel contraction assay American journal of physiology. Heart and circulatory physiology Medium 24633547
2014 DAPK3 loss in 3D acinar morphogenesis model enlarges acinar size via accelerated proliferation; epistasis analysis shows simultaneous knockdown of RAPTOR (mTORC1 component) reverses enlarged acinar size, placing DAPK3 upstream of mTORC1 as a suppressor. Constitutive DAPK3 knockout mice are embryonic lethal. Lentiviral shRNA knockdown, 3D morphogenesis model, rapamycin sensitivity assay, RAPTOR knockdown epistasis, constitutive knockout mouse generation Molecular cancer research : MCR Medium 25304685
2019 DAPK3 silencing blocks autophagosome-lysosome fusion by reducing assembly of the STX17-SNAP29-VAMP8 SNARE complex via mediation of SNAP29, impeding autophagy in high-glucose-treated trophoblast cells. siRNA knockdown, autophagy flux assay, SNARE complex co-immunoprecipitation Molecular and cellular endocrinology Medium 31811899
2020 DAPK3 phosphorylates cancer-associated mutations (T112M, D161N, P216S) result in reduced MRLC phosphorylation at the contractile ring during cytokinesis, leading to increased multinucleated cells and cytokinesis failure. EGFP-DAPK3 mutant expression, cytokinesis rate quantification, phospho-MRLC immunofluorescence at contractile ring Biochemical and biophysical research communications Medium 33032825
2020 DAPK3 is recruited to RNA polymerase II in a BCR-activation-dependent manner and mediates histone H3 Thr-6 and Thr-11 phosphorylation at immediate early gene loci (EGR1, DUSP2); DAPK3 inhibition impacts mRNA processing rather than transcription initiation per se. ChIP (DAPK3 recruitment to Pol II), DAPK inhibitor treatment, ibrutinib comparison, mRNA and histone phosphorylation assays in CLL cells Molecular oncology Medium 32306542
2022 DAPK3 modulates UBE3A E3 ligase activity by interfering with PKA phosphorylation of UBE3A, thereby regulating PBRM1 protein stability in renal cancer; RBPJ acts upstream of DAPK3 in this axis (RBPJ/DAPK3/UBE3A/PBRM1/p21). Mass spectrometry (PBRM1 interactome), co-immunoprecipitation, ubiquitination assay, functional epistasis in RCC cells Cell death & disease Medium 35368029
2015 DAPK3 is targeted by miR-17/20a; DAPK3 acts as a p53-activating kinase; loss of DAPK3 via miR-17/20a targeting leads to p53-dependent transcriptional de-repression of the oncomiRs, and DAPK3 is required to prevent genome instability upon miR-17/20a depletion. miRNA target validation, DAPK3 knockdown/overexpression, p53 reporter assay, genome instability assay The Journal of biological chemistry Medium 26117336
2023 CSFV NS5A protein activates autophagy via the PP2A-DAPK3-Beclin 1 axis: NS5A interacts with PPP2R1A and DAPK3, causing PP2A to dissociate from Beclin 1 and associate with DAPK3; PP2A dephosphorylates DAPK3 to activate its kinase activity, and activated DAPK3 phosphorylates Beclin 1. Co-immunoprecipitation, kinase activity assay, autophagy flux assay in viral infection context Journal of virology Medium 38038430
2022 ZIPK directly interacts with STAT5A in the nucleus under high-glucose conditions; ZIPK is essential for high-glucose-induced p53 expression and ROS accumulation, and ZIPK activity is required upstream of STAT5A-mediated NOS2/p53 induction. Co-immunoprecipitation (ZIPK-STAT5A nuclear interaction), siRNA knockdown, overexpression, pharmacological inhibitor (TC-DAPK6) in diabetic rat model Acta biochimica et biophysica Sinica Low 39030705
2022 ZIPK inhibits HIV-1 replication by suppressing LTR-driven gene expression; HIV-1 Nef interacts with ZIPK and induces its proteasomal degradation, and ZIPK phosphorylates STAT3 at Ser-727 to inhibit its activity, which Nef counteracts by degrading ZIPK. ZIPK overexpression/knockdown with LTR reporter assay, Co-immunoprecipitation (Nef-ZIPK), proteasome inhibitor rescue, STAT3 Ser-727 phosphorylation assay Biochemical and biophysical research communications Medium 35961135
2021 ZIPK is required for TNF-α-induced ICAM-1 and VCAM-1 expression and monocyte adhesion in endothelial cells; TNF-α upregulates ZIPK transcription, and ZIPK functions upstream of NF-κB activation (TNF-α/ZIPK/NF-κB axis). ZIPK-specific inhibitor (Tc-DAPK6), siRNA knockdown, NF-κB activation assay, adhesion molecule expression assay, monocyte adhesion assay Acta biochimica et biophysica Sinica Medium 33710297
2025 ZIPK phosphorylates smooth muscle myosin regulatory light chain (MRLC) sequentially: first at Ser-19, then at Thr-18; phosphorylation of SMM is slower than isolated MRLC because the C-terminal domain of ZIPK interacts with the myosin heavy chain, causing competitive binding that suppresses MRLC phosphorylation in the intact SMM context. Quantitative mass spectrometry on phosphomimic/unphosphorylatable MRLC mutants, co-sedimentation assay (ZIPK-SMM heavy chain interaction), kinetic modeling bioRxivpreprint Medium bio_10.1101_2025.08.15.670483
2026 UNC5B promotes post-stroke microglial pyroptosis via DAPK3; DAPK3 interacts with and phosphorylates mevalonate kinase (MVK), and disruption of the DAPK3-MVK complex by UNC5B knockdown or DAPK3 inhibition suppresses pyroptosis. Co-immunoprecipitation (DAPK3-MVK), UNC5B/MVK knockdown, DAPK3 pharmacological inhibition, pyroptosis assays, photothrombosis stroke model Neurochemical research Medium 41498970
2024 ZIPK inhibition suppresses focal adhesion kinase (FAK-pY397) phosphorylation and promotes FAK nuclear translocation in vascular smooth muscle cells; ZIPK regulates CDC14A levels, and CDC14A co-localizes with both ZIPK and FAK by proximity ligation assay; CDC14A silencing increases FAK phosphorylation, suggesting ZIPK acts through a ZIPK-CDC14A partnership to control FAK during VSMC migration. Pharmacological inhibition (HS38), siRNA knockdown, proximity ligation assay (PLA), immunofluorescence, phospho-protein western blotting bioRxivpreprint Low 38496458
2024 DAPK3 promotes cellular senescence in brain endothelial cells by phosphorylating and inactivating PGC1α via the AKT pathway, resulting in decreased expression of mitochondrial metabolism genes (ATP5G1, BDNF, COX5A). siRNA knockdown, dominant-negative mutant (DAPK3-P216S), senescence assays (SA-β-gal, tube formation, proliferation), phospho-PGC1α western blot The journals of gerontology. Series A Low 38563090
2026 Insig1 directly interacts with DAPK3 and stabilizes DAPK3 protein levels; conditional tubular Insig1 knockout ameliorates AKI, and pharmacological DAPK3 inhibition (HS148) recapitulates this renoprotective effect. Proteomics (Insig1 interactome identification of Dapk3), conditional knockout mice, siRNA knockdown, in vitro cisplatin injury model, pharmacological inhibition in vivo Journal of advanced research Medium 42144057

Source papers

Stage 0 corpus · 46 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-β pathway. Nature immunology 92 33767426
2016 Regulation of Beclin 1 Protein Phosphorylation and Autophagy by Protein Phosphatase 2A (PP2A) and Death-associated Protein Kinase 3 (DAPK3). The Journal of biological chemistry 90 26994142
2020 DAPK3 inhibits gastric cancer progression via activation of ULK1-dependent autophagy. Cell death and differentiation 71 33037394
2011 Cancer-associated loss-of-function mutations implicate DAPK3 as a tumor-suppressing kinase. Cancer research 67 21487036
2021 VIRMA contributes to non-small cell lung cancer progression via N6-methyladenosine-dependent DAPK3 post-transcriptional modification. Cancer letters 51 34520821
2013 Fluorescence linked enzyme chemoproteomic strategy for discovery of a potent and selective DAPK1 and ZIPK inhibitor. ACS chemical biology 42 24070067
2017 Anacardic acid induces cell apoptosis of prostatic cancer through autophagy by ER stress/DAPK3/Akt signaling pathway. Oncology reports 38 28731173
2016 Activation of AKT negatively regulates the pro-apoptotic function of death-associated protein kinase 3 (DAPK3) in prostate cancer. Cancer letters 35 27126362
2014 Zipper interacting protein kinase (ZIPK): function and signaling. Apoptosis : an international journal on programmed cell death 32 24193917
2015 Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. Oncotarget 30 25797270
2009 Cardiac myosin is a substrate for zipper-interacting protein kinase (ZIPK). The Journal of biological chemistry 29 20038585
2019 ZIPK mediates endothelial cell contraction through myosin light chain phosphorylation and is required for ischemic-reperfusion injury. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27 31180722
2011 Zipper-interacting protein kinase (ZIPK) modulates canonical Wnt/beta-catenin signaling through interaction with Nemo-like kinase and T-cell factor 4 (NLK/TCF4). The Journal of biological chemistry 26 21454679
2016 Insulin and Glucose Alter Death-Associated Protein Kinase 3 (DAPK3) DNA Methylation in Human Skeletal Muscle. Diabetes 25 28011458
2022 Sirt7 associates with ELK1 to participate in hyperglycemia memory and diabetic nephropathy via modulation of DAPK3 expression and endothelial inflammation. Translational research : the journal of laboratory and clinical medicine 24 35470010
2018 Targeting Pim Kinases and DAPK3 to Control Hypertension. Cell chemical biology 23 30033129
2015 Oncogenic miR-17/20a Forms a Positive Feed-forward Loop with the p53 Kinase DAPK3 to Promote Tumorigenesis. The Journal of biological chemistry 22 26117336
2019 Silencing DAPK3 blocks the autophagosome-lysosome fusion by mediating SNAP29 in trophoblast cells under high glucose treatment. Molecular and cellular endocrinology 20 31811899
2015 Estrogen modulation of the ethanol-evoked myocardial oxidative stress and dysfunction via DAPK3/Akt/ERK activation in male rats. Toxicology and applied pharmacology 19 26111663
2021 Elevated ZIPK is required for TNF-α-induced cell adhesion molecule expression and leucocyte adhesion in endothelial cells. Acta biochimica et biophysica Sinica 18 33710297
2011 New modularity of DAP-kinases: alternative splicing of the DRP-1 gene produces a ZIPk-like isoform. PloS one 18 21408167
2008 The pro-apoptotic protein Par-4 facilitates vascular contractility by cytoskeletal targeting of ZIPK. Journal of cellular and molecular medicine 18 18505470
2007 ZIPK: a unique case of murine-specific divergence of a conserved vertebrate gene. PLoS genetics 17 17953487
2023 YTHDF2 promotes gallbladder cancer progression and gemcitabine resistance via m6A-dependent DAPK3 degradation. Cancer science 16 37700438
2014 ZIPK is critical for the motility and contractility of VSMCs through the regulation of nonmuscle myosin II isoforms. American journal of physiology. Heart and circulatory physiology 15 24633547
2022 The RBPJ/DAPK3/UBE3A signaling axis induces PBRM1 degradation to modulate the sensitivity of renal cell carcinoma to CDK4/6 inhibitors. Cell death & disease 14 35368029
2010 Phosphorylation-dependent control of ZIPK nuclear import is species specific. Cellular signalling 14 20854903
2021 ZIPK activates the IL-6/STAT3 signaling pathway and promotes cisplatin resistance in gastric cancer cells. FEBS open bio 10 34375503
2014 DAPK3 suppresses acini morphogenesis and is required for mouse development. Molecular cancer research : MCR 10 25304685
2023 Classical swine fever virus NS5A protein activates autophagy via the PP2A-DAPK3-Beclin 1 axis. Journal of virology 9 38038430
2020 Impairment of cytokinesis by cancer-associated DAPK3 mutations. Biochemical and biophysical research communications 8 33032825
2025 DAPK3 is Essential for DBP-Induced Autophagy of Mouse Leydig Cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 7 40047320
2024 Inhibition of DAPK3 Suppresses Radiation-Induced Cellular Senescence by Activation of a PGC1α-Dependent Metabolism Pathway in Brain Endothelial Cells. The journals of gerontology. Series A, Biological sciences and medical sciences 5 38563090
2020 The phosphorylation of hCDC14A modulated by ZIPK regulates autophagy of murine pancreatic islet β-TC3 cells upon glucose stimulation. European review for medical and pharmacological sciences 5 33090408
2023 The effect of aspartame on accelerating caspase-dependent apoptosis of pancreatic islet via ZIPK/STAT3/caspase 3 signaling pathway. Journal of physiology and biochemistry 4 37906422
2022 Molecular Network Analyses Implicate Death-Associated Protein Kinase 3 (DAPK3) as a Key Factor in Colitis-Associated Dysplasia Progression. Inflammatory bowel diseases 4 35604388
2020 DAPK3 participates in the mRNA processing of immediate early genes in chronic lymphocytic leukaemia. Molecular oncology 4 32306542
2024 ZIPK collaborates with STAT5A in p53-mediated ROS accumulation in hyperglycemia-induced vascular injury. Acta biochimica et biophysica Sinica 3 39030705
2022 Zipper interacting protein kinase (ZIPK) is a negative regulator of HIV-1 replication that is restricted by viral Nef protein through proteasomal degradation. Biochemical and biophysical research communications 3 35961135
2015 Biophysical changes of ATP binding pocket may explain loss of kinase activity in mutant DAPK3 in cancer: A molecular dynamic simulation analysis. Gene 3 26748242
2025 Multifaceted role of zipper-interacting protein kinase beyond cell death: Implication of ZIPK dysregulation in neuronal and vascular injuries. Pharmacological research 1 40409521
2025 DAPK3-Ablation Regulates the AMPK/mTOR-GPX4 Signaling Pathway to Affect Biological Functions of Staphylococcus aureus-Treated Bone Marrow Mesenchymal Stem Cells and Potentially Ameliorate Osteomyelitis. Molecular biotechnology 1 40601185
2026 UNC5B Promotes Post-Stroke Microglial Pyroptosis via DAPK3/MVK Pathway. Neurochemical research 0 41498970
2026 Insig1 deficiency protects against acute kidney injury via targeting Dapk3. Journal of advanced research 0 42144057
2025 An Inhibitor of Death-Associated Protein Kinase 3 (DAPK3) Disrupts Hippo Signaling and Intestinal Epithelial Regeneration in Murine DSS-Induced Colitis. Digestive diseases and sciences 0 41201700
2024 Cooperative involvement of zipper-interacting protein kinase (ZIPK) and the dual-specificity cell-division cycle 14A phosphatase (CDC14A) in vascular smooth muscle cell migration. bioRxiv : the preprint server for biology 0 38496458

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