Affinage

DCLK2

Serine/threonine-protein kinase DCLK2 · UniProt Q8N568

Length
766 aa
Mass
83.6 kDa
Annotated
2026-06-09
25 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DCLK2 is a dual-function neuronal protein combining microtubule-regulatory and serine/threonine kinase activities, with roles spanning cytoskeletal dynamics, neuronal development, transcriptional control, and oncogenic signaling (PMID:15611072, PMID:19342486). Its N-terminal doublecortin-like domain binds and stabilizes microtubules against depolymerization, while a separable kinase domain functions independently; autophosphorylation lowers microtubule affinity, providing a phosphorylation-dependent switch for microtubule dynamics (PMID:15611072). Genetically, Dclk2 acts redundantly with Dcx to control hippocampal lamination, pyramidal dendritic arborization, and inhibitory circuit maturation, and double-null mice develop spontaneous hippocampal seizures with loss of somatostatin-positive interneurons (PMID:19342486). As a kinase, DCLK2 phosphorylates substrates to control gene expression: it phosphorylates the transcription factor Ehf, driving its nuclear exit, derepressing Caspase1/Caspase3, and promoting neuronal pyroptosis in cerebral ischemia (PMID:38513137), and it relocates to the nucleus under hyperosmotic stress to phosphorylate JDP2 in a histone-dependent manner (PMID:24582561). In cancer, DCLK2 directly binds and phosphorylates TBK1 on Ser172 to activate oncogenic signaling in clear cell renal cell carcinoma, an axis antagonized by BBOX1 (PMID:38211588, PMID:39934163), and it drives epithelial-mesenchymal transition and metastasis in breast cancer (PMID:36477947).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2004 High

    Established the bipartite architecture of DCLK2, showing that microtubule binding and kinase activity reside in independent domains and that autophosphorylation provides a reversible switch governing microtubule affinity.

    Evidence Biochemical domain analysis, MT binding and cold-depolymerization assays, autophosphorylation assay, and neuronal immunolocalization

    PMID:15611072

    Open questions at the time
    • Physiological trigger for autophosphorylation in vivo not identified
    • No structural model of the DC-kinase interplay
    • Endogenous kinase substrates not defined here
  2. 2006 Medium

    Distinguished DCLK2 from related CaM kinases by showing it does not activate CREB but instead represses CRE-dependent transcription, implicating it in transcriptional control beyond cytoskeletal regulation.

    Evidence CRE-reporter and CREB phosphorylation assays with overexpression, compared against CaMKI/IV/II

    PMID:16684769

    Open questions at the time
    • Direct substrate mediating TORC2 phosphorylation not established
    • Overexpression-based; endogenous relevance unconfirmed
    • Single lab
  3. 2009 High

    Defined the developmental role of Dclk2, showing genetic redundancy with Dcx in hippocampal lamination and inhibitory circuit maturation and a causal link to epilepsy.

    Evidence Dcx;Dclk2 double-knockout mice with EEG, histology, electrophysiology, and in situ hybridization

    PMID:19342486

    Open questions at the time
    • Molecular substrates underlying lamination defects unknown
    • Single-knockout Dclk2 phenotype minimal, obscuring its independent contribution
    • Mechanism linking cytoskeletal/kinase activity to interneuron loss unresolved
  4. 2014 Medium

    Showed stress-regulated nuclear translocation of the DCLK2 kinase fragment and identified JDP2 as a histone-dependent substrate, linking the kinase to stress-responsive transcriptional regulation.

    Evidence Yeast two-hybrid, subcellular fractionation under hyperosmotic stress, and in vitro kinase assay (zebrafish ortholog)

    PMID:24582561

    Open questions at the time
    • Functional consequence of JDP2 phosphorylation not determined
    • Zebrafish ortholog; human conservation untested
    • Requirement for histone mechanistically unexplained
  5. 2022 Medium

    Identified a pro-metastatic role for DCLK2 in breast cancer, distinguishing its invasion-promoting function from proliferation and linking it to EMT and Wnt signaling.

    Evidence Lentiviral gain/loss-of-function, migration/invasion assays, tail-vein metastasis model, EMT marker Western blots, LF3 inhibitor treatment

    PMID:36477947

    Open questions at the time
    • Direct kinase substrate driving EMT not identified
    • Whether DCLK2 is a TCF4/β-catenin target or upstream regulator unclear
    • Single lab
  6. 2023 Low

    Placed DCLK2 as a kinase coupling synaptic activity to chromatin remodeling by mediating activity-dependent BAF complex phosphorylation.

    Evidence Kinase inhibition with mass spectrometry of BAF composition and phosphorylation in depolarized cortical neurons (preprint)

    PMID:37873481

    Open questions at the time
    • Preprint; no direct binding or mutagenesis shown
    • BAF interaction inferred indirectly from inhibitor effect
    • Phosphosites on BAF subunits not mapped
  7. 2024 High

    Defined DCLK2 as a direct upstream activating kinase of TBK1 in renal cancer, establishing a druggable oncogenic kinase relationship and identifying a tumor-predominant short isoform.

    Evidence Kinome-wide siRNA screen, Co-IP, in vitro kinase assay with Ser172 site mapping, knockdown/overexpression, and orthotopic xenografts

    PMID:38211588

    Open questions at the time
    • Determinants of DCLK2203 isoform predominance unknown
    • Whether DC domain contributes to TBK1 regulation untested
    • Generalizability beyond ccRCC unaddressed
  8. 2024 Medium

    Connected upstream Cpeb4-mediated Dclk2 induction to a pyroptotic transcriptional program via Ehf phosphorylation, defining a mechanism for neuronal death in cerebral ischemia.

    Evidence mRNA stability assays, knockdown in HT22 cells and CCI mouse model, Ehf subcellular fractionation, Caspase1/3 promoter assays, and kinase assay

    PMID:38513137

    Open questions at the time
    • Ehf phosphosite not mapped
    • Whether nuclear export is direct consequence of phosphorylation unproven
    • Single lab
  9. 2025 Medium

    Corroborated and contextualized the DCLK2-TBK1 axis by identifying BBOX1 as an antagonist that blocks the DCLK2-TBK1 interaction in ccRCC.

    Evidence Co-IP interaction-disruption, xenograft tumor growth, and transcriptomic analysis

    PMID:39934163

    Open questions at the time
    • Mechanism by which BBOX1 disrupts the interaction unresolved
    • Whether BBOX1 acts catalytically or by competition unknown
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DCLK2's microtubule-binding and kinase activities are coordinated across its distinct neuronal-developmental, transcriptional, and oncogenic contexts, and what governs substrate and isoform selection, remains unresolved.
  • No unified model linking the DC domain to kinase substrate choice
  • Structural basis of substrate recognition (TBK1, Ehf, JDP2) undefined
  • Regulation of subcellular partitioning between cytoplasm and nucleus poorly understood

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0016740 transferase activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1643685 Disease 2 R-HSA-1266738 Developmental Biology 1 R-HSA-5357801 Programmed Cell Death 1
Partners
BBOX1DCXEHFJDP2TBK1

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 DCLK2 (DCK2) has microtubule (MT) binding activity associated with its doublecortin-like (DC) domain, and protein kinase activity mediated by a separate kinase domain, with the two domains functioning independently. Overexpression of DCK2 stabilizes the MT cytoskeleton against cold-induced depolymerization. Autophosphorylation of DCK2 strongly reduces its affinity for MTs, suggesting a phosphorylation-dependent switch for reversible control of MT dynamics. In sympathetic neurons, DCK2 localizes to the cell body and terminal segments of axons and dendrites. Biochemical domain analysis, MT binding assays, cold-induced depolymerization assay, autophosphorylation assay, immunofluorescence localization in sympathetic neurons The Journal of biological chemistry High 15611072
2006 DCLK2 (CLICK-II/DCAMKL2) is a CaM kinase I/IV-related kinase highly expressed in neurons. Unlike CaMKI/CaMKIV and CaMKII which activate CREB-dependent transcription, DCLK2 is unable to significantly phosphorylate CREB Ser-133 and instead inhibits CRE-dependent gene expression by a dominant mechanism bypassing CREB, mediated by phosphorylated TORC2. CRE-reporter assay, CREB phosphorylation assay, overexpression in cells, comparison with CaMKI/CaMKIV/CaMKII The Journal of biological chemistry Medium 16684769
2009 Dcx and Dclk2 are coexpressed in the developing hippocampus, and double-null (Dcx;Dclk2) mice display spontaneous seizures originating in the hippocampus, dosage-dependent disrupted hippocampal lamination, cell-autonomous simplification of pyramidal dendritic arborizations, and reduced inhibitory synaptic tone. Loss of somatostatin-positive interneurons and elevated c-fos were identified, indicating that hippocampal dysmaturation and insufficient inhibitory input underlie epilepsy in this model. Genetic double-knockout mouse model, EEG, immunohistochemistry, electrophysiology, in situ hybridization Proceedings of the National Academy of Sciences of the United States of America High 19342486
2014 The kinase fragment of zebrafish DCLK2 (zDCLK2) translocates from the cytoplasm into the nucleus under hyperosmotic stress (NaCl or mannitol). The kinase domain interacts with the transcription factor JDP2, identified by two-hybrid screening, and phosphorylates JDP2 efficiently only in the presence of histone. Two-hybrid screening, subcellular fractionation/localization under hyperosmotic conditions, in vitro kinase assay with JDP2 and histone Biochemical and biophysical research communications Medium 24582561
2024 DCLK2 directly binds to and phosphorylates TBK1 on Ser172, activating TBK1 signaling in clear cell renal cell carcinoma (ccRCC). A short isoform, DCLK2203, predominates in ccRCC and promotes cell growth and tumorigenesis via TBK1 phosphorylation and activation. Depletion of DCLK2 inhibits anchorage-independent colony growth and kidney tumorigenesis in orthotopic xenograft models. Kinome-wide siRNA screen, Co-immunoprecipitation, in vitro kinase assay, site-specific phosphorylation (Ser172), overexpression/knockdown cell lines, orthotopic xenograft mouse models Molecular cell High 38211588
2025 BBOX1 suppresses ccRCC tumorigenesis by disrupting TBK1 activation through preventing TBK1's interaction with its upstream activator DCLK2, establishing a BBOX1-DCLK2-TBK1 axis in ccRCC metabolic dysregulation. Co-immunoprecipitation (interaction disruption), xenograft tumor growth assay, transcriptomic analysis Nature communications Medium 39934163
2024 Cpeb4 upregulates Dclk2 expression by increasing Dclk2 mRNA stability. Dclk2 then phosphorylates the transcription factor Ehf, causing p-Ehf to exit the nucleus, which reduces Ehf's repression of Caspase1 and Caspase3 promoters and thereby promotes neuronal pyroptosis in chronic cerebral ischemia models. mRNA stability assays, knockdown experiments in HT22 cells and CCI mouse model, subcellular fractionation of Ehf, promoter activity assays for Caspase1/Caspase3, kinase assay (Dclk2 phosphorylating Ehf) Journal of cerebral blood flow and metabolism Medium 38513137
2022 DCLK2 promotes breast cancer cell invasion and metastasis. Silencing DCLK2 does not affect proliferation but significantly suppresses migration, invasion, and lung metastasis. Overexpression of DCLK2 enhances migratory and invasive abilities of normal breast epithelial cells. DCLK2 knockdown blocks the epithelial-mesenchymal transition (EMT) process. TCF4/β-catenin inhibitor LF3 downregulates DCLK2 expression. Lentiviral overexpression and knockdown, scratch/Transwell migration and invasion assays, tail vein metastasis in vivo model, Western blot for EMT markers Clinical & translational oncology Medium 36477947
2023 DCLK2 was identified as a BAF (SWI/SNF) complex-interacting kinase in neurons; inhibition of DCLK2 attenuates activity-dependent BAF complex phosphorylation selectively, placing DCLK2 as a kinase that mediates synaptic activity-induced phosphorylation of BAF complexes. Chemical perturbation (kinase inhibition), mass spectrometry of BAF complex composition and phosphorylation in depolarized primary cortical neurons bioRxivpreprint Low 37873481

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD. Science translational medicine 284 21832240
2018 Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis. Annals of neurology 116 29572931
1981 Cardiac output during cardiopulmonary resuscitation at various compression rates and durations. The American journal of physiology 99 7282953
2019 Genetics of resilience: Implications from genome-wide association studies and candidate genes of the stress response system in posttraumatic stress disorder and depression. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 71 31583809
1996 Altered regulation of G1 cyclins in oxidant-induced growth arrest of lung alveolar epithelial cells. Accumulation of inactive cyclin E-DCK2 complexes. The Journal of biological chemistry 71 8810266
2009 Mice lacking doublecortin and doublecortin-like kinase 2 display altered hippocampal neuronal maturation and spontaneous seizures. Proceedings of the National Academy of Sciences of the United States of America 64 19342486
2013 Epilepsy associated with autism and attention deficit hyperactivity disorder: is there a genetic link? Brain & development 59 23726375
2019 Genome-wide analyses of psychological resilience in U.S. Army soldiers. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 45 31081985
2013 Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones. European journal of medicinal chemistry 40 24239623
2006 Molecular identification and characterization of a family of kinases with homology to Ca2+/calmodulin-dependent protein kinases I/IV. The Journal of biological chemistry 32 16684769
2005 dMi-2 chromatin binding and remodeling activities are regulated by dCK2 phosphorylation. The Journal of biological chemistry 30 16223721
2004 Doublecortin kinase-2, a novel doublecortin-related protein kinase associated with terminal segments of axons and dendrites. The Journal of biological chemistry 29 15611072
2017 Transcriptomic difference in bovine blastocysts following vitrification and slow freezing at morula stage. PloS one 28 29095916
2008 Alternative transcripts of Dclk1 and Dclk2 and their expression in doublecortin knockout mice. Developmental neuroscience 18 18075264
2021 Analysis of retrotransposon subfamily DNA methylation reveals novel early epigenetic changes in chronic lymphocytic leukemia. Haematologica 17 31919093
2014 Nuclear translocation of doublecortin-like protein kinase and phosphorylation of a transcription factor JDP2. Biochemical and biophysical research communications 11 24582561
2024 Kinome-wide siRNA screen identifies a DCLK2-TBK1 oncogenic signaling axis in clear cell renal cell carcinoma. Molecular cell 10 38211588
2019 Exome sequencing study of partial agenesis of the corpus callosum in men with developmental delay, epilepsy, and microcephaly. Molecular genetics & genomic medicine 10 31578829
2020 Gene discovery for high-density lipoprotein cholesterol level change over time in prospective family studies. Atherosclerosis 9 32109663
2025 BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma. Nature communications 7 39934163
2015 Hippocampal transcriptional and neurogenic changes evoked by combination yohimbine and imipramine treatment. Progress in neuro-psychopharmacology & biological psychiatry 7 25784603
2022 Doublecortin-like kinase 2 promotes breast cancer cell invasion and metastasis. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 5 36477947
2024 Cpeb4-mediated Dclk2 promotes neuronal pyroptosis induced by chronic cerebral ischemia through phosphorylation of Ehf. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 4 38513137
2023 Synaptic Activity Causes Minute-scale Changes in BAF Complex Composition and Function. bioRxiv : the preprint server for biology 4 37873481
2024 Transcriptomic Profiling Reveals Altered Expression of Genes Involved in Metabolic and Immune Processes in NDV-Infected Chicken Embryos. Metabolites 0 39728450

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