Affinage

DCLK1

Serine/threonine-protein kinase DCLK1 · UniProt O15075

Length
740 aa
Mass
82.2 kDa
Annotated
2026-06-09
100 papers in source corpus 33 papers cited in narrative 33 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

DCLK1 is a bifunctional microtubule-associated serine/threonine kinase whose two activities are structurally and functionally separable: an N-terminal doublecortin-like domain binds purified tubulin and drives microtubule polymerization and bundling independent of catalytic activity, while a distinct C-terminal kinase domain phosphorylates protein substrates (PMID:11124993). The kinase domain is held in an autoinhibited conformation by a C-terminal autoinhibitory domain (AID) that occludes the ATP-binding site; truncation of the C-terminus elevates activity ~10-fold, and Ca²⁺-dependent binding of the neuronal calcium sensor HPCAL1 to the AID releases this autoinhibition, while cancer-associated AID mutations constitutively upregulate kinase activity (PMID:34977835, PMID:14741399). In the nervous system DCLK1 decorates a subset of dendritic microtubules to direct KIF1/kinesin-3-dependent dense-core vesicle trafficking and dendrite development, and phosphorylates MAP7D1 at Ser315 to promote cortical axon elongation (PMID:26758546, PMID:27503845). Beyond neurons, DCLK1 marks regenerative and tumor-initiating cell populations: Dclk1+ tuft/stem cells support intestinal and pancreatic epithelial restoration after injury and, in oncogenic Kras or Apc-mutant contexts, behave as cancer-initiating/tumor stem cells whose ablation regresses tumors without harming normal tissue (PMID:27058937, PMID:23202126, PMID:30478383). In cancer its kinase activity drives EMT, stemness, and an inflammatory microenvironment through defined substrates and partners—phosphorylating IKKβ at S177/181 to activate NF-κB in macrophages (PMID:36896602), XRCC5/Ku80 to transcriptionally induce COX-2/PGE2 (PMID:35910805), and CCAR1 at Ser343 to stabilize β-catenin signaling (PMID:35522902)—and through repression of tumor-suppressive miRNA programs (let-7a, miR-200, miR-145) that control pluripotency factors, KRAS, and EMT transcription factors (PMID:19445940, PMID:21285251, PMID:24040120). DCLK1 further promotes immune evasion via CXCL1-driven MDSC recruitment and M2 macrophage polarization (PMID:36309200, PMID:32371580). DCLK1 expression itself is controlled epigenetically by KDM3A-mediated H3K9 demethylation at its promoter and by a switch to an alternate NF-κB/LEF1-driven β-promoter producing a short isoform in cancer (PMID:31442435, PMID:26447334, PMID:30446587).

Mechanistic history

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

    Established that DCLK1 is a dual-function protein—a microtubule-polymerizing MAP and an active kinase—whose two activities are genetically separable, framing all later mechanistic work.

    Evidence In vitro microtubule polymerization with purified protein, kinase assays on MBP, and kinase-dead mutagenesis in cells

    PMID:11124993

    Open questions at the time
    • Physiological kinase substrates not identified
    • Regulation of the two activities in vivo unaddressed
  2. 2004 High

    Defined the C-terminus as an autoinhibitory module by showing its removal increases kinase activity ~10-fold, and that splice variants differ in subcellular localization.

    Evidence In vitro kinase assays on CaMK substrates with C-terminal truncation mutants and immunofluorescence

    PMID:14741399

    Open questions at the time
    • Structural basis of autoinhibition not resolved
    • Physiological trigger for de-repression unknown
  3. 2016 High

    Identified neuronal roles for DCLK1: MAP7D1-Ser315 phosphorylation drives axon elongation and dendritic-microtubule labeling directs KIF1-dependent cargo, linking kinase and MAP functions to neuronal morphogenesis.

    Evidence Phosphoproteomic substrate ID with phosphomimetic rescue; kinesin family-wide screen and knockdown in neurons

    PMID:26758546 PMID:27503845

    Open questions at the time
    • How DCLK1 selects dendritic microtubule subsets is unknown
    • Whether KIF1 guidance requires DCLK1 kinase activity not established
  4. 2021 High

    Resolved the autoinhibition mechanism structurally and identified its physiological release switch, showing the AID blocks the ATP site and HPCAL1 binds the AID in a Ca²⁺-dependent manner to activate the kinase.

    Evidence Crystal structure of the autoinhibited kinase domain plus HPCAL1–AID binding and Ca²⁺-activation assays; inhibitor co-crystals

    PMID:34545159 PMID:34977835

    Open questions at the time
    • Whether HPCAL1 activation operates outside neurons unknown
    • Cellular contexts that supply the Ca²⁺ signal not mapped
  5. 2013 High

    Demonstrated an in vivo developmental role outside the nervous system, placing DCLK1 as a Runx2 antagonist controlling osteoblast differentiation and bone mass.

    Evidence Dclk1-null mice with bone phenotyping and Runx2+/-;Dclk1-/- double-mutant epistasis

    PMID:23918955

    Open questions at the time
    • Molecular mechanism of Runx2 antagonism not defined
    • Whether kinase activity is required unaddressed
  6. 2016 High

    Established Dclk1+ cells as injury-responsive regenerative/cancer-initiating populations through lineage tracing and ablation, distinguishing tumor stem cells from normal stem cells.

    Evidence Dclk1-CreER lineage tracing and conditional cell ablation in pancreatitis/Kras and ApcMin/+ models

    PMID:23202126 PMID:24123696 PMID:27058937

    Open questions at the time
    • Cell-intrinsic molecular program conferring stemness not fully defined
    • Relationship between marker status and DCLK1 enzymatic function unclear
  7. 2018 Medium

    Linked Dclk1 in tuft cells to injury-induced ATM activation and COX-2/PGE2 production driving epithelial proliferation, establishing a DNA-damage/inflammation axis.

    Evidence Conditional intestinal Dclk1 knockout, irradiation, Co-IP for Dclk1–ATM, and PGE2 organoid rescue

    PMID:27876863 PMID:30478383

    Open questions at the time
    • Whether Dclk1–ATM interaction is direct/kinase-dependent not resolved
    • Paracrine signal identity incompletely defined
  8. 2013 Medium

    Positioned DCLK1 as a master repressor of tumor-suppressive miRNA networks (let-7a, miR-200, miR-145) controlling pluripotency factors, KRAS, and EMT transcription factors.

    Evidence siRNA knockdown with luciferase reporters and RT-PCR in colorectal/pancreatic cancer cells and xenografts

    PMID:19445940 PMID:21285251 PMID:24040120

    Open questions at the time
    • Molecular mechanism by which DCLK1 controls miRNA biogenesis unknown
    • Whether kinase activity is required not established
  9. 2022 Medium

    Identified direct kinase substrates and binding partners driving cancer inflammation and stemness: IKKβ (NF-κB), XRCC5/Ku80 (COX-2/PGE2), and CCAR1 (β-catenin stabilization).

    Evidence Co-IP/LC-MS-MS partner identification, in vitro kinase assays on defined sites, and conditional KO/inhibition in vivo

    PMID:35522902 PMID:35910805 PMID:36896602

    Open questions at the time
    • Substrate specificity determinants not mapped
    • Relative contribution of each substrate in vivo unclear
  10. 2022 High

    Defined DCLK1's role in immune evasion via CXCL1-mediated MDSC recruitment and M2 macrophage polarization suppressing CD8+ T-cell activity.

    Evidence CRISPR DCLK1 knockout with in vivo CXCL1 rescue, MDSC sorting/co-culture, and macrophage polarization assays

    PMID:32371580 PMID:36309200

    Open questions at the time
    • Mechanism linking DCLK1 kinase activity to CXCL1 induction unresolved
    • Whether MDSC and M2 axes are independent not determined
  11. 2020 Medium

    Connected DCLK1 to additional cancer effectors: kinase-dependent extracellular-vesicle cargo selection, KRAS activation, and ERK/RhoA/YAP signaling driving EMT.

    Evidence Overexpression/knockout with sEV proteomics, RAS pull-down and Co-IP, ChIP, and pathway immunoblots across pancreatic/breast/lung models

    PMID:28148261 PMID:28179411 PMID:31223610 PMID:31467540 PMID:32755567 PMID:33991177 PMID:36369000

    Open questions at the time
    • Direct versus indirect engagement of KRAS/RhoA/YAP not fully separated
    • CDK11 as a substrate remains preliminary
  12. 2019 High

    Explained how DCLK1 expression is itself reprogrammed in cancer: KDM3A H3K9 demethylation activates its promoter and an NF-κB/LEF1-driven alternate β-promoter produces a short oncogenic isoform.

    Evidence ChIP, promoter-reporter assays, gain/loss-of-function, and in vivo tumor models; miR-195/HuR 3'-UTR translational control

    PMID:26447334 PMID:30446587 PMID:31442435 PMID:33788631

    Open questions at the time
    • Functional differences between long and short isoforms not fully resolved
    • Upstream signals selecting promoter usage incompletely defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how DCLK1's MAP versus kinase functions and its long versus short isoforms are partitioned to dictate context-specific outcomes across neurons, epithelial regeneration, and the many cancer signaling axes attributed to it.
  • No unified model linking isoform expression to specific substrate engagement
  • Whether neuronal HPCAL1/Ca²⁺ activation operates in cancer cells untested
  • Which cancer phenotypes require catalytic activity versus MAP function not systematically dissected

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:0008092 cytoskeletal protein binding 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005856 cytoskeleton 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
ATMCCAR1CDK11HPCAL1IKBKBKRASMAP7D1XRCC5

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 DCAMKL1/DCLK1 protein associates with microtubules and stimulates polymerization of purified tubulin, forming aster-like microtubule structures. Overexpressed DCAMKL1 causes striking microtubule bundling in cell lines and primary neural cells. DCAMKL1 also encodes a functional kinase capable of phosphorylating myelin basic protein and itself (autophosphorylation). Elimination of kinase activity has no detectable effect on microtubule polymerization activity, indicating these two functions are separable. In vitro microtubule polymerization assay with purified protein; overexpression in cell lines; kinase activity assay with MBP substrate; kinase-dead mutagenesis; time-lapse live-cell imaging of GFP-fusion The Journal of neuroscience High 11124993
2016 DCLK1 labels a subset of dendritic microtubules and is required for kinesin-3 (KIF1)-dependent dense-core vesicle trafficking into dendrites and for dendrite development. Screening of all 45 kinesin family members identified KIF1/kinesin-3 and KIF21/kinesin-4 subfamily members as capable of dendritic transport; DCLK1 on dendritic microtubules provides local signals directing KIF1-dependent cargo specifically to dendrites. Kinesin family-wide screen in living cells; live imaging of cargo transport in hippocampal neurons; DCLK1 knockdown with phenotypic readout (DCV trafficking, dendrite development) The EMBO journal High 26758546
2016 DCLK1 phosphorylates MAP7D1 (microtubule-associated protein 7 domain containing 1) at serine 315 to promote axon elongation of cortical neurons. MAP7D1 was identified as a DCLK1 substrate by proteomic analysis; knockdown of MAP7D1 impairs callosal axon elongation but not radial migration. Overexpression of phosphomimetic MAP7D1-S315E fully rescues axon elongation defects in Dclk1-knockdown neurons, whereas wild-type MAP7D1 does not. Phosphoproteomics/proteomic substrate identification; shRNA knockdown in cortical neurons; in utero electroporation; phosphomimetic rescue experiment Developmental neurobiology High 27503845
2021 DCLK1 kinase domain adopts an autoinhibited state in which the C-terminal autoinhibitory domain (AID) blocks the ATP-binding site competitively with ATP. The neuronal calcium sensor HPCAL1 binds directly to the AID in a Ca²⁺-dependent manner, releasing autoinhibition and activating DCLK1 kinase activity. Cancer-associated mutations in the AID disrupt autoinhibition to upregulate kinase activity. Crystal structure of DCLK1 kinase domain in autoinhibited state; biochemical binding assays (HPCAL1–AID interaction); Ca²⁺-dependent activation assay; analysis of cancer-associated AID mutations Innovation (Cambridge (Mass.)) High 34977835
2021 Crystal structures of the DCLK1 kinase domain in complex with selective inhibitor DCLK1-IN-1 and its precursors were determined, revealing that DCLK1-IN-1 induces a drastic conformational change of the ATP binding site explaining its high selectivity. DCLK1-IN-1 binds DCLK1 long isoforms but does not prevent DCLK1's microtubule-associated protein (MAP) function. X-ray crystallography of kinase domain–inhibitor co-crystals; structure-activity relationship analysis; functional assay distinguishing kinase vs. MAP activity Communications biology High 34545159
2020 Using a DCLK1 chemical biology toolkit (inhibitor DCLK1-IN-1, inhibitor-resistant G532A mutant, kinase-dead D511N and D533N mutants), DCLK1 kinase activity was linked to RNA processing. Phosphoproteomics identified CDK11 as a potential substrate of DCLK1 kinase activity. Pharmacological inhibition with DCLK1-IN-1; engineered inhibitor-resistant and kinase-dead cell lines; phosphoproteomics Cell chemical biology Medium 32755567
2004 Two DCLK-short splice variants (DCLK-short-A and -B) both phosphorylate autocamtide and syntide (CaMK-specific substrates), confirming kinase activity. Removal of the C-terminal end of DCLK-short produces a ~10-fold increase in kinase activity, demonstrating that distinct C-termini function as autoinhibitory domains. The two variants localize differently: both are cytoplasmic, but DCLK-short-B also localizes to growth-cone-like structures and near the nucleus. In vitro kinase assay with CaMK substrates; C-terminal truncation mutagenesis; immunofluorescence localization in cells Brain research. Molecular brain research High 14741399
2013 DCAMKL1 represses osteoblast differentiation/activation by antagonizing Runx2, the master transcription factor of osteoblasts. Dcamkl1-null mice display elevated bone mass secondary to increased bone formation by osteoblasts. Genetic epistasis showed that key elements of the cleidocranial dysplasia phenotype in Runx2+/- mice are reversed by introduction of a Dcamkl1-null allele, establishing in vivo genetic linkage between DCAMKL1 and Runx2. Targeted gene disruption (Dcamkl1-null mice); shRNA screen (forward genetic); bone mass phenotyping; Runx2+/-;Dcamkl1-/- double-mutant epistasis The Journal of experimental medicine High 23918955
2023 Macrophage DCLK1 promotes atherosclerosis by directly interacting with IKKβ and phosphorylating IKKβ at S177/181, thereby facilitating NF-κB activation and inflammatory gene expression. Coimmunoprecipitation followed by LC-MS/MS identified IKKβ as a DCLK1-binding protein; macrophage-specific DCLK1 deletion attenuates atherosclerosis in ApoE-/- mice. Co-immunoprecipitation + LC-MS/MS; in vitro kinase assay on IKKβ; macrophage-specific conditional knockout mice; pharmacological DCLK1 inhibition in vivo EMBO molecular medicine High 36896602
2023 Macrophage-specific DCLK1 knockout (but not cardiomyocyte-specific knockout) prevents high-fat diet-induced cardiac dysfunction, hypertrophy, and fibrosis. DCLK1 mediates RIP2/TAK1 phosphorylation and subsequent inflammatory cytokine release in macrophages exposed to palmitate/HFD, which promotes hypertrophy in cardiomyocytes and fibrosis in fibroblasts. Cell-type-specific conditional knockout mice; RNA sequencing; in vitro macrophage-cardiomyocyte/fibroblast co-culture; pharmacological DCLK1 inhibition in vivo Cell death & disease Medium 37443105
2009 DCAMKL-1 is a negative regulator of let-7a miRNA biogenesis in intestinal stem and colorectal cancer cells. siRNA-mediated knockdown of DCAMKL-1 in colon cancer cells and xenografts results in increased pri-let-7a miRNA, decreased luciferase activity from a let-7a reporter, and decreased c-Myc expression. DCAMKL-1+ cells isolated by FACS have significantly lower pri-let-7a compared with more differentiated cells. siRNA knockdown; luciferase reporter assay for let-7a; FACS isolation of DCAMKL-1+ cells; tumor xenograft growth assay; real-time RT-PCR Gastroenterology Medium 19445940
2011 DCAMKL-1 knockdown in human pancreatic cancer cells induces miR-200a (an EMT inhibitor), with downregulation of EMT transcription factors ZEB1, ZEB2, Snail, Slug, and Twist. Additionally, DCAMKL-1 knockdown downregulates c-Myc and KRAS through a let-7a-dependent mechanism and downregulates Notch-1 through a miR-144-dependent mechanism, establishing DCAMKL-1 as a regulator of multiple miRNA-dependent pathways controlling EMT. siRNA knockdown in pancreatic cancer cells; miRNA quantification by RT-PCR; immunoblot for downstream targets; KRAS transgenic mouse model colocalization Cancer research Medium 21285251
2013 DCLK1 knockdown using nanoparticle-encapsulated siRNA in pancreatic xenografts results in increased miR-145, leading to decreased pluripotency factors OCT4, SOX2, NANOG, KLF4, KRAS, and RREB1; increased let-7a, decreasing LIN28B; and increased miR-200, decreasing VEGFR1, VEGFR2, and EMT transcription factors. Luciferase-based reporter assays confirmed DCLK1-dependent post-transcriptional regulation of miR-145, miR-200, and let-7a downstream targets. siRNA nanoparticle delivery in xenograft model; luciferase reporter assay; immunoblot; RT-PCR PloS one Medium 24040120
2018 DCLK1 induces NF-κBp65 subunit expression through the PI3K/Akt/Sp1 axis and activates NF-κBp65 through the PI3K/Akt/IκBα pathway during EMT in colorectal cancer cells. Silencing DCLK1 inhibits invasion and metastasis in vivo. siRNA knockdown; pharmacological pathway inhibitors; immunoblot for pathway components; in vivo xenograft invasion assay International journal of cancer Medium 29277893
2018 Dclk1 expression in tuft cells is important for inflammation-induced COX2 expression and prostaglandin E2 (PGE2) production in vivo. Loss of Dclk1 in intestinal epithelial cells impairs inflammation-induced proliferative response of colonic organoids, and exogenous PGE2 rescues proliferative defects in Dclk1-deficient organoids. Dclk1 is required for Dclk1-ATM interaction and COX2 activation in response to injury. Conditional intestinal epithelial Dclk1 knockout mice; organoid culture; PGE2 rescue experiment; immunostaining; qPCR Cell death and differentiation Medium 30478383
2016 Dclk1 expressed in tuft cells regulates ATM-mediated DNA damage response following radiation injury. Isolated intestinal epithelial cells from VillinCre;Dclk1f/f mice showed reduced injury-induced ATM and COX2 activation, reduced pro-survival gene expression, and reduced self-renewal ability. Interaction with Dclk1 is critical for ATM activation. Dclk1+ tuft cells regulate the broader intestinal epithelium through a paracrine mechanism. Conditional intestinal epithelial Dclk1 knockout mice; total body irradiation; ATM pathway assessment by immunoblot; self-renewal assay; co-IP for Dclk1-ATM interaction Scientific reports Medium 27876863
2019 DCLK1 overexpression in pancreatic cancer cells drives >2-fold increase in invasion and drug resistance and increases KRAS activation, as measured by a RAS pull-down assay. Co-immunoprecipitation demonstrated DCLK1–KRAS interaction. High DCLK1 expression in TCGA PAAD correlates with activated PI3K/AKT/MTOR pathway signaling consistent with elevated KRAS activity. Stable lentiviral DCLK1-isoform2 overexpression; Matrigel invasion assay; RAS activation pull-down assay; co-immunoprecipitation; Everolimus/LY294002/ABT-199 drug resistance assays; KPC mouse model Journal of oncology Medium 31467540
2022 DCLK1 binds and phosphorylates XRCC5 (Ku80), which in turn transcriptionally activates cyclooxygenase-2 (COX-2) expression and enhances prostaglandin E2 (PGE2) production, generating an inflammatory tumor microenvironment and driving aggressive behavior of colorectal cancer cells. This mechanism was identified by comprehensive proteomics/genomics analysis and validated functionally in CRC mouse models. Proteomics and genomics analyses to identify DCLK1 binding partners; Co-IP for DCLK1–XRCC5 interaction; in vitro kinase assay; COX-2/PGE2 functional measurements; CRC mouse models Theranostics Medium 35910805
2020 DCLK1 influences small extracellular vesicle (sEV/exosome) biogenesis and cargo selection in a kinase-dependent manner in gastric cancer cells. sEVs from DCLK1-overexpressing cells promote migration of parental cells. Quantitative proteomics of sEVs identified enrichment of migratory/adhesion regulators (STRAP, CORO1B, BCAM, COL3A, CCN1). Treatment with DCLK1-IN-1 reversed increases in sEV size/concentration and kinase-dependent cargo selection of EV biogenesis proteins (KTN1, CHMP1A, MYO1G) and migration proteins. Stable DCLK1 overexpression; sEV isolation; quantitative proteomics of sEVs; DCLK1-IN-1 pharmacological inhibition; migration assay Proteomics Medium 33991177
2019 KDM3A histone demethylase binds to the DCLK1 promoter and increases DCLK1 expression by removing H3K9me2 methylation marks. Knockdown of KDM3A in pancreatic cancer cells reduces DCLK1 levels; overexpression of KDM3A in non-cancerous HPNE cells increases DCLK1. This epigenetic regulation was confirmed by ChIP assay identifying KDM3A binding sites in the DCLK1 promoter. KDM3A knockdown and overexpression in pancreatic cell lines; ChIP assay for KDM3A binding at DCLK1 promoter; RNA sequencing; immunofluorescence co-localization; orthotopic tumor models Gastroenterology High 31442435
2015 Human colorectal cancers predominantly express a short DCLK1 isoform (DCLK1-S) from an alternate β-promoter located in Intron V of the DCLK1 gene, while normal colons express DCLK1-L from the 5'(α)-promoter. Activated NF-κBp65 binding to NF-κB cis-elements activates the β-promoter in cancer cells, whereas β-catenin/TCF4/LEF binding sites activate the α-promoter. This was confirmed by promoter-reporter and molecular biology approaches. In silico promoter analysis; promoter-reporter assays; molecular biology characterization of isoforms; NF-κBp65 and β-catenin functional studies; cohort analysis of isoform expression Scientific reports Medium 26447334
2018 LEF1 (lymphoid enhancer-binding factor 1) directly binds the DCLK1-B promoter to transcriptionally activate DCLK1-B expression. Niclosamide blocks this interaction, reducing DCLK1-B expression. DCLK1-B depletion impairs cancer stemness, reduces survival, and sensitizes CRC to chemoradiation. Chromatin immunoprecipitation; promoter-reporter assays; siRNA knockdown of LEF1 and DCLK1-B; in vivo xenograft and AOM/DSS models Clinical cancer research Medium 30446587
2021 miR-195 directly interacts with the Dclk1 mRNA 3'-UTR and inhibits DCLK1 translation. RNA-binding protein HuR competes with miR-195 for binding to Dclk1 mRNA and increases DCLK1 expression. Transgenic miR-195 overexpression in mice reduces DCLK1-positive tuft cells and increases vulnerability of the gut barrier. Luciferase reporter assay with Dclk1 3'-UTR; intestinal epithelial miR-195 transgenic mice; organoid culture; RNA pulldown/RIP for HuR-Dclk1 mRNA interaction American journal of physiology. Cell physiology Medium 33788631
2022 DCLK1 promotes immune escape in colorectal cancer by upregulating CXCL1, which recruits MDSCs through CXCR2 to suppress CD8+ T cell activity. DCLK1-/- tumor cells (CRISPR/Cas9) lose tumorigenicity under immune surveillance. Overexpression of CXCL1 rescued in vivo tumor growth of DCLK1-/- cells. CRISPR/Cas9 DCLK1 knockout tumor cells; subcutaneous and orthotopic tumor transplant models; flow cytometry of tumor-infiltrating immune cells; MDSC sorting and T-cell co-culture; RNA sequencing; CXCL1 rescue experiment Cellular and molecular gastroenterology and hepatology High 36309200
2016 Dclk1+ cells are necessary for pancreatic regeneration following injury. In vivo, loss of Dclk1+ cells has detrimental effects after cerulein-induced pancreatitis. In vitro, Dclk1+ cells proliferate readily and sustain pancreatic organoid growth. In the context of oncogenic Kras, experimental pancreatitis converts Kras-mutant Dclk1+ cells into potent cancer-initiating cells. Genetic lineage tracing (Dclk1-CreER); cerulein-induced pancreatitis model; Dclk1+ cell ablation; in vitro organoid growth assay; Kras mutant mouse model Cell stem cell High 27058937
2012 Dclk1 marks tumor stem cells (TSCs) rather than normal stem cells in the intestine of ApcMin/+ mice. Lineage tracing showed that Dclk1+ cells continuously produce tumor progeny in polyps. Specific ablation of Dclk1-positive TSCs resulted in marked regression of polyps without apparent damage to the normal intestine. Genetic lineage tracing (Dclk1-CreER;Rosa26-reporter); Dclk1+ cell-specific ablation in ApcMin/+ mice; polyp quantification; histological analysis of normal intestine Nature genetics High 23202126
2014 Dclk1 deletion in intestinal epithelial cells (VillinCre;Dclk1flox/flox) results in failure to maintain tight junctions after radiation injury and early lethality (~day 5 vs. day 10 in controls), demonstrating a functional role for Dclk1 in epithelial restoration after genotoxic insult. Widespread gene expression changes were detected in isolated intestinal epithelia during homeostasis in Dclk1-deficient mice. Conditional intestinal Dclk1 knockout mice; total body irradiation; survival analysis; tight junction assessment; global gene expression profiling Stem cells (Dayton, Ohio) Medium 24123696
2016 DCLK1 overexpression in pancreatic neuroendocrine tumor (PNET) cells induces EMT-related gene signatures including upregulation of Slug/SNAI2, N-Cadherin, and Vimentin. QGP1-DCLK1 cells showed increased migration, formed larger xenograft tumors, and activated p-FAK (Tyr925), p-ERK1/2, p-AKT, Paxillin, and Cyclin D1. Pharmacological inhibition or knockdown of DCLK1 abolished expression of these molecules. DCLK1 overexpression in QGP1 cells; xenograft tumor model; wound-healing migration assay; immunoblot for FAK/ERK/AKT; pharmacological and siRNA inhibition Molecular cancer research Medium 28179411
2022 Thrombin activates DCLK1, which then activates RhoA and YAP in lung epithelial cells. YAP undergoes dephosphorylation at Ser127 and translocates to the nucleus. YAP and p65 are recruited to the NF-κB site of the IL-8/CXCL8 promoter, enhancing IL-8 expression. DCLK1 siRNA inhibited RhoA and YAP activation and blocked YAP/p65 recruitment to the IL-8 promoter. DCLK1/RhoA/YAP activation was ERK-dependent (inhibited by U0126). siRNA knockdown of DCLK1/RhoA/YAP; DCLK1 inhibitor LRRK2-IN-1; κB-luciferase reporter assay; ChIP assay for YAP/p65 at IL-8 promoter; Western blot for pathway components; in vivo asthma model Journal of biomedical science Medium 36369000
2022 DCLK1 interacts with CCAR1 (cell cycle and apoptosis regulator 1) through its C-terminal domain and phosphorylates CCAR1 at Ser343, which is essential for CCAR1 stabilization. DCLK1 positively regulates β-catenin signaling via CCAR1, which maintains cancer stemness and 5-FU resistance in colorectal cancer cells. Co-immunoprecipitation for DCLK1–CCAR1 interaction; in vitro kinase assay for CCAR1 phosphorylation at Ser343; DCLK1/CCAR1 siRNA knockdown; β-catenin pathway analysis; 5-FU resistant cell line models; in vivo xenograft assay Clinical and translational medicine Medium 35522902
2017 Knockdown of Dclk1 in ApcMin/+ mice attenuates intestinal adenomas and adenocarcinoma, decreases pro-survival signaling (including NF-κB/RELA and NOTCH1 pathways), reduces pluripotency factors, and impairs self-renewal. Knocking down RELA, NOTCH1 signaling, and DCLK1 in colon cancer cells in vitro reduces tumor cell self-renewal and survival, establishing Dclk1 as a regulator of pro-survival and stemness signaling in intestinal tumors. Dclk1 knockdown in ApcMin/+ mice; siRNA knockdown of RELA and NOTCH1 in colon cancer cells; FACS; IHC; Western blot; clonogenic self-renewal assays Molecular cancer Medium 28148261
2020 DCLK1-isoform2 overexpression in pancreatic cancer cells causes polarization of M1-macrophages toward an immunosuppressive M2 phenotype via secreted chemokines/cytokines. DCLK1-isoform2-educated M2-macrophages enhance parental PDAC cell migration, invasion, and self-renewal, and inhibit CD8+ T-cell proliferation and granzyme-B activation. Inhibition of DCLK1 in an organoid co-culture system enhanced CD8+ T-cell activation and organoid death. DCLK1-isoform2 stable overexpression; macrophage polarization assay; CD8+ T-cell co-culture; organoid co-culture with DCLK1 inhibition; KPCY autochthonous mouse model immunostaining Molecular cancer therapeutics Medium 32371580
2019 DCLK1 overexpression promotes EMT and activates the ERK MAPK pathway in breast cancer cells, leading to enhanced expression of MT1-MMP. CRISPR/Cas9-mediated DCLK1 knockout reduces EMT markers (decreases ZO-1 loss, reduces ZEB1 and Vimentin), and reduces migration and invasion. This identifies ERK MAPK/MT1-MMP as a downstream pathway of DCLK1 in breast cancer metastasis. CRISPR/Cas9 DCLK1 knockout; stable DCLK1 overexpression; migration/invasion assays; immunoblot for EMT and ERK MAPK pathway markers; MT1-MMP expression analysis BioMed research international Medium 31223610

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nature genetics 336 23202126
2013 DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. Gastroenterology 265 24096005
2016 Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis. Cell stem cell 191 27058937
2011 DCAMKL-1 regulates epithelial-mesenchymal transition in human pancreatic cells through a miR-200a-dependent mechanism. Cancer research 182 21285251
2000 DCAMKL1 encodes a protein kinase with homology to doublecortin that regulates microtubule polymerization. The Journal of neuroscience : the official journal of the Society for Neuroscience 166 11124993
2016 Microtubule-binding protein doublecortin-like kinase 1 (DCLK1) guides kinesin-3-mediated cargo transport to dendrites. The EMBO journal 139 26758546
2013 DCLK1 regulates pluripotency and angiogenic factors via microRNA-dependent mechanisms in pancreatic cancer. PloS one 123 24040120
2014 XMD8-92 inhibits pancreatic tumor xenograft growth via a DCLK1-dependent mechanism. Cancer letters 111 24880079
2014 Curcumin promotes autophagic survival of a subset of colon cancer stem cells, which are ablated by DCLK1-siRNA. Cancer research 104 24626093
2011 Gastric tuft cells express DCLK1 and are expanded in hyperplasia. Histochemistry and cell biology 102 21688022
2009 Selective blockade of DCAMKL-1 results in tumor growth arrest by a Let-7a MicroRNA-dependent mechanism. Gastroenterology 101 19445940
2017 Dclk1, a tumor stem cell marker, regulates pro-survival signaling and self-renewal of intestinal tumor cells. Molecular cancer 93 28148261
2015 DCLK1 is a broadly dysregulated target against epithelial-mesenchymal transition, focal adhesion, and stemness in clear cell renal carcinoma. Oncotarget 85 25605241
2018 Dclk1 in tuft cells promotes inflammation-driven epithelial restitution and mitigates chronic colitis. Cell death and differentiation 83 30478383
2017 Dclk1-expressing tuft cells: critical modulators of the intestinal niche? American journal of physiology. Gastrointestinal and liver physiology 81 28684459
2018 DCLK1 promotes epithelial-mesenchymal transition via the PI3K/Akt/NF-κB pathway in colorectal cancer. International journal of cancer 75 29277893
2014 DCLK1 facilitates intestinal tumor growth via enhancing pluripotency and epithelial mesenchymal transition. Oncotarget 73 25211188
2016 miR-137 Regulates the Tumorigenicity of Colon Cancer Stem Cells through the Inhibition of DCLK1. Molecular cancer research : MCR 71 26747706
2014 Brief report: Dclk1 deletion in tuft cells results in impaired epithelial repair after radiation injury. Stem cells (Dayton, Ohio) 71 24123696
1998 Expression and chromosomal localization of KIAA0369, a putative kinase structurally related to Doublecortin. Journal of human genetics 71 9747029
1999 KIAA0369, doublecortin-like kinase, is expressed during brain development. Journal of neuroscience research 69 10533048
2016 Dominant Expression of DCLK1 in Human Pancreatic Cancer Stem Cells Accelerates Tumor Invasion and Metastasis. PloS one 68 26764906
2010 Identification of a novel putative pancreatic stem/progenitor cell marker DCAMKL-1 in normal mouse pancreas. American journal of physiology. Gastrointestinal and liver physiology 66 20522640
2020 Cancer Stem Cell Marker DCLK1 Correlates with Tumorigenic Immune Infiltrates in the Colon and Gastric Adenocarcinoma Microenvironments. Cancers 65 31979136
2019 The Histone Demethylase KDM3A, Increased in Human Pancreatic Tumors, Regulates Expression of DCLK1 and Promotes Tumorigenesis in Mice. Gastroenterology 64 31442435
2018 Alternative splice variants of DCLK1 mark cancer stem cells, promote self-renewal and drug-resistance, and can be targeted to inhibit tumorigenesis in kidney cancer. International journal of cancer 63 29577277
2015 Epigenetic changes and alternate promoter usage by human colon cancers for expressing DCLK1-isoforms: Clinical Implications. Scientific reports 61 26447334
2016 Functional implication of Dclk1 and Dclk1-expressing cells in cancer. Small GTPases 60 27458755
2018 Inhibition of LEF1-Mediated DCLK1 by Niclosamide Attenuates Colorectal Cancer Stemness. Clinical cancer research : an official journal of the American Association for Cancer Research 59 30446587
1999 DCAMKL1, a brain-specific transmembrane protein on 13q12.3 that is similar to doublecortin (DCX). Genomics 57 10036192
1999 High expression of doublecortin and KIAA0369 protein in fetal brain suggests their specific role in neuronal migration. The American journal of pathology 57 10550327
2017 MicroRNA-195 Suppresses the Progression of Pancreatic Cancer by Targeting DCLK1. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 55 29224010
2013 The microtubule-associated protein DCAMKL1 regulates osteoblast function via repression of Runx2. The Journal of experimental medicine 54 23918955
2022 Inhibition of DCLK1 sensitizes resistant lung adenocarcinomas to EGFR-TKI through suppression of Wnt/β-Catenin activity and cancer stemness. Cancer letters 52 35157971
2014 The recently suggested intestinal cancer stem cell marker DCLK1 is an epigenetic biomarker for colorectal cancer. Epigenetics 51 24384857
2012 DCLK1 immunoreactivity in colorectal neoplasia. Clinical and experimental gastroenterology 51 22557932
2018 Enhancement of Sensitivity to Chemo/Radiation Therapy by Using miR-15b against DCLK1 in Colorectal Cancer. Stem cell reports 50 30449704
2016 Regulatory Roles of Dclk1 in Epithelial Mesenchymal Transition and Cancer Stem Cells. Journal of carcinogenesis & mutagenesis 49 27335684
2020 Extracellular vesicles-encapsulated let-7i shed from bone mesenchymal stem cells suppress lung cancer via KDM3A/DCLK1/FXYD3 axis. Journal of cellular and molecular medicine 46 33350586
2019 DCLK1 Monoclonal Antibody-Based CAR-T Cells as a Novel Treatment Strategy against Human Colorectal Cancers. Cancers 46 31878090
2015 Plasma DCLK1 is a marker of hepatocellular carcinoma (HCC): Targeting DCLK1 prevents HCC tumor xenograft growth via a microRNA-dependent mechanism. Oncotarget 46 26468984
2023 Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses. EMBO molecular medicine 45 36896602
2016 miR-613 inhibits the growth and invasiveness of human hepatocellular carcinoma via targeting DCLK1. Biochemical and biophysical research communications 45 27049311
2015 Dclk1+ small intestinal epithelial tuft cells display the hallmarks of quiescence and self-renewal. Oncotarget 45 26362399
2017 Modified miR-15a has therapeutic potential for improving treatment of advanced stage colorectal cancer through inhibition of BCL2, BMI1, YAP1 and DCLK1. Oncotarget 44 29416778
2020 LncRNA SNHG1 promotes EMT process in gastric cancer cells through regulation of the miR-15b/DCLK1/Notch1 axis. BMC gastroenterology 41 32423385
2018 RETRACTED: miR-539 enhances chemosensitivity to cisplatin in non-small cell lung cancer by targeting DCLK1. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 41 30119173
2021 LncRNA SNHG1 contributes to the cisplatin resistance and progression of NSCLC via miR-330-5p/DCLK1 axis. Experimental and molecular pathology 40 33753110
2020 Tuft and Cancer Stem Cell Marker DCLK1: A New Target to Enhance Anti-Tumor Immunity in the Tumor Microenvironment. Cancers 40 33348546
2021 DCLK1, a Putative Stem Cell Marker in Human Cholangiocarcinoma. Hepatology (Baltimore, Md.) 38 32978808
2020 DCLK1 Regulates Tumor Stemness and Cisplatin Resistance in Non-small Cell Lung Cancer via ABCD-Member-4. Molecular therapy oncolytics 38 32637578
2005 Expression of doublecortin (DCX) and doublecortin-like kinase (DCLK) within the developing chick brain. Developmental dynamics : an official publication of the American Association of Anatomists 38 15614772
2019 DCLK1 Plays a Metastatic-Promoting Role in Human Breast Cancer Cells. BioMed research international 37 31223610
2016 DCLK1 phosphorylates the microtubule-associated protein MAP7D1 to promote axon elongation in cortical neurons. Developmental neurobiology 37 27503845
2015 Upregulation of circulating cancer stem cell marker, DCLK1 but not Lgr5, in chemoradiotherapy-treated colorectal cancer patients. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 37 25631749
2021 DCLK1 autoinhibition and activation in tumorigenesis. Innovation (Cambridge (Mass.)) 36 34977835
2020 DCLK1-Isoform2 Alternative Splice Variant Promotes Pancreatic Tumor Immunosuppressive M2-Macrophage Polarization. Molecular cancer therapeutics 36 32371580
2019 Overexpression of DCLK1-AL Increases Tumor Cell Invasion, Drug Resistance, and KRAS Activation and Can Be Targeted to Inhibit Tumorigenesis in Pancreatic Cancer. Journal of oncology 36 31467540
2017 Pancreatic Neuroendocrine Tumors and EMT Behavior Are Driven by the CSC Marker DCLK1. Molecular cancer research : MCR 36 28179411
2004 Functional differences between two DCLK splice variants. Brain research. Molecular brain research 36 14741399
2016 Intestinal tuft cells regulate the ATM mediated DNA Damage response via Dclk1 dependent mechanism for crypt restitution following radiation injury. Scientific reports 35 27876863
1999 Genomic structure, chromosomal mapping, and expression pattern of human DCAMKL1 (KIAA0369), a homologue of DCX (XLIS). Genomics 35 10051403
2013 Inhibition of Notch signaling reduces the number of surviving Dclk1+ reserve crypt epithelial stem cells following radiation injury. American journal of physiology. Gastrointestinal and liver physiology 34 24368703
2022 DCLK1 promotes colorectal cancer stemness and aggressiveness via the XRCC5/COX2 axis. Theranostics 32 35910805
2019 Inhibition of DCLK1 down-regulates PD-L1 expression through Hippo pathway in human pancreatic cancer. Life sciences 32 31837335
2017 A novel antibody against cancer stem cell biomarker, DCLK1-S, is potentially useful for assessing colon cancer risk after screening colonoscopy. Laboratory investigation; a journal of technical methods and pathology 31 28414327
2014 DCLK1 is detectable in plasma of patients with Barrett's esophagus and esophageal adenocarcinoma. Digestive diseases and sciences 31 25283374
2022 Targeting DCLK1 overcomes 5-fluorouracil resistance in colorectal cancer through inhibiting CCAR1/β-catenin pathway-mediated cancer stemness. Clinical and translational medicine 29 35522902
2016 Survival of Patients with Gastrointestinal Cancers Can Be Predicted by a Surrogate microRNA Signature for Cancer Stem-like Cells Marked by DCLK1 Kinase. Cancer research 28 27287716
2022 Pleiotropic effects of DCLK1 in cancer and cancer stem cells. Frontiers in molecular biosciences 27 36250024
2021 MicroRNA-195 regulates Tuft cell function in the intestinal epithelium by altering translation of DCLK1. American journal of physiology. Cell physiology 26 33788631
2021 Inhibition of DCLK1 with DCLK1-IN-1 Suppresses Renal Cell Carcinoma Invasion and Stemness and Promotes Cytotoxic T-Cell-Mediated Anti-Tumor Immunity. Cancers 26 34830884
2015 Inflammatory and oncogenic roles of a tumor stem cell marker doublecortin-like kinase (DCLK1) in virus-induced chronic liver diseases. Oncotarget 26 25948779
2021 Cancer stem cell marker DCLK1 reprograms small extracellular vesicles toward migratory phenotype in gastric cancer cells. Proteomics 25 33991177
2021 Structural basis for small molecule targeting of Doublecortin Like Kinase 1 with DCLK1-IN-1. Communications biology 25 34545159
2016 Epigenetic regulation of human DCLK-1 gene during colon-carcinogenesis: clinical and mechanistic implications. Stem cell investigation 25 27777940
2023 Macrophage DCLK1 promotes obesity-induced cardiomyopathy via activating RIP2/TAK1 signaling pathway. Cell death & disease 24 37443105
2022 Inhibition of DCLK1 kinase reverses epithelial-mesenchymal transition and restores T-cell activity in pancreatic ductal adenocarcinoma. Translational oncology 24 34998236
2012 DCLK1 variants are associated across schizophrenia and attention deficit/hyperactivity disorder. PloS one 24 22539971
2012 Immunolocalization of DCAMKL-1, a putative intestinal stem cell marker, in normal colonic tissue. Pathology, research and practice 23 22749579
2023 Targeting DCLK1 attenuates tumor stemness and evokes antitumor immunity in triple-negative breast cancer by inhibiting IL-6/STAT3 signaling. Breast cancer research : BCR 22 37069669
2021 Doublecortin-Like Kinase 1 (DCLK1) Is a Novel NOTCH Pathway Signaling Regulator in Head and Neck Squamous Cell Carcinoma. Frontiers in oncology 22 34336664
2018 DCLK1 plays an important role in colorectal cancer tumorgenesis through the regulation of miR-200c. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 22 29656186
2016 Evaluation of circulating cellular DCLK1 protein, as the most promising colorectal cancer stem cell marker, using immunoassay based methods. Cancer biomarkers : section A of Disease markers 22 27802206
2010 Altered expression of a putative progenitor cell marker DCAMKL1 in the rat gastric mucosa in regeneration, metaplasia and dysplasia. BMC gastroenterology 22 20565818
2019 DCLK1 promotes malignant progression of breast cancer by regulating Wnt/β-Catenin signaling pathway. European review for medical and pharmacological sciences 21 31773701
2018 Dclk1 Inhibition Cancels 5-FU-induced Cell-cycle Arrest and Decreases Cell Survival in Colorectal Cancer. Anticancer research 21 30396941
2021 DCLK1-Short Splice Variant Promotes Esophageal Squamous Cell Carcinoma Progression via the MAPK/ERK/MMP2 Pathway. Molecular cancer research : MCR 20 34610960
2019 Increased expression of DCLK1, a novel putative CSC maker, is associated with tumor aggressiveness and worse disease-specific survival in patients with bladder carcinomas. Experimental and molecular pathology 20 31028726
2021 DCLK1 and its interaction partners: An effective therapeutic target for colorectal cancer. Oncology letters 19 34733368
2020 Synthesis and Structure-Activity Relationships of DCLK1 Kinase Inhibitors Based on a 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one Scaffold. Journal of medicinal chemistry 19 32530623
2016 Potential Mechanism of Neurite Outgrowth Enhanced by Electrical Stimulation: Involvement of MicroRNA-363-5p Targeting DCLK1 Expression in Rat. Neurochemical research 19 27900578
2022 Long noncoding RNA BMPR1B-AS1 facilitates endometrial cancer cell proliferation and metastasis by sponging miR-7-2-3p to modulate the DCLK1/Akt/NF-κB pathway. Cell cycle (Georgetown, Tex.) 18 35404759
2022 DCLK1 Suppresses Tumor-Specific Cytotoxic T Lymphocyte Function Through Recruitment of MDSCs via the CXCL1-CXCR2 Axis. Cellular and molecular gastroenterology and hepatology 18 36309200
2021 DCLK1 isoforms and aberrant Notch signaling in the regulation of human and murine colitis. Cell death discovery 18 34226497
2018 Pancreatic DCLK1+ cells originate distinctly from PDX1+ progenitors and contribute to the initiation of intraductal papillary mucinous neoplasm in mice. Cancer letters 18 29526803
2008 Alternative transcripts of Dclk1 and Dclk2 and their expression in doublecortin knockout mice. Developmental neuroscience 18 18075264
2022 Thrombin induces IL-8/CXCL8 expression by DCLK1-dependent RhoA and YAP activation in human lung epithelial cells. Journal of biomedical science 17 36369000
2020 Chemical Biology Toolkit for DCLK1 Reveals Connection to RNA Processing. Cell chemical biology 17 32755567
2022 Role of DCLK1 in oncogenic signaling (Review). International journal of oncology 16 36148883

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