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Discovery of a selective inhibitor of Doublecortin Like Kinase 1

ABSTRACT: Doublecortin like kinase 1 (DCLK1) is an understudied kinase that is upregulated in a wide range of cancers, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about its potential as a therapeutic target. We leveraged chemoproteomic profiling and structure-based design to develop the first selective, in vivo-compatible chemical probe of the DCLK1 kinase domain, DCLK1-IN-1. We demonstrate activity of DCLK1-IN-1 against clinically relevant patient-derived PDAC organoid models and use a combination of RNA sequencing, proteomics and phosphoproteomics analysis to reveal that DCLK1 inhibition modulates proteins and pathways associated with cell motility in this context. DCLK1-IN-1 will serve as a versatile tool to investigate DCLK1 biology and establish its role in cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140490 | GEO | 2020/04/06

REPOSITORIES: GEO

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Doublecortin-like kinase 1 activates NF-κB to induce inflammatory responses by binding directly to IKKβ

Project description:Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein kinase, is involved in neurogenesis, and its levels are elevated in various human cancers. Recent studies suggest that DCLK1 may relate to inflammatory responses in the mouse model of colitis. However, cellular pathways engaged by DCLK1, and potential substrates of the kinase remain undefined. To understand how DCLK1 regulates inflammatory responses, we utilized the well-established lipopolysaccharide (LPS)-stimulated macrophages and mouse model. Through a range of macrophage-based and cell-free platforms, we discovered that DCLK1 binds directly with the inhibitor of κB kinase β (IKKβ) and induces IKKβ phosphorylation on Ser177/181 to initiate nuclear factor-κB (NF-κB) pathway. Deficiency in DCLK1, achieved by silencing or through pharmacological inhibition, prevented LPS-induced NF-κB activation and cytokine production in macrophages. We further show that mice with myeloid-specific DCLK1 knockout or DCLK1 inhibitor treatment are protected against LPS-induced acute lung injury and septic death. Our studies report a novel functional role of macrophage DCLK1 as a direct IKKβ regulator in inflammatory signaling and suggest targeted therapy against DCLK1 for inflammatory diseases.

2023-03-20 | GSE224030 | GEO

Gene expression profiles of Dclk1+ and Dclk1- PDAC cells

Project description:Doublecortin-like kinase 1 (Dclk1) is known as a cancer stem cell marker of pancreatic ductal adenocarcinoma (PDAC). But the functional evidence to define the stem cell activity of these cells within tumors has not been explored. We compared the gene expression profiles of Dclk1-positive and -negative PDACs cells.

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Dclk1+ mouse pancreatic progenitor cells

Project description:Dclk1 (Doublecortin like kinase-1) labels a rare population of long-lived and largely quiescent cells in the adult mouse pancreas. The expression of Dclk1+ vs Dclk1- pancreatic cells (mostly acinar) is observed.

2016-04-11 | GSE74429 | GEO

DCLK1 small extracellular vesicle proteome

Project description:Doublecortin-like kinase 1 (DCLK1) is a putative cancer stem cell marker, a promising diagnostic and prognostic maker for malignant tumors and a proposed driver gene for gastric cancer. Here we show that DCLK1 expression in the gastric cancer cell line MKN1 impacts EV biogenesis both quantitatively and qualitatively in a kinase dependent manner, revealing a hitherto unknown role for this putative oncogenic kinase. Importantly, the proteome of EVs isolated from DCLK1 expressing gastric cancer cells is enriched for proteins involved in tumor-promoting biological processes, raising the prospect of establishing DCLK1 as a novel anti-cancer target.

2021-03-23 | PXD021371 | Pride

Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses

Project description:Atherosclerosis is a chronic inflammatory disease with high morbidity and mortality rates worldwide. Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein kinase, is involved in neurogenesis and human cancers. However, the role of DCLK1 in atherosclerosis remains undefined. In this study, we identified up-regulated DCLK1 in macrophages in atherosclerotic lesions of ApoE-/- mice fed an HFD and determined that macrophage-specific DCLK1 deletion attenuates atherosclerosis by reducing inflammation in mice. Mechanistically, RNA sequencing analysis indicated that DCLK1 mediates oxLDL-induced inflammation via NF-κB signaling pathway in primary macrophages. Co-immunoprecipitation followed by LC-MS/MS analysis identified IKKβ as a binding protein of DCLK1. We confirmed that DCLK1 directly interacts with IKKβ and phosphorylates IKKβ at S177/181, thereby facilitating subsequent NF-κB activation and inflammatory gene expression in macrophages. Finally, a pharmacological inhibitor of DCLK1 prevents atherosclerotic progression and inflammation both in vitro and in vivo. Our findings demonstrated that macrophage DCLK1 promotes inflammatory atherosclerosis by binding to IKKβ and activating IKKβ/NF-κB. This study reports DCLK1 as a new IKKβ regulator in inflammation and a potential therapeutic target for inflammatory atherosclerosis.

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Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses

2023-02-27 | PXD039083 | Pride

Gene expression profile of Dclk1+ murine normal intestinal and tumor cells

Project description:Accumulating evidence has shown the existence of tumor stem cells, and many researchers and clinicians are focusing on the therapeutic potential of targeting tumor stem cells. Previously, we reported that doublecortin like kinase 1 (Dclk1) marks tumor stem cells but not normal stem cells in ApcMin/+ mouse intestine, and that selective ablation of Dclk1+ cells results in collapse of the intestinal tumors without any apparent damages in the normal mucosa. Here, we sought to clarify gene expresion profile of Dclk1+ cells by microarray analyses in mouse normal intestinal epithelium and ApcMin/+ mouse intestinal tumors. Microarray analyses demonstrated that genes related to microtubules and actin cytoskeleton (e.g., Rac2) were highly expressed in Dclk1+ normal intestinal and tumor cells. We found the expression of Src family kinases (i.e., Hck, Lyn, Csk, and Ptpn6) in Dclk1+ normal intestinal and tumor cells.

2017-06-05 | GSE99387 | GEO

Discovery of a selective inhibitor of Doublecortin Like Kinase 1

Project description:Discovery of a selective inhibitor of Doublecortin Like Kinase 1

| PRJNA589887 | ENA

Gene expression profiles of Dclk1+ and Dclk1- PDAC cells

Project description:Gene expression profiles of Dclk1+ and Dclk1- PDAC cells

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Adult enteric Dclk1-positive glial and neuronal cells reveal distinct responses to acute intestinal injury

Project description:Intestinal ganglionic cells in the adult enteric nervous system (ENS) are continually exposed to stimuli from the surrounding microenvironment, and need at times to respond to disturbed homeostasis following acute intestinal injury. The kinase DCLK1 and intestinal Dclk1-positive cells have been reported to contribute to intestinal regeneration. While Dclk1-positive cells are present in adult enteric ganglia, their cellular identity and response to acute injury have not been investigated in detail. Here, we reveal the presence of distinct Dclk1-tdTom+/CD49b+ glial-like and Dclk1-tdTom+/CD49b- neuronal cell types in adult myenteric ganglia. These ganglionic cells demonstrate distinct patterns of tracing over time, yet show a similar expansion in response to elevated serotonergic signaling. Interestingly, Dclk1-tdTom+ glial-like and neuronal cell types appear resistant to acute irradiation injury-mediated cell death. Moreover, Dclk1-tdTom+/CD49b+ glial-like cells show prominent changes in gene expression profiles induced by injury, in contrast to Dclk1-tdTom+/CD49b- neuronal cell types. Finally, subsets of Dclk1-tdTom+/CD49b+ glial-like cells demonstrate prominent overlap with Nestin and p75NTR, and strong responses to elevated serotonergic signaling or acute injury. These findings, together with their role in early development and their neural-crest like gene expression signature, suggest the presence of reserve progenitor cells in the adult Dclk1 glial cell lineage.

2021-10-31 | GSE156031 | GEO

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