ArticleThe Journal of experimental medicine2020
Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism.
Article in The Journal of experimental medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 67 citations in OpenAlex.
- Targeting PGAM1 Y119 phosphorylation resensitizes non-small-cell lung cancer to cisplatin therapy by promoting oxidative stress and DNA damage.The Journal of biological chemistry · 2026Article
- CLK3 regulates tumor angiogenesis by modulating HIF1α ubiquitination.Cancer gene therapy · 2026Article
- Review
- USP13 depletion sensitizes colorectal cancer cells to necroptosis by destabilizing cIAP2 proteins.Cell death and differentiation · 2026Article
- Decoding SR protein regulation: kinases, phosphatases, and therapeutic targeting strategies.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Amino acid metabolic reprogramming: future prospects for cholangiocarcinoma therapy.Cell death discovery · 2026Review
- Ubiquitin-specific protease 13 promotes colorectal cancer progression by stabilizing mitogen-activated protein kinase kinase 3.Molecular biomedicine · 2025Article
- USP13 promotes colorectal cancer progression by deubiquitinating and stabilizing HIF-1α.Cell communication and signaling : CCS · 2025Article
- Construction of a Zebrafish Model of Cardiac Hypertrophy Caused by ATIC Gene Deletion and Preliminary Exploration of Aerobic Exercise Improvement.International journal of molecular sciences · 2025Article
- Purine metabolism: a pan-cancer metabolic dysregulation across circulation and tissues.Molecular cancer · 2025Article
- Cleavage of CAD by caspase-3 determines the cancer cell fate during chemotherapy.Nature communications · 2025Article
- Exploring Mechanisms and Biomarkers of Breast Cancer Invasion and Migration: An Explainable Gene-Pathway-Compounds Neural Network.Cancer medicine · 2025Article
- Targeting RNA splicing modulation: new perspectives for anticancer strategy?Journal of experimental & clinical cancer research : CR · 2025Review
- Dehydroabietylamine exerts antitumor effects by affecting nucleotide metabolism in gastric cancer.Carcinogenesis · 2024Article
- Preliminary Metabolomics Study Suggests Favorable Metabolic Changes in the Plasma of Breast Cancer Patients after Surgery and Adjuvant Treatment.Biomedicines · 2024Article
- CLK3 promotes tumor proliferation by activating MYC signaling.Cell division · 2024Article
- NEK6 dampens FOXO3 nuclear translocation to stabilize C-MYC and promotes subsequent de novo purine synthesis to support ovarian cancer chemoresistance.Cell death & disease · 2024Article
- PKM2 functions as a histidine kinase to phosphorylate PGAM1 and increase glycolysis shunts in cancer.The EMBO journal · 2024Article
- In silico identification of a novel Cdc2-like kinase 2 (CLK2) inhibitor in triple negative breast cancer.Protein science : a publication of the Protein Society · 2024Article
- 2-Desaza-annomontine (C81) impedes angiogenesis through reduced VEGFR2 expression derived from inhibition of CDC2-like kinases.Angiogenesis · 2024Article
Corrections and comments
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Authors and funding
20 authors at 11 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
CDC-like kinase 3 (CLK3) is a dual specificity kinase that functions on substrates containing serine/threonine and tyrosine. But its role in human cancer remains unknown. Herein, we demonstrated that CLK3 was significantly up-regulated in cholangiocarcinoma (CCA) and identified a recurrent Q607R somatic substitution that represented a gain-of-function mutation in the CLK3 kinase domain. Gene ontology term enrichment suggested that high CLK3 expression in CCA patients mainly was associated with nucleotide metabolism reprogramming, which was further confirmed by comparing metabolic profiling of CCA cells. CLK3 directly phosphorylated USP13 at Y708, which promoted its binding to c-Myc, thereby preventing Fbxl14-mediated c-Myc ubiquitination and activating the transcription of purine metabolic genes. Notably, the CCA-associated CLK3-Q607R mutant induced USP13-Y708 phosphorylation and enhanced the activity of c-Myc. In turn, c-Myc transcriptionally up-regulated CLK3. Finally, we identified tacrine hydrochloride as a potential drug to inhibit aberrant CLK3-induced CCA. These findings demonstrate that CLK3 plays a crucial role in CCA purine metabolism, suggesting a potential therapeutic utility.
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