ArticleScience signaling2015
Binding of the sphingolipid S1P to hTERT stabilizes telomerase at the nuclear periphery by allosterically mimicking protein phosphorylation.
Article in Science signaling, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers, 1 of them a synthesis that pooled it.
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Who cites it
92 citing papers in PubMed, 1 synthesis or guideline pooled it, 144 citations in OpenAlex.
- Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)Autophagy · 2021Guideline
- DHCR24 regulates endothelial senescence through the SPHK2/SPNS2-S1P axis.Biogerontology · 2026Article
- Sphingosine kinase-2 inhibition promotes immunogenic differentiation of myeloid-derived suppressor cells through an Acetyl-CoA carboxylase-phosphatidylcholine axis.Nature communications · 2026Article
- Review
- Opaganib Protects Against High-Fat Diet-Induced Hypercholesterolemia and Liver Steatosis in Mice.Diabetes, metabolic syndrome and obesity : targets and therapy · 2026Article
- Sphingosine kinase 1 is integral for elastin deficiency-induced arterial hypermuscularization.Nature cardiovascular research · 2026Article
- Sphingosine 1-phosphate signalling in cancer stem cells.Oncogenesis · 2025Review
- Tetrandrine regulates NAADP-mediated calcium signaling through a LIMP-2-dependent and sphingosine-mediated mechanism.Nature communications · 2025Article
- Sphingolipid metabolism dysregulation: A cause for lung cancer development, progression, and resistance to therapies.Chinese medical journal pulmonary and critical care medicine · 2025Review
- Regulation of cellular senescence in tumor progression and therapeutic targeting: mechanisms and pathways.Molecular cancer · 2025Review
- Sphingolipid signaling in kidney diseases.American journal of physiology. Renal physiology · 2025Review
- Review
- H. Pylori-Facilitated TERT/Wnt/β-Catenin Triggers Spasmolytic Polypeptide-Expressing Metaplasia and Oxyntic Atrophy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Mechanisms and potential therapeutic targets of SphK1 and SphK2 in hepatocellular carcinoma.Frontiers in medicine · 2025Review
- A role for plasma membrane CaPflugers Archiv : European journal of physiology · 2024Article
- Targeting SNAI1-Mediated Colorectal Cancer Chemoresistance and Stemness by Sphingosine Kinase 2 Inhibition.World journal of oncology · 2024Article
- Opaganib Downregulates N-Myc Expression and Suppresses In Vitro and In Vivo Growth of Neuroblastoma Cells.Cancers · 2024Article
- The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target.Cancer cell international · 2024Review
- The regulations of telomerase reverse transcriptase (TERT) in cancer.Cell death & disease · 2024Review
- Sphingosine kinase 1/S1P receptor signaling axis is essential for cellular uptake of Neisseria meningitidis in brain endothelial cells.PLoS pathogens · 2023Article
32 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
During DNA replication, the enzyme telomerase maintains the ends of chromosomes, called telomeres. Shortened telomeres trigger cell senescence, and cancer cells often have increased telomerase activity to promote their ability to proliferate indefinitely. The catalytic subunit, human telomerase reverse transcriptase (hTERT), is stabilized by phosphorylation. We found that the lysophospholipid sphingosine 1-phosphate (S1P), generated by sphingosine kinase 2 (SK2), bound hTERT at the nuclear periphery in human and mouse fibroblasts. Docking predictions and mutational analyses revealed that binding occurred between a hydroxyl group (C'3-OH) in S1P and Asp(684) in hTERT. Inhibiting or depleting SK2 or mutating the S1P binding site decreased the stability of hTERT in cultured cells and promoted senescence and loss of telomere integrity. S1P binding inhibited the interaction of hTERT with makorin ring finger protein 1 (MKRN1), an E3 ubiquitin ligase that tags hTERT for degradation. Murine Lewis lung carcinoma (LLC) cells formed smaller tumors in mice lacking SK2 than in wild-type mice, and knocking down SK2 in LLC cells before implantation into mice suppressed their growth. Pharmacologically inhibiting SK2 decreased the growth of subcutaneous A549 lung cancer cell-derived xenografts in mice, and expression of wild-type hTERT, but not an S1P-binding mutant, restored tumor growth. Thus, our data suggest that S1P binding to hTERT allosterically mimicks phosphorylation, promoting telomerase stability and hence telomere maintenance, cell proliferation, and tumor growth.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.