دورية أكاديمية
Two widely used RSK inhibitors, BI-D1870 and SL0101, alter mTORC1 signaling in a RSK-independent manner.
| العنوان: | Two widely used RSK inhibitors, BI-D1870 and SL0101, alter mTORC1 signaling in a RSK-independent manner. |
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| المؤلفون: | Roffé M; International Research Center, A.C. Camargo Cancer Center, Brazil. National Institute of Science and Technology in Oncogenomics (INCITO)., Lupinacci FC; International Research Center, A.C. Camargo Cancer Center, Brazil. National Institute of Science and Technology in Oncogenomics (INCITO)., Soares LC; International Research Center, A.C. Camargo Cancer Center, Brazil. National Institute of Science and Technology in Oncogenomics (INCITO)., Hajj GN; International Research Center, A.C. Camargo Cancer Center, Brazil. National Institute of Science and Technology in Oncogenomics (INCITO)., Martins VR; International Research Center, A.C. Camargo Cancer Center, Brazil. National Institute of Science and Technology in Oncogenomics (INCITO).. Electronic address: vmartins@cipe.accamargo.org.br. |
| المصدر: | Cellular signalling [Cell Signal] 2015 Aug; Vol. 27 (8), pp. 1630-42. Date of Electronic Publication: 2015 Apr 16. |
| نوع المنشور: | Comparative Study; Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 8904683 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-3913 (Electronic) Linking ISSN: 08986568 NLM ISO Abbreviation: Cell Signal Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Oxford : Elsevier Science Ltd Original Publication: Oxford ; New York : Pergamon Press, 1988- |
| مواضيع طبية MeSH: | Benzopyrans/*pharmacology , Monosaccharides/*pharmacology , Multiprotein Complexes/*antagonists & inhibitors , Protein Kinase Inhibitors/*pharmacology , Pteridines/*pharmacology , Ribosomal Protein S6 Kinases, 90-kDa/*antagonists & inhibitors , Signal Transduction/*drug effects , TOR Serine-Threonine Kinases/*antagonists & inhibitors, Cell Line, Tumor ; Cell Proliferation/drug effects ; Data Mining ; Dose-Response Relationship, Drug ; Glioblastoma/enzymology ; Glioblastoma/genetics ; Glioblastoma/pathology ; HEK293 Cells ; Humans ; Mechanistic Target of Rapamycin Complex 1 ; Multiprotein Complexes/metabolism ; Phosphorylation ; RNA Interference ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Ribosomal Protein S6 Kinases, 90-kDa/genetics ; Ribosomal Protein S6 Kinases, 90-kDa/metabolism ; Substrate Specificity ; TOR Serine-Threonine Kinases/metabolism ; Time Factors ; Transfection ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins |
| مستخلص: | The 90 kDa ribosomal S6 kinases (RSK) are effectors of the Ras-ERK1/2 signaling pathway. RSK signaling controls proliferation and protein synthesis, and is altered in several types of tumors. BI-D1870 and SL0101 are two widely used inhibitors of RSK. After revision of the literature, discrepancies in the effects of the inhibitors were identified. Herein we report that while SL0101 inhibited mTORC1-p70S6K signaling, BI-D1870 increased p70S6K activation. Both effects were independent of ERK1/2 and RSK, and thus nonspecific. We also demonstrated how these opposite nonspecific effects mislead the identification of the RSK-dependent phosphorylation of rpS6 (S235/236), a known RSK and p70S6K substrate. Phosphorylation of tuberin at S1798 by RSK was proposed to mediate ERK1/2-dependent activation of mTORC1-p70S6K signaling. In glioblastoma-derived cells, phosphorylation of tuberin was abolished after RSK depletion or ERK1/2 inhibition, suggesting that RSK is its main kinase. However, RSK depletion did not reduce PMA-dependent p70S6K phosphorylation, which suggests that tuberin phosphorylation at S1798 is not the main mediator of ERK1/2-dependent activation of mTORC1. Remarkably, tuberin phosphorylation (S1798) followed the activation status of RSK in different cells and experimental conditions, suggesting that phosphorylation of that residue could be used as readout for RSK activation in cells. We confirmed the difference in the effects of SL0101 and BI-D1870 in cellular proliferation assays. Rapamycin potentiated the inhibition of proliferation induced by BI-D1870, but not by SL0101. We thus conclude that SL0101 and BI-D1870 induce distinct off-target effects in mTORC1-p70S6K signaling, and thus, the functions previously ascribed to RSK based on these inhibitors should be reassessed. (Copyright © 2015 Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: BI-D1870; Ribosomal protein S6 (rpS6); SL0101; Tuberin (TSC2); p70 ribosomal S6 kinase (p70S6K); p90 kDa ribosomal S6 kinase (RSK) |
| المشرفين على المادة: | 0 (BI D1870) 0 (Benzopyrans) 0 (Monosaccharides) 0 (Multiprotein Complexes) 0 (Protein Kinase Inhibitors) 0 (Pteridines) 0 (SL0101) 0 (TSC2 protein, human) 0 (Tuberous Sclerosis Complex 2 Protein) 0 (Tumor Suppressor Proteins) EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) EC 2.7.11.1 (RPS6KA1 protein, human) EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa) EC 2.7.11.1 (TOR Serine-Threonine Kinases) EC 2.7.11.1 (ribosomal protein S6 kinase, 90kDa, polypeptide 3) |
| تواريخ الأحداث: | Date Created: 20150419 Date Completed: 20160223 Latest Revision: 20211203 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1016/j.cellsig.2015.04.004 |
| PMID: | 25889895 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1873-3913 |
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| DOI: | 10.1016/j.cellsig.2015.04.004 |