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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Two widely used RSK inhibitors, BI-D1870 and SL0101, alter mTORC1 signaling in a RSK-independent manner

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Roffe, Martin [1] ; Lupinacci, Fernancla C. [1] ; Soares, Luana C. [1] ; Hajj, Glaucia N. [1] ; Martins, Vilma R. [1]
Total Authors: 5
[1] Int Res Ctr, AC Camargo Canc Ctr, Brazil Natl Inst Sci & Technol Oncogen INCITO, Sao Paulo, SP - Brazil
Total Affiliations: 1
Document type: Journal article
Source: CELLULAR SIGNALLING; v. 27, n. 8, p. 1630-1642, AUG 2015.
Web of Science Citations: 10

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. (C) 2015 Elsevier Inc All rights reserved. (AU)

FAPESP's process: 13/25025-6 - Role of mTOR and RSK in tumorigenesis process in gliomas
Grantee:Luana Campos Soares
Support Opportunities: Scholarships in Brazil - Master
FAPESP's process: 11/21350-4 - Protein Synthesis Regulation by Sumoylation
Grantee:Martín Roffé
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 13/03315-2 - Translatomic applied to the discovery of molecular alterations in gliomas
Grantee:Fernanda Cristina Sulla Lupinacci
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 09/14027-2 - Mechanisms associated with the function of prion protein and its ligand STI1/Hop: therapeutic approaches
Grantee:Vilma Regina Martins
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 12/04370-4 - Translational control in the nervous system: tumor mechanisms
Grantee:Glaucia Noeli Maroso Hajj
Support Opportunities: Regular Research Grants