RAS/ERK Signaling Promotes Site-specific Ribosomal Protein S6 Phosphorylation via RSK and Stimulates Cap-dependent Translation*

By Philippe P Roux, D. Shahbazian, Hieu S. Vu, Marina K. Holz, M. Cohen, J. Taunton, Nahum Sonenberg, J. Blenis. Journal of Biological Chemistry, 2007

763 citations recorded by the source corpus.

Converging signals from the mammalian target of rapamycin (mTOR) and phosphoinositide 3-kinase (PI3K) pathways are well established to modulate translation initiation. Less is known regarding the molecular basis of protein synthesis regulated by other inputs, such as agonists of the Ras/extracellular signal-regulated kinase (ERK) signaling cascade. Ribosomal protein (rp) S6 is a component of the 40S ribosomal subunit that becomes phosphorylated at several serine residues upon mitogen stimulation, but the exact molecular mechanisms regulating its phosphorylation and the function of phosphorylated rpS6 is poorly understood. Here, we provide evidence that activation of the p90 ribosomal S6 kinases (RSKs) by serum, growth factors, tumor promoting phorbol esters, and oncogenic Ras is required for rpS6 phosphorylation downstream of the Ras/ERK signaling cascade. We demonstrate that while ribosomal S6 kinase 1 (S6K1) phosphorylates rpS6 at all sites, RSK exclusively phosphorylates rpS6 at Ser235/236 in vitro and in vivo using an mTOR-independent mechanism. Mutation of rpS6 at Ser235/236 reveals that phosphorylation of these sites promotes its recruitment to the 7-methylguanosine cap complex, suggesting that Ras/ERK signaling regulates assembly of the translation preinitiation complex. These data demonstrate that RSK provides an mTOR-independent pathway linking the Ras/ERK signaling cascade to the translational machinery.

Subfields: Molecular Biology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/71f3e905d0a56248dc1bbe9827aa8637a48e89cc

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Citations in the corpus

Antitumor Activity of Rapamycin in a Phase I Trial for Patients with Recurrent PTEN-Deficient Glioblastoma (2008, background): “This paradox might be explained by mTOR-independent phosphorylation of the 235/ 236 site [20,21] and suggests that the 240/244 site may be a preferred endpoint for assessment of mTOR activity.”
The Ras-ERK and PI3K-mTOR Pathways: Cross-talk and Compensation (2011, background): “These phosphorylations positively regulate rpS6 binding to the 7-methylguanosine cap complex, subsequent cap-dependent translation, and cell size [85, 86].”
Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue (2013, background): “Because ribosomal S6 protein kinase (p90RSK) has been shown to phosphorylate RPS6 in an ERK1/2-dependent manner, we asked whether clusters with high levels of RPS6 phosphorylation were associated with high levels of activated ERK1/2 modifications at the single-cell level (24).”
The PTEN–PI3K pathway: of feedbacks and cross-talks (2008, background): “p90RSK phosphorylates the ribosomal protein S6 at Ser235/236 therefore promoting its activation upon Ras–MAPK upregulation (Roux et al., 2007).”
The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients (2019, background): “KRAS is implicated in regulation of the oncogenic S6 protein translation pathway through both ERK-dependent activation of RSK, which phosphorylates S6 at Ser235/236, and cross-talk with the PI3K and mTOR pathway that additionally phosphorylates S6 at Ser240/244 (29).”
The RSK family of kinases: emerging roles in cellular signalling (2008, background): “The role of RSK in regulating site-specific rpS6 phosphorylation and translation in somatic cells has also been recently readdresse”
Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases (2011, background): “Whereas S6K1/2 phosphorylate all sites on rpS6, RSK1/2 specifically phosphorylate Ser235 and Ser236 in response to Ras/MAPK pathway activation (303).”