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RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation.

ABSTRACT: The extent and duration of MAPK (mitogen-activated protein kinase) signalling govern a diversity of normal and aberrant cellular outcomes. Genetic and pharmacological disruption of the MAPK-activated kinase RSK (ribosomal S6 kinase) leads to elevated MAPK activity indicative of a RSK-dependent negative feedback loop. Using biochemical, pharmacological and quantitative MS approaches we show that RSK phosphorylates the Ras activator SOS1 (Son of Sevenless homologue 1) in cultured cells on two C-terminal residues, Ser(1134) and Ser(1161). Furthermore, we find that RSK-dependent SOS1 phosphorylation creates 14-3-3-binding sites. We show that mutating Ser(1134) and Ser(1161) disrupts 14-3-3 binding and modestly increases and extends MAPK activation. Together these data suggest that one mechanism whereby RSK negatively regulates MAPK activation is via site-specific SOS1 phosphorylation.

SUBMITTER: Saha M

PROVIDER: S-EPMC4198020 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation.

Saha Madhurima M Carriere Audrey A Cheerathodi Mujeeburahiman M Zhang Xiaocui X Lavoie Geneviève G Rush John J Roux Philippe P PP Ballif Bryan A BA

The Biochemical journal 20121001 1

The extent and duration of MAPK (mitogen-activated protein kinase) signalling govern a diversity of normal and aberrant cellular outcomes. Genetic and pharmacological disruption of the MAPK-activated kinase RSK (ribosomal S6 kinase) leads to elevated MAPK activity indicative of a RSK-dependent negative feedback loop. Using biochemical, pharmacological and quantitative MS approaches we show that RSK phosphorylates the Ras activator SOS1 (Son of Sevenless homologue 1) in cultured cells on two C-te ...[more]

PMID: 22827337

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Project description:Retinoic acid inducible gene-I (Rig-I) has been well documented as a cytosolic pattern recognition receptor that can sense viral RNA ligands to initiate the interferon-mediated antiviral immunity. However, little is known about the biological behaviors of Rig-I devoid of viral infection. Herein, we investigated the roles of Rig-I in the regulation of cellular senescence. In comparison to wild-type counterparts, Rig-I-/- mice displayed the accelerated loss of hair, less responsiveness to gentle physical stimuli and shorten survival time. Likewise, Rig-I deficiency rendered mouse embryonic fibroblasts (MEFs) more susceptible to the serial passages-associated replicative senescence. By performing a transcriptome analysis, we identified integrins at the intersections of biological pathways affected by Rig-I. Among these, integrin β3 was negatively regulated by Rig-I, and significantly upregulated with the occurrence of senescence. Gene silencing of Itgb3 (encoding integrin β3) retarded the progression of cellular senescence in both WT and Rig-I-/- MEFs. Notably, this effect was more prominent in Rig-I-/- MEFs. Furthermore, p38 MAPK was a key downstream molecule for integrin β3-mediated senescence, and overactivated in senescent Rig-I-/- MEFs. Taken together, Rig-I deficiency contributes to cellular senescence through amplifying integrin β3/p38 MAPK signaling. Our findings provide the evidence that Rig-I is a key regulator of cellular senescence, which will be helpful in better understanding its function without viral infection.Abbreviations: Rig-I: retinoic acid inducible gene-I; SASP: senescence-associated secretory phenotype; ECM: extracellular matrix; Itgb3: integrin beta 3; PRR: pattern recognition receptor; MEFs: mouse embryonic fibroblasts; Il-1β: interleukin-1 beta; Il-6: interleukin-6; Il-8: interleukin-8; Cxcl1: chemokine (C-X-C motif) ligand 1; Ccl2: chemokine (C-C motif) ligand 2; WT, wild type; BM: bone marrow; MAPK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinases; JNK: Jun N-terminal kinases; SA-β-gal: senescence-associated β-galactosidase; qPCR: quantitative reverse-transcription PCR; PBS: phosphate-buffered saline.

Dataset Information

RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation.

Publications

RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation.

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