SKAR Links Pre-mRNA Splicing to mTOR/S6K1-Mediated Enhanced Translation Efficiency of Spliced mRNAs

Max, Xiaoju; Yoon, Sang Oh; Richardson, Celeste; Jülich, Kristina; Blenis, John

doi:10.1016/j.cell.2008.02.031

Cited by 286 publications

(240 citation statements)

References 40 publications

Supporting

Mentioning

227

Contrasting

Unclassified

Order By: Relevance

“…ELAV1 and a cluster of differentially regulated [s/t]Q substrates (e.g., NUCL, NFIP2, DHX9, HNRPU, K1967) comprise the messenger ribonucleoprotein particle complex (Fig. S6, Table S1, and Datasets S1 and S2), which packages and exports mRNA from the nucleus and itself is regulated by the mTOR and ribosomal S6 kinase (42). SIRT7 is associated with the TPR of the nuclear pore complex, THOC2 (which controls RNA export by binding spliced mRNAs), the ribosome biogenesis factor BMS1, and the ribonuclease POP1.…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteomic characterization of DNA damage response in melanoma cells following MEK/PI3K dual inhibition

Kirkpatrick¹,

Bustos²,

Dogan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Phosphoproteomic characterization of DNA damage response in melanoma cells following MEK/PI3K dual inhibition

Kirkpatrick¹,

Bustos²,

Dogan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Such a difference is attributable, in part, to the EJC (deposited as a consequence of splicing) rather than to splicing per se. Furthermore, insulin treatment increases the enhanced translation of intron-containing mRNA compared with intronless mRNA through recruitment of activated ribosomal protein S6 kinase 1 (S6K1) to newly spliced mRNAs via the EJC component S6K1 Aly/REF-like substrate (SKAR) (24). Despite these advances in understanding of the role of EJCs in CT, molecular mechanisms of the possible communication between the CT complex and the EJC are poorly understood.…”

Section: Significancementioning

confidence: 99%

eIF4AIII enhances translation of nuclear cap-binding complex–bound mRNAs by promoting disruption of secondary structures in 5′UTR

Choe

Ryu

Park

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

It has long been considered that intron-containing (spliced) mRNAs are translationally more active than intronless mRNAs (identical mRNA not produced by splicing). The splicing-dependent translational enhancement is mediated, in part, by the exon junction complex (EJC). Nonetheless, the molecular mechanism by which each EJC component contributes to the translational enhancement remains unclear. Here, we demonstrate the previously unappreciated role of eukaryotic translation initiation factor 4AIII (eIF4AIII), a component of EJC, in the translation of mRNAs bound by the nuclear cap-binding complex (CBC), a heterodimer of cap-binding protein 80 (CBP80) and CBP20. eIF4AIII is recruited to the 5′-end of mRNAs bound by the CBC by direct interaction with the CBCdependent translation initiation factor (CTIF); this recruitment of eIF4AIII is independent of the presence of introns (deposited EJCs after splicing). Polysome fractionation, tethering experiments, and in vitro reconstitution experiments using recombinant proteins show that eIF4AIII promotes efficient unwinding of secondary structures in 5′UTR, and consequently enhances CBC-dependent translation in vivo and in vitro. Therefore, our data provide evidence that eIF4AIII is a specific translation initiation factor for CBC-dependent translation.eIF4AIII | cap-binding complex | translation | CTIF | nonsense-mediated mRNA decay I n mammalian cells, translation initiation is driven by two major cap-binding proteins (CBPs). One is the nuclear cap-binding complex (CBC), which is a heterodimer of nuclear CBP80 and CBP20 (CBP80/20) (1), and the other is the eukaryotic translation initiation factor (eIF) 4E, which is a major cytoplasmic CBP (2). The CBC binds the 5′-cap structure of a newly synthesized mRNA in the nucleus and then directly interacts with an eIF4G-like scaffold protein called CBP80/20-dependent translation initiation factor (CTIF) (3). Because CTIF is mostly present on the cytoplasmic side of the nuclear envelope and is found in the nucleus (3), the interaction between the CBC and CTIF may occur either in the nucleus or during mRNA export through the nuclear pore complex. In the cytoplasm, at the 5′-end of mRNA, the CBC-CTIF complex recruits the eIF3 complex (4) and then the 40S small subunit of the ribosome, thereby directing the socalled "first" (or pioneer) round of translation (1).Translation of a CBC-bound mRNA precedes that of the eIF4E-bound mRNA, because the CBC-bound mRNA is a precursor form of the eIF4E-bound mRNA (5). The timing of the replacement of the CBC by eIF4E has not yet been elucidated; however, it is known that the replacement is mediated by the action of importin α/β in a translation-independent manner (6). The replaced eIF4E at the 5′-end of mRNA recruits a scaffold protein, eIF4GI or eIF4GII, which recruits eIF3 and eIF4AI/II and, eventually, the 40S ribosomal subunit. Then, the recruited 40S subunit scans the mRNA until it reaches the authentic translation initiation codon AUG. Efficient ribosome scanning requires either eIF4AI or e...

show abstract

“…More recently, it was also demonstrated that the mTOR kinase and S6K2 have the ability to regulate cell proliferation and cell cycle progression (15,16). Most studies on S6K regulation and function focused on S6K1, establishing that S6K1 is able to regulate a number of key cellular processes, including insulin metabolism (17,18), cell survival (19,20), translation (21)(22)(23)(24), and more recently RNA splicing (25). Inactive S6K1 was reported to localize on the translational preinitiation complex through its interaction with eukaryotic initiation factor 3.…”

mentioning

confidence: 99%

Involvement of Heterogeneous Ribonucleoprotein F in the Regulation of Cell Proliferation via the Mammalian Target of Rapamycin/S6 Kinase 2 Pathway

Goh

Pardo

Michael

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

The S6 kinases (S6Ks) have been linked to a number of cellular processes, including translation, insulin metabolism, cell survival, and RNA splicing. Signaling via the phosphotidylinositol 3-kinase and mammalian target of rapamycin (mTOR) pathways is critical in regulating the activity and subcellular localization of S6Ks. To date, nuclear functions of both S6K isoforms, S6K1 and S6K2, are not well understood. To better understand S6K nuclear roles, we employed affinity purification of S6Ks from nuclear preparations followed by mass spectrometry analysis for the identification of novel binding partners. In this study, we report that in contrast to S6K1, the S6K2 isoform specifically associates with a number of RNA-binding proteins, including heterogeneous ribonucleoproteins (hnRNPs). We focused on studying the mechanism and physiological relevance of the S6K2 interaction with hnRNP F/H. Interestingly, the S6K2-hnRNP F/H interaction was not affected by mitogenic stimulation, whereas mTOR binding to hnRNP F/H was induced by serum stimulation. In addition, we define a new role of hnRNP F in driving cell proliferation, which could be partially attenuated by rapamycin treatment. S6K2-driven cell proliferation, on the other hand, could be blocked by small interfering RNA-mediated down-regulation of hnRNP F. These results demonstrate that the specific interaction between mTOR and S6K2 with hnRNPs is implicated in the regulation of cell proliferation.Regulation of cellular processes by extracellular stimuli, such as growth factors and nutrients, is an essential process in cell size and cell cycle control. The mammalian target of rapamycin (mTOR) 2 is a key regulator of cellular signaling and is highly dependent on the presence of nutrients, as well as growth factor-stimulated signaling from the phosphotidylinositol 3-kinase (PI3K) pathway. Activation of PI3K by a number of growth factor receptors leads to increased levels of phosphatidylinositol 3,4,5-triphosphate (1), a secondary messenger that recruits downstream kinases, such as 3-phosphoinositide-dependent kinase 1 (PDK1), to the plasma membrane (2). Membrane-associated PDK1 in turn phosphorylates and activates Akt at the T loop (3, 4), whereas activated Akt phosphorylation of tuberous sclerosis complex 2 (TSC2) blocks its inhibitory role in mTOR signaling (5, 6). TSC2 forms a heterodimer with TSC1, which as a complex acts as a GTPase activator toward the small GTPase, Rheb (Ras homolog enriched in brain) (7,8). Rheb associates directly with the catalytic domain of mTOR and activates it by antagonizing FKBP38, the proposed endogenous inhibitor of mTOR (9). Activated mTOR with its interacting partner protein Raptor, as part of the mTOR complex I (mTORC1) is able to phosphorylate S6Ks (at Thr 389 in S6K1 and Thr 388 in S6K2) (10). This early phosphorylation event is required for subsequent phosphorylation by PDK1 of Thr 229 and Thr 228 in the activation loops of S6K1 and S6K2, respectively (11). Phosphorylation by both mTORC1 and PDK1 leads to S6K activation, resul...

show abstract

SKAR Links Pre-mRNA Splicing to mTOR/S6K1-Mediated Enhanced Translation Efficiency of Spliced mRNAs

Cited by 286 publications

References 40 publications

Phosphoproteomic characterization of DNA damage response in melanoma cells following MEK/PI3K dual inhibition

Phosphoproteomic characterization of DNA damage response in melanoma cells following MEK/PI3K dual inhibition

eIF4AIII enhances translation of nuclear cap-binding complex–bound mRNAs by promoting disruption of secondary structures in 5′UTR

Involvement of Heterogeneous Ribonucleoprotein F in the Regulation of Cell Proliferation via the Mammalian Target of Rapamycin/S6 Kinase 2 Pathway

Contact Info

Product

Resources

About