Identification of S6K2 as a centrosome‐located kinase

Rossi, R.; Pester, J.; McDowell, M.D.; Soza, Samuela; Montecucco, Alessandra; Lee-Fruman, Kay K

doi:10.1016/j.febslet.2007.07.047

Cited by 32 publications

(23 citation statements)

References 24 publications

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“…[26][27][28][29] Phosphorylation at Thr421/Ser424 of p70S6K1, a downstream effector of mTOR, is also strongly upregulated during mitosis, and the S6 kinase p54S6K2 has been identified as a centrosome-located kinase throughout the cell cycle. [30][31][32] Our current findings confirm that mTOR Ser2481 autophosphorylation, a recently described pharmacodynamic biomarker that directly monitors the effects of rapamycin on the assembly and function of mTORC complexes, should be added to the growing list of phospho-active forms of proteins of the AMPK/mTOR/S6K1 signaling axis that reside at the mitotic and cytokinetic apparatus.…”

Section: Anti-phospho-mtorsupporting

confidence: 69%

Ser2481-autophosphorylated mTOR colocalizes with chromosomal passenger proteins during mammalian cell cytokinesis

et al. 2012

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Section: Anti-phospho-mtorsupporting

confidence: 69%

Ser2481-autophosphorylated mTOR colocalizes with chromosomal passenger proteins during mammalian cell cytokinesis

et al. 2012

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“…The presence of a C-terminal nuclear localization sequence in S6K2 and other structural differences between the two S6K isoforms indicate that S6K2 has a potential role independent of its S6K1 isoform (27,28). This has partly been elucidated, because S6K2 but not S6K1 has been shown to be localized to centrosomes in cells (54). In addition, it has also been reported that S6K2 but not S6K1 is able to regulate cell survival (20).…”

Section: Discussionmentioning

confidence: 93%

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

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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...

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“…S6K2 was found in protein complexes by the centrosome in the nuclear membrane (Rossi et al 2007), and the results of an in silico study indicated domains of the S6K2 to connect to chromatin (Ismail et al 2014). In vitro data indicated that S6K2, not S6K1 or AKT, binds histone 3 and that this was dependent on the C-terminal nuclear localization signal in the S6K2 protein.…”

Section: Discussionmentioning

confidence: 99%

S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts

Bostner¹,

Karlsson²,

Eding³

et al. 2015

Endocrine-Related Cancer

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Detection of signals in the mammalian target of rapamycin (mTOR) and the estrogen receptor (ER) pathways may be a future clinical tool for the prediction of adjuvant treatment response in primary breast cancer. Using immunohistological staining, we investigated the value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen benefit in two independent clinical trials comparing adjuvant tamoxifen with no tamoxifen or 5 years versus 2 years of tamoxifen treatment. In addition, the prognostic value of the S6Ks was evaluated. We found that S6K1 correlated with proliferation, HER2 status, and cytoplasmic AKT activity, whereas high protein expression levels of S6K2 and phosphorylated (p) S6K were more common in ER-positive, and low-proliferative tumors with pAKT-s473 localized to the nucelus. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen effect (hazard ratio (HR): 1.07, 95% CI: 0.53-2.81, PZ0.84), compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation (HR: 0.42, 95% CI: 0.29-0.62, P!0.00001). Also S6K1 and S6K2 activation, indicated by pS6K-t389 expression, was associated with low benefit from tamoxifen (HR: 0.97, 95% CI: 0.50-1.87, PZ0.92). In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis in a multivariate analysis, PZ0.00041 (cytoplasm), PZ0.016 (nucleus). In conclusion, the mTOR-activated kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity and intracellular localization may provide biomarkers for breast cancer treatment, allowing the identification of a group of patients less likely to benefit from tamoxifen and thus in need of an alternative or additional targeted treatment.

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Identification of S6K2 as a centrosome‐located kinase

Cited by 32 publications

References 24 publications

Ser2481-autophosphorylated mTOR colocalizes with chromosomal passenger proteins during mammalian cell cytokinesis

Ser2481-autophosphorylated mTOR colocalizes with chromosomal passenger proteins during mammalian cell cytokinesis

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

S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts

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