SKAR Is a Specific Target of S6 Kinase 1 in Cell Growth Control

Richardson, Celeste; Bröenstrup, Mark; Fingar, Diane C.; Jülich, Kristina; Ballif, Bryan A.; Gygi, Steven P.; Blenis, John

doi:10.1016/j.cub.2004.08.061

Cited by 172 publications

(166 citation statements)

References 38 publications

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“…These data are consistent with the ability of rapamycin-resistant mutants of S6K1 to partially restore rapamycin-suppressed E2F-dependent transcription and to partially rescue rapamycin-inhibited proliferation of vascular smooth muscle cells (Brennan et al, 1999;Vinals et al, 1999); furthermore, embryonic stem cells lacking S6K1 proliferate in culture at a reduced rate (Kawasome et al, 1998). Consistent with RNAi against S6K1 delaying G 1 phase progression, cells containing reduced S6K1 expression exhibit reduced cell size (Fingar et al, 2004;Richardson et al, submitted).…”

Section: Rheb An Activator Of Tor That Is Inhibited By Tsc2supporting

confidence: 75%

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

2004

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Cell growth (an increase in cell mass and size through macromolecular biosynthesis) and cell cycle progression are generally tightly coupled, allowing cells to proliferate continuously while maintaining their size. The target of rapamycin (TOR) is an evolutionarily conserved kinase that integrates signals from nutrients (amino acids and energy) and growth factors (in higher eukaryotes) to regulate cell growth and cell cycle progression coordinately. In mammals, TOR is best known to regulate translation through the ribosomal protein S6 kinases (S6Ks) and the eukaryotic translation initiation factor 4E-binding proteins. Consistent with the contribution of translation to growth, TOR regulates cell, organ, and organismal size. The identification of the tumor suppressor proteins tuberous sclerosis1 and 2 (TSC1 and 2) and Ras-homolog enriched in brain (Rheb) has biochemically linked the TOR and phosphatidylinositol 3-kinase (PI3K) pathways, providing a mechanism for the crosstalk that occurs between these pathways. TOR is emerging as a novel antitumor target, since the TOR inhibitor rapamycin appears to be effective against tumors resulting from aberrantly high PI3K signaling. Not only may inhibition of TOR be effective in cancer treatment, but rapamycin is an FDA-approved immunosuppressive and cardiology drug. We review here what is known (and not known) about the function of TOR in cellular and animal physiology.

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Section: Rheb An Activator Of Tor That Is Inhibited By Tsc2supporting

confidence: 75%

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

2004

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“…ERH is known to interact with the zinc-finger protein CIZ1, a promoter of DNA replication that interacts with p21 (Cip1), a CDK2 inhibitor critical for cell cycle regulation (31). Moreover, ERH interacts with SKAR, a cell growth regulator in the S6K1-signaling pathway (32). We propose from these protein interactions that HOTS may mediate its tumor suppressor activity by targeting DNA replication and cell cycle regulation.…”

Section: Resultsmentioning

confidence: 96%

A nucleolar protein, H19 opposite tumor suppressor ( HOTS ), is a tumor growth inhibitor encoded by a human imprinted H19 antisense transcript

Onyango

Feinberg

2011

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

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The H19 gene, which localizes within a chromosomal region on human chromosome 11p15 that is commonly lost in Wilms tumor (WT), encodes an imprinted untranslated RNA. However, the biological significance of the H19 noncoding transcript remains unresolved because replacement of the RNA transcript with a neocassette has no obvious phenotypic effect. Here we show that the human H19 locus also encodes a maternally expressed, translated gene, antisense to the known H19 transcript, which is conserved in primates. This gene, termed HOTS for H 19 o pposite t umor s uppressor, encodes a protein that localizes to the nucleus and nucleolus and that interacts with the human enhancer of rudimentary homolog (ERH) protein. WTs that show loss of heterozygosity of 11p15 or loss of imprinting of IGF2 also silence HOTS (7/7 and 10/10, respectively). Overexpression of HOTS inhibits Wilms, rhabdoid, rhabdomyosarcoma, and choriocarcinoma tumor cell growth, and silencing HOTS by RNAi increases in vitro colony formation and in vivo tumor growth. These results demonstrate that the human H19 locus harbors an imprinted gene encoding a tumor suppressor protein within the long-sought WT2 locus.

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“…Despite the description of several new substrates, little is known about isoform specificity (Ruvinsky and Meyuhas, 2006). Although animal models suggest the existence of specific targets for each kinase, SKAR is the only isoforms-specific target described so far-for S6K1 (Richardson et al, 2004). We report here that Rictor is a direct target of S6K1 and that S6K1 rather than S6K2 is likely to be the major kinase responsible for Rictor phosphorylation at Thr1135, suggesting that Rictor may play a role in the non-redundant functional specificity of S6K1.…”

Section: Discussionmentioning

confidence: 99%

Rictor is a novel target of p70 S6 kinase-1

et al. 2009

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The rapamycin-insensitive companion of mammalian target of rapamycin (mTOR) (Rictor) is a key member of mTOR complex-2 (mTORC2), which phosphorylates the AGC kinases Akt/PKB, PKC and SGK1 at a C-terminal hydrophobic motif. We identified several novel sites on Rictor that are phosphorylated, including Thr1135, which is conserved across all vertebrates. Phosphorylation of this site on Rictor is stimulated by amino acids and growth factors through a rapamycin-sensitive signaling cascade. We demonstrate here that Rictor is a direct target of the ribosomal protein S6 kinase-1 (S6K1). Rictor phosphorylation at Thr1135 does not lead to major changes in mTORC2-kinase activity. However, phosphorylation of this site turns over rapidly and mediates 14-3-3 binding to Rictor and mTORC2, providing possibility for altered interactions of the complex. These findings reveal an unexpected signaling input into mTORC2, which is regulated by amino acids, growth factors and rapamycin.

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SKAR Is a Specific Target of S6 Kinase 1 in Cell Growth Control

Abstract: We have identified a novel and specific target of S6K1, SKAR, which regulates cell growth. The homology of SKAR to the Aly/REF family links S6K1 with mRNA biogenesis in the control of cell growth.

Cited by 172 publications

References 38 publications

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

A nucleolar protein, H19 opposite tumor suppressor ( HOTS ), is a tumor growth inhibitor encoded by a human imprinted H19 antisense transcript

Rictor is a novel target of p70 S6 kinase-1

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