Tuberin Regulates p70 S6 Kinase Activation and Ribosomal Protein S6 Phosphorylation

Goncharova, Elena A.; Goncharov, Dmitry A.; Eszterhas, Andrew J.; Hunter, Deborah; Glassberg, Marilyn K.; Yeung, Raymond S.; Walker, Cheryl L.; Noonan, Daniel J.; Kwiatkowski, David J.; Chou, Margaret M.; Panettieri, Reynold A.; Krymskaya, Vera P.

doi:10.1074/jbc.m202678200

Cited by 395 publications

(182 citation statements)

References 59 publications

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“…S6K colocalizes with those stress fibers in the lamellipodia of moving leukocytes (42), and its phosphorylation induces migration of vascular smooth cells (43,44) and chick embryo fibroblasts (45). S6K mediates leukocyte chemotaxis induced by the human growth factor GM-CSF, which is inhibited by rapamycin at subnanomolar concentrations.…”

Section: Discussionmentioning

confidence: 99%

Phosphatidic Acid Is a Leukocyte Chemoattractant That Acts through S6 Kinase Signaling

Frondorf

Henkels

Frohman

et al. 2010

Journal of Biological Chemistry

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Phosphatidic acid (PA) is a pleiotropic lipid second messenger in mammalian cells. We report here that extracellular PA acts as a leukocyte chemoattractant, as membrane-soluble dioleoyl-PA (DOPA) elicits actin polymerization and chemotaxis of human neutrophils and differentiated proleukemic HL-60 cells. We show that the mechanism for this involves the S6 kinase (S6K) signaling enzyme. Chemotaxis was inhibited >90% by the S6K inhibitors rapamycin and bisindolylmaleimide and by S6K1 silencing using double-stranded RNA. However, it was only moderately (ϳ30%) inhibited by mTOR siRNA, indicating the presence of an mTOR-independent mechanism for S6K. Exogenous PA led to robust time-and dose-dependent increases in S6K enzymatic activity and Thr 421 /Ser 424 phosphorylation, further supporting a PA/S6K connection. We also investigated whether intracellular PA production affects cell migration. Overexpression of phospholipase D2 (PLD2) and, to a lesser extent, PLD1, resulted in elevation of both S6K activity and chemokinesis, whereas PLD silencing was inhibitory. Because the lipase-inactive PLD2 mutants K444R and K758R neither activated S6K nor induced chemotaxis, intracellular PA is needed for this form of cell migration. Lastly, we demonstrated a connection between extracellular and intracellular PA. Using an enhanced green fluorescent protein-derived PA sensor (pEGFPSpo20PABD), we showed that exogenous PA or PA generated in situ by bacterial (Streptomyces chromofuscus) PLD enters the cell and accumulates in vesicle-like cytoplasmic structures. In summary, we report the discovery of PA as a leukocyte chemoattractant via cell entry and activation of S6K to mediate the cytoskeletal actin polymerization and leukocyte chemotaxis required for the immune function of these cells.

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Section: Discussionmentioning

confidence: 99%

Phosphatidic Acid Is a Leukocyte Chemoattractant That Acts through S6 Kinase Signaling

Frondorf

Henkels

Frohman

et al. 2010

Journal of Biological Chemistry

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“…The TSC1 and TSC2 tumor suppressor genes have recently been implicated to play a role in negatively regulating mTOR in the PI3K signaling cascade (23,24). As a result, tumors secondary to the inactivation of these genes have elevated levels of p70 S6 kinase activity that is reversible by rapamycin, a specific mTOR inhibitor (7).…”

Section: Discussionmentioning

confidence: 99%

The Tuberin-Hamartin Complex Negatively Regulates β-Catenin Signaling Activity

Mak¹,

Takemaru

Kenerson³

et al. 2003

Journal of Biological Chemistry

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Tuberous sclerosis complex (TSC) is characterized by the formation of hamartomas in multiple organs resulting from mutations in the TSC1 or TSC2 gene. Their protein products, hamartin and tuberin, respectively, form a functional complex that affects cell growth, differentiation, and proliferation. Several lines of evidence, including renal tumors derived from TSC2؉/؊ animals, suggest that the loss or inhibition of tuberin is associated with up-regulation of cyclin D1. As cyclin D1 can be regulated through the canonical Wnt/␤-catenin signaling pathway, we hypothesize that the cell proliferative effects of hamartin and tuberin are partly mediated through ␤-catenin. In this study, total ␤-catenin protein levels were found to be elevated in the TSC2-related renal tumors. Ectopic expression of hamartin and wild-type tuberin, but not mutant tuberin, reduced ␤-catenin steady-state levels and its half-life. The TSC1-TSC2 complex also inhibited Wnt-1 stimulated Tcf/LEF luciferase reporter activity. This inhibition was eliminated by constitutively active ␤-catenin but not by Disheveled, suggesting that hamartin and tuberin function at the level of the ␤-catenin degradation complex. Indeed, hamartin and tuberin co-immunoprecipitated with glycogen synthase kinase 3 ␤ and Axin, components of this complex in a Wnt-1-dependent manner. Our data suggest that hamartin and tuberin negatively regulate ␤-catenin stability and activity by participating in the ␤-catenin degradation complex.

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“…Importantly, TSC2 alleles derived from TSC patients fail to inhibit phosphorylation of S6K1 and 4E-BP1 (Inoki et al, 2002;Tee et al, 2003b). Mammalian cells lacking TSC1 or TSC2 also exhibit increased S6K1 phosphorylation and activity that is rapamycin sensitive (Gao et al, 2002;Goncharova et al, 2002). Moreover, mutants of S6K1 that are insensitive to an mTOR input, and thus resistant to the inhibitory effect of rapamycin, are not inhibited by an overexpressed TSC1/2 complex (Inoki et al, 2002;Tee et al, 2002).…”

Section: Tsc1/2 a Novel Negative Regulator Of Tormentioning

confidence: 99%

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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Tuberin Regulates p70 S6 Kinase Activation and Ribosomal Protein S6 Phosphorylation

Cited by 395 publications

References 59 publications

Phosphatidic Acid Is a Leukocyte Chemoattractant That Acts through S6 Kinase Signaling

Phosphatidic Acid Is a Leukocyte Chemoattractant That Acts through S6 Kinase Signaling

The Tuberin-Hamartin Complex Negatively Regulates β-Catenin Signaling Activity

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

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