Mammalian Target of Rapamycin-dependent Phosphorylation of PHAS-I in Four (S/T)P Sites Detected by Phospho-specific Antibodies

Mothe-Satney, Isabelle; Brunn, Gregory J.; McMahon, Lloyd; Capaldo, Christopher; Abraham, Robert T.; Lawrence, John C.

doi:10.1074/jbc.m006005200

Cited by 124 publications

(149 citation statements)

References 33 publications

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“…The observed decreases in phosphorylation of 4E-BP1 could be a Figure 7c). The lack of inhibition of phosphorylation of 4E-BP1 at Thr 36/45 is consistent with similar observations in the literature (Gingras et al, 1999a(Gingras et al, , 2001bMothe-Satney et al, 2000a). On the other hand, the lack of inhibition of Ser 64 phosphorylation is surprising since rapamycin is known to affect this site and Ser 64 dephosphorylation of the endogenous 4E-BP1 did take place, confirming that rapamycin was functional in the cells (data not shown).…”

Section: P53 Activation and Rapamycin Have Additive Effects On The Insupporting

confidence: 81%

Regulation of the phosphorylation and integrity of protein synthesis initiation factor eIF4GI and the translational repressor 4E-BP1 by p53

Constantinou

Clemens

2005

Oncogene

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Activation of a temperature-sensitive form of mouse p53 in murine erythroleukaemia cells rapidly inhibits protein synthesis and causes early dephosphorylation and cleavage of protein synthesis initiation factor eIF4GI and the eIF4E-binding protein 4E-BP1. Dephosphorylated 4E-BP1 and the cleaved products of 4E-BP1 and eIF4GI associate with eIF4E under these conditions, concomitant with decreased interaction of full-length eIF4GI with eIF4E. These changes may play an important role in preventing formation of the eIF4F complex and thus the initiation of protein synthesis. As observed previously for eIF4GI, the cleavage of 4E-BP1 is insensitive to the general caspase inhibitor z-VAD.FMK, consistent with a caspase-independent mechanism of factor modification and regulation of protein synthesis. Comparison of the p53-induced patterns of eIF4GI and 4E-BP1 dephosphorylation and cleavage with those caused by the mTOR inhibitor rapamycin indicates that p53 activation and rapamycin have distinct but additive effects. Moreover, p53 activation inhibits rapamycin-insensitive protein kinase activity against 4E-BP1. P53 and rapamycin have additive effects on the inhibition of overall protein synthesis. These data suggest that the inhibition of protein synthesis by p53 is largely independent of the regulation of rapamycin-sensitive mTOR in the system under investigation.

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Section: P53 Activation and Rapamycin Have Additive Effects On The Insupporting

confidence: 81%

Regulation of the phosphorylation and integrity of protein synthesis initiation factor eIF4GI and the translational repressor 4E-BP1 by p53

Constantinou

Clemens

2005

Oncogene

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“…Phosphorylation at both threonines 37 and 46 is thought to be a priming event that is absolutely required for mitogen-induced serine 65 and threonine 70 phosphorylation, which results in the release of eIF4E (Gingras et al, 1999a(Gingras et al, , 2001aMothe-Satney et al, 2000a). Phosphorylation of threonine 70 appears to be required for the subsequent phosphorylation of serine 65 (Gingras et al, 1999a(Gingras et al, , 2001aMothe-Satney et al, 2000a, 2000b. Threonines 37 and 46 are basally phosphorylated in the absence of serum and stimulated only slightly by serum (Gingras et al, 1999a).…”

Section: Signaling To 4e-bp1: Regulation Of Cap-dependent Translationmentioning

confidence: 99%

“…In the presence of sufficient growth factors and nutrients, major sites of 4E-BP1 phosphorylation include the proline-directed sites threonines 37 and 46, serine 65, and threonine 70 (reviewed in Gingras et al, 2001b). Phosphorylation at both threonines 37 and 46 is thought to be a priming event that is absolutely required for mitogen-induced serine 65 and threonine 70 phosphorylation, which results in the release of eIF4E (Gingras et al, 1999a(Gingras et al, , 2001aMothe-Satney et al, 2000a). Phosphorylation of threonine 70 appears to be required for the subsequent phosphorylation of serine 65 (Gingras et al, 1999a(Gingras et al, , 2001aMothe-Satney et al, 2000a, 2000b.…”

Section: Signaling To 4e-bp1: Regulation Of Cap-dependent Translationmentioning

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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“…The sites conform to a (Ser/Thr)-Pro motif (7) with the exception of Ser-111, which is followed by Gln. Thr-36, Thr-45, Ser-64, and Thr-69 are phosphorylated in response to insulin (7,9,10), and these sites are conserved in PHAS-I proteins from different species as well as in the two other PHAS isoforms (2). The Ser-111 site is found in mammalian PHAS-I proteins, but not in the PHAS-I proteins from other vertebrates such as chicken or fish, or in mammalian PHAS-II or PHAS-III (2).…”

mentioning

confidence: 99%

Ser-64 and Ser-111 in PHAS-I Are Dispensable for Insulin-stimulated Dissociation from eIF4E

Ferguson

Mothe-Satney

Lawrence

2003

Journal of Biological Chemistry

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Mammalian Target of Rapamycin-dependent Phosphorylation of PHAS-I in Four (S/T)P Sites Detected by Phospho-specific Antibodies

Cited by 124 publications

References 33 publications

Regulation of the phosphorylation and integrity of protein synthesis initiation factor eIF4GI and the translational repressor 4E-BP1 by p53

Regulation of the phosphorylation and integrity of protein synthesis initiation factor eIF4GI and the translational repressor 4E-BP1 by p53

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

Ser-64 and Ser-111 in PHAS-I Are Dispensable for Insulin-stimulated Dissociation from eIF4E

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