Chapter 2 Cell Signaling in Protein Synthesis

Mahoney, Sarah J.; Dempsey, Jamie M.; Blenis, John

doi:10.1016/s1877-1173(09)90002-3

Cited by 71 publications

(37 citation statements)

References 299 publications

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“…The majority of protein synthesis is thought to occur through a cap-dependent mechanism (Mahoney et al , 2009); therefore, we set out to determine whether overexpression of Rheb could induce an increase in cap-dependent translation. In these experiments, muscles were cotransfected with GFP or Rheb and a dual-luciferase bicistronic reporter of cap-dependent translation (Carter and Sarnow, 2000).…”

Section: Resultsmentioning

confidence: 99%

A Phosphatidylinositol 3-Kinase/Protein Kinase B-independent Activation of Mammalian Target of Rapamycin Signaling Is Sufficient to Induce Skeletal Muscle Hypertrophy

Goodman

Miu

Frey

et al. 2010

MBoC

105

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It has been widely proposed that signaling by mammalian target of rapamycin (mTOR) is both necessary and sufficient for the induction of skeletal muscle hypertrophy. Evidence for this hypothesis is largely based on studies that used stimuli that activate mTOR via a phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB)-dependent mechanism. However, the stimulation of signaling by PI3K/PKB also can activate several mTOR-independent growth-promoting events; thus, it is not clear whether signaling by mTOR is permissive, or sufficient, for the induction of hypertrophy. Furthermore, the presumed role of mTOR in hypertrophy is derived from studies that used rapamycin to inhibit mTOR; yet, there is very little direct evidence that mTOR is the rapamycin-sensitive element that confers the hypertrophic response. In this study, we determined that, in skeletal muscle, overexpression of Rheb stimulates a PI3K/PKBindependent activation of mTOR signaling, and this is sufficient for the induction of a rapamycin-sensitive hypertrophic response. Transgenic mice with muscle specific expression of various mTOR mutants also were used to demonstrate that mTOR is the rapamycin-sensitive element that conferred the hypertrophic response and that the kinase activity of mTOR is necessary for this event. Combined, these results provide direct genetic evidence that a PI3K/PKB-independent activation of mTOR signaling is sufficient to induce hypertrophy. In summary, overexpression of Rheb activates mTOR signaling via a PI3K/PKB-independent mechanism and is sufficient to induce skeletal muscle hypertrophy. The hypertrophic effects of Rheb are driven through a rapamycin-sensitive (RS) mechanism, mTOR is the RS element that confers the hypertrophy, and the kinase activity of mTOR is necessary for this event.

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Section: Resultsmentioning

confidence: 99%

A Phosphatidylinositol 3-Kinase/Protein Kinase B-independent Activation of Mammalian Target of Rapamycin Signaling Is Sufficient to Induce Skeletal Muscle Hypertrophy

Goodman

Miu

Frey

et al. 2010

MBoC

105

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“…The implications of the particular CK2 substrate interactions that we identified in Table 2 and Supplementary Table 4 suggest a wide range of biologically processes being affected. For example, CK2 catalyzed phosphorylation of eEF2 kinase and WASL (N-WASP), inhibited by CK2 phosphorylation on Thr344, could influence translation 43 and cytoskeletal dynamics 44,45 , respectively. In contrast, pThr344-CK2 is more active as a kinase toward histone chaperone NAP1L3, which could modulate chromatin dynamics 46 .…”

Section: Discussionmentioning

confidence: 99%

Regulation of CK2 by phosphorylation and O-GlcNAcylation revealed by semisynthesis

et al. 2012

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Protein Ser/Thr kinase CK2 (casein kinase II) is involved in a myriad of cellular processes including cell growth and proliferation by phosphorylating hundreds of substrates, yet the regulation process of CK2 function is poorly understood. Here we report that the CK2 catalytic subunit CK2α is modified by O-GlcNAc on Ser347, proximal to a cyclin-dependent kinase phosphorylation site (Thr344) on the same protein. We use protein semisynthesis to show that Thr344 phosphorylation increases CK2α cellular stability via Pin1 interaction whereas Ser347 glycosylation appears to be antagonistic to Thr344 phosphorylation and permissive to proteasomal degradation. By performing kinase assays with the site-specifically modified phospho- and glyco-modified CK2α in combination with CK2β and Pin1 binding partners on human protein microarrays, we show that CK2 kinase substrate selectivity is modulated by these specific posttranslational modifications. This study suggests how a promiscuous protein kinase can be regulated at multiple levels to achieve particular biological outputs.

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“…eEF2K is phosphorylated and inhibited by SAPK (JNK) (on S359), RSK and S6K1 (on S366), and phosphorylated and activated by AMPK (on S398) [49]. Thus eEF2K integrates a variety of diverse signaling pathways, and potentially may be targeted through different strategies.…”

Section: Discussionmentioning

confidence: 99%

Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer

et al. 2012

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IntroductionTranslation initiation is activated in cancer through increase in eukaryotic initiation factor 4E (eIF4E), eIF4G, phosphorylated eIF4E-binding protein (p4E-BP1) and phosphorylated ribosomal protein S6 (pS6), and decreased programmed cell death protein 4 (pdcd4), a translational inhibitor. Further, translation elongation is deregulated though alterations in eukaryotic elongation factor 2 (eEF2) and eEF2 kinase (eEF2K). We sought to determine the association of these translational aberrations with clinical-pathologic factors and survival outcomes in hormone receptor-positive breast cancer.MethodsPrimary tumors were collected from 190 patients with Stage I to III hormone receptor-positive breast cancer. Expression of eIF4E, eIF4G, 4E-BP1, p4E-BP1 T37/46, p4E-BP1 S65, p4E-BP1 T70, S6, pS6 S235/236, pS6 S240/244, pdcd4, eEF2 and eEF2K was assessed by reverse phase protein arrays. Univariable and multivariable analyses for recurrence-free survival (RFS) and overall survival (OS) were performed.ResultsHigh eEF2, S6, pS6 S240/244, p4E-BP1 T70, and low pdcd4 were significantly associated with node positivity. Median follow-up for living patients was 96 months.High p4E-BP1 T36/47, p4E-BP1 S65, p4E-BP1 T70 and 4E-BP1 were associated with worse RFS. High p4E-BP1 T70 and pS6 S235/236, and low pdcd4, were associated with worse OS. In multivariable analysis, in addition to positive nodes, p4E-BP1 S65 remained a significant predictor of RFS (HR = 1.62, 95% CI = 1.13-2.31; P = 0.008). In addition to age, pS6 S235/236 (HR = 1.73, 95% CI = 1.03-2.90, P = 0.039), eEF2K (HR = 2.19, 95% CI = 1.35-3.56, P = 0.002) and pdcd4 (HR = 0.42, 95% CI = 0.25-0.70, P = 0.001) were associated with OS.ConclusionsIncreased pS6, p4E-BP1, eEF2K and decreased pdcd4 are associated with poor prognosis in hormone receptor-positive breast cancer, suggesting their role as prognostic markers and therapeutic targets.

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Chapter 2 Cell Signaling in Protein Synthesis

Cited by 71 publications

References 299 publications

A Phosphatidylinositol 3-Kinase/Protein Kinase B-independent Activation of Mammalian Target of Rapamycin Signaling Is Sufficient to Induce Skeletal Muscle Hypertrophy

A Phosphatidylinositol 3-Kinase/Protein Kinase B-independent Activation of Mammalian Target of Rapamycin Signaling Is Sufficient to Induce Skeletal Muscle Hypertrophy

Regulation of CK2 by phosphorylation and O-GlcNAcylation revealed by semisynthesis

Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer

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