Mechanism of Ribosomal p70S6 Kinase Activation by Granulocyte Macrophage Colony-stimulating Factor in Neutrophils

Lehman, Jason A.; Calvo, Vı́ctor; Gómez‐Cambronero, Julian

doi:10.1074/jbc.m300376200

Cited by 77 publications

(29 citation statements)

References 57 publications

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“…Rapamycin inhibited significant changes in p70S6K-Thr 389 phosphorylation, with the strongest inhibition detected at 15 min post-HFS. p70S6K activation is thought to additionally require prior phosphorylation of an ERK-dependent site (Thr 421 /Ser 424 ) located in the module IV region of the enzyme (41,42). We found that U0126, but not rapamycin, blocked phosphorylation of the ERK-site on p70S6K (Fig.…”

Section: Ltp Maintenance In the Dentate Gyrus Does Not Requirementioning

confidence: 61%

Novel Translational Control in Arc-dependent Long Term Potentiation Consolidation in Vivo

Panja

Dagytė

Bidinosti

et al. 2009

Journal of Biological Chemistry

101

114

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Regulation of translation factor activity plays a major role in protein synthesis-dependent forms of synaptic plasticity. We examined translational control across the critical period of Arc synthesis underlying consolidation of long term potentiation (LTP) in the dentate gyrus of intact, anesthetized rats. LTP induction by high frequency stimulation (HFS) evoked phosphorylation of the cap-binding protein eukaryotic initiation factor 4E (eIF4E) and dephosphorylation of eIF2␣ on a protracted time course matching the time-window of Arc translation. Local infusion of the ERK inhibitor U0126 inhibited LTP maintenance and Arc protein expression, blocked changes in eIF4E and eIF2␣ phosphorylation state, and prevented initiation complex (eIF4F) formation. Surprisingly, inhibition of the mTOR protein complex 1 (mTORC1) with rapamycin did not impair LTP maintenance or Arc synthesis nor did it inhibit eIF4F formation or phosphorylation of eIF4E. Rapamycin nonetheless blocked mTOR signaling to p70 S6 kinase and ribosomal protein S6 and inhibited synthesis of components of the translational machinery. Using immunohistochemistry and in situ hybridization, we show that Arc protein expression depends on dual, ERK-dependent transcription and translation. Arc translation is selectively blocked by pharmacological inhibition of mitogen-activated protein kinase-interacting kinase (MNK), the kinase coupling ERK to eIF4E phosphorylation. Furthermore, MNK signaling was required for eIF4F formation. These results support a dominant role for ERK-MNK signaling in control of translational initiation and Arc synthesis during LTP consolidation in the dentate gyrus. In contrast, mTORC1 signaling is activated but nonessential for Arc synthesis and LTP. The work, thus, identifies translational control mechanisms uniquely tuned to Arc-dependent LTP consolidation in live rats.The adult mammalian brain is known to express diverse forms of activity-dependent synaptic plasticity (1, 2). Bursts of synaptic activity can induce short term changes in synaptic strength, but more stable modifications typically require modulation of gene expression at the transcriptional and post-transcriptional levels (3, 4). Through post-transcriptional regulation, synaptic activity may dictate the time and place of neuronal protein synthesis.Regulated phosphorylation of translation factors and other ribosome-associated proteins is a major mechanism for controlling the activity of the translational machinery (5, 6). Translation control studies of LTP 2 have concentrated mainly on the Schaffer-collateral input to hippocampal CA1 pyramidal cells. Studies employing knock-out mice and pharmacological inhibitors support a role for eukaryotic initiation factor 4E (eIF4E) and eIF2␣ in consolidation of LTP in the CA1 region and long term memory (7-10). The function of the cap-binding protein eIF4E during translational initiation is controlled by eIF4E-binding proteins (4E-BPs), which inhibit initiation complex (eIF4F) formation by competing with the scaffolding protein eIF4G for...

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Section: Ltp Maintenance In the Dentate Gyrus Does Not Requirementioning

confidence: 61%

Novel Translational Control in Arc-dependent Long Term Potentiation Consolidation in Vivo

Panja

Dagytė

Bidinosti

et al. 2009

Journal of Biological Chemistry

101

114

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“…Thus, the specific effects of hVps34 on Thr 389 phosphorylation are consistent with a specific regulation of S6K1 phosphorylation by mTOR. We also examined phosphorylation of S6K1 at Thr 421 / Ser 424 , a putative Erk site (51). In control cells, we observed significant basal Thr 421 /Ser 424 phosphorylation, with a decrease in electrophoretic mobility of the phosphorylated protein upon insulin stimulation (Fig.…”

Section: Resultsmentioning

confidence: 89%

hVps34 Is a Nutrient-regulated Lipid Kinase Required for Activation of p70 S6 Kinase

Byfield

Murray

Backer

2005

Journal of Biological Chemistry

467

383

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Mammalian cells respond to nutrient deprivation by inhibiting energy consuming processes, such as proliferation and protein synthesis, and by stimulating catabolic processes, such as autophagy. p70 S6 kinase (S6K1) plays a central role during nutritional regulation of translation. S6K1 is activated by growth factors such as insulin, and by mammalian target of rapamycin (mTOR), which is itself regulated by amino acids. The Class IA phosphatidylinositol (PI) 3-kinase plays a well recognized role in the regulation of S6K1. We now present evidence that the Class III PI 3-kinase, hVps34, also regulates S6K1, and is a critical component of the nutrient sensing apparatus. Overexpression of hVps34 or the associated hVps15 kinase activates S6K1, and insulin stimulation of S6K1 is blocked by microinjection of inhibitory anti-hVps34 antibodies, overexpression of a FYVE domain construct that sequesters the hVps34 product PI(3)P, or small interfering RNA-mediated knock-down of hVps34. hVps34 is not part of the insulin input to S6K1, as it is not stimulated by insulin, and inhibition of hVps34 has no effect on phosphorylation of Akt or TSC2 in insulin-stimulated cells. However, hVps34 is inhibited by amino acid or glucose starvation, suggesting that it lies on the nutrient-regulated pathway to S6K1. Consistent with this, hVps34 is also inhibited by activation of the AMP-activated kinase, which inhibits mTOR/S6K1 in glucose-starved cells. hVps34 appears to lie upstream of mTOR, as small interfering RNA knock-down of hVps34 inhibits the phosphorylation of another mTOR substrate, eIF4E-binding protein-1 (4EBP1). Our data suggest that hVps34 is a nutrient-regulated lipid kinase that integrates amino acid and glucose inputs to mTOR and S6K1. p70 S6 kinase (S6K1) 2 regulates protein synthesis, cell size, and proliferation in response to cellular nutritional status and hormonal stimulation (1). Regulation of S6K1 by insulin and nutrients involves a complex pathway that includes mTOR as well as the p85/p110 PI 3-kinases and the downstream kinases PDK-1 and Akt. Phosphorylation of S6K1 at Thr 389 is regulated by mTOR, which either directly phosphorylates S6K1 or inhibits its dephosphorylation (2, 3). Thr 389 is present in a C-terminal hydrophobic motif, and its phosphorylation facilitates docking of PDK-1 and phosphorylation of the S6K1 activation loop (4). mTOR activity is regulated by at least three upstream inputs: amino acids, glucose, and growth factors. Amino acids, particularly leucine, regulate the formation of a nutrient sensing complex with Raptor and G␤L/LST8 (referred to as TORC1) that facilitates the recognition of substrates by mTOR under nutrient-replete conditions (5-8). In glucose-starved cells, mTOR is inhibited by the activation of AMPK (9 -11). Finally, growth factor stimulation leads to activation of Akt and phosphorylation of the TSC1/TSC2 complex (reviewed in Refs. 12-14). Akt-mediated phosphorylation inhibits the GAP activity of TSC1/TSC2 toward the Rheb GTPase, leading to Rheb activation (15-21). Rheb binds di...

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“…Phosphorylation of the Thr229 and Thr389 sites depends on the Akt pathway and Thr389 is phosphorylated by mTOR. Furthermore, phosphorylation of Thr389 requires phosphorylation of Thr421/Ser424 through the Erk pathway (Zhang et al, 2001;Lehman et al, 2003;Tsokas et al, 2007). Thus, p70S6k is activated by both the Akt and Erk pathways.…”

Section: 6mentioning

confidence: 97%

Roles of Ets-1 and p70S6 kinase in chondrogenic and gliogenic specification of mouse mesencephalic neural crest cells

Sugiura

2010

Mechanisms of Development

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Fibroblast growth factors (FGFs) have been shown to promote the chondrogenic and gliogenic specification of mouse mesencephalic neural crest cells through Notch signaling [Nakanishi, K., Chan, S.Y., Ito, K., 2007. Notch signaling is required for the chondrogenic specification of mouse mesencephalic neural crest cells. Mech. Dev. 124, 190-203; Ijuin, K., Nakanishi, K., Ito, K., 2008. Different downstream pathways for Notch signaling are required for gliogenic and chondrogenic specification of mouse mesencephalic neural crest cells. Mech. Dev. 125, 462-474]. In the present study, we analyzed FGF signaling pathways in chondrogenic and gliogenic specification. The promotion of chondrogenesis by FGF-2 was significantly suppressed by U0126, an inhibitor of the extracellular signal-regulated protein kinase (Erk) pathway, and by Erk-1 siRNA. Chondrogenesis was also prevented by the dominant negative Ets-1 expression vector. In contrast, Ets-1 was irrelevant to gliogenesis. The promotion of gliogenesis by FGF-2 was not only inhibited by U0126 but also by LY294002 and rapamycin, inhibitors of the Akt pathway, and by Akt-1 siRNA. Furthermore, gliogenesis was dramatically prevented by blocking the expression of p70S6 kinase (p70S6k), which is activated by both the Erk and Akt pathways, with p70S6k siRNA. These results suggest that Ets-1 activated by the Erk pathway promotes chondrogenic specification and p70S6k activated by both the Erk and Akt pathways plays an important role in gliogenic specification.

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Mechanism of Ribosomal p70S6 Kinase Activation by Granulocyte Macrophage Colony-stimulating Factor in Neutrophils

Cited by 77 publications

References 57 publications

Novel Translational Control in Arc-dependent Long Term Potentiation Consolidation in Vivo

Novel Translational Control in Arc-dependent Long Term Potentiation Consolidation in Vivo

hVps34 Is a Nutrient-regulated Lipid Kinase Required for Activation of p70 S6 Kinase

Roles of Ets-1 and p70S6 kinase in chondrogenic and gliogenic specification of mouse mesencephalic neural crest cells

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