Akt regulates nuclear/cytoplasmic localization of tuberin

Rosner, Margit; Freilinger, Angelika; Hengstschläger, Markus

doi:10.1038/sj.onc.1209812

Cited by 55 publications

(41 citation statements)

References 43 publications

(86 reference statements)

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“…Both of these kinases phosphorylate and thereby inactivate the TSC1·TSC2 complex, leading to a stimulation of mTORC1 signaling. In the present study, immobilization did not reduce phosphorylation of TSC2 at Ser 939 , a site directly phosphorylated by Akt (44). The possibility that immobilization promoted reduced phosphorylation of TSC2 by ERK1/2 could not be tested in the present study because of the lack of an antibody that reliably detects rat TSC2 phosphorylated at Ser 644 , a site phosphorylated by ERK1/2 (31).…”

Section: Discussionmentioning

confidence: 60%

The mTORC1 signaling repressors REDD1/2 are rapidly induced and activation of p70S6K1 by leucine is defective in skeletal muscle of an immobilized rat hindlimb

Kelleher

Kimball

Dennis

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

118

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Kelleher AR, Kimball SR, Dennis MD, Schilder RJ, Jefferson LS. The mTORC1 signaling repressors REDD1/2 are rapidly induced and activation of p70S6K1 by leucine is defective in skeletal muscle of an immobilized rat hindlimb. Am J Physiol Endocrinol Metab 304: E229 -E236, 2013. First published November 27, 2012; doi:10.1152/ajpendo.00409.2012.-Limb immobilization, limb suspension, and bed rest cause substantial loss of skeletal muscle mass, a phenomenon termed disuse atrophy. To acquire new knowledge that will assist in the development of therapeutic strategies for minimizing disuse atrophy, the present study was undertaken with the aim of identifying molecular mechanisms that mediate control of protein synthesis and mechanistic target of rapamycin complex 1 (mTORC1) signaling. Male Sprague-Dawley rats were subjected to unilateral hindlimb immobilization for 1, 2, 3, or 7 days or served as nonimmobilized controls. Following an overnight fast, rats received either saline or L-leucine by oral gavage as a nutrient stimulus. Hindlimb skeletal muscles were extracted 30 min postgavage and analyzed for the rate of protein synthesis, mRNA expression, phosphorylation state of key proteins in the mTORC1 signaling pathway, and mTORC1 signaling repressors. In the basal state, mTORC1 signaling and protein synthesis were repressed within 24 h in the soleus of an immobilized compared with a nonimmobilized hindlimb. These responses were accompanied by a concomitant induction in expression of the mTORC1 repressors regulated in development and DNA damage responses (REDD) 1/2. The nutrient stimulus produced an elevation of similar magnitude in mTORC1 signaling in both the immobilized and nonimmobilized muscle. In contrast, phosphorylation of 70-kDa ribosomal protein S6 kinase 1 (p70S6K1) on Thr 229 and Thr 389 in response to the nutrient stimulus was severely blunted. Phosphorylation of Thr 229 by PDK1 is a prerequisite for phosphorylation of Thr 389 by mTORC1, suggesting that signaling through PDK1 is impaired in response to immobilization. In conclusion, the results show an immobilization-induced attenuation of mTORC1 signaling mediated by induction of REDD1/2 and defective p70S6K1 phosphorylation.casting; anabolic resistance; 70-kilodalton ribosomal protein S6 kinase 1; 4E-binding protein 1; puromycin; mechanistic target of rapamycin complex 1; regulated in development and DNA damage responses 1/2 PROFOUND WASTING OF SKELETAL muscle, referred to as disuse atrophy, occurs in response to limb immobilization (10, 15, 16), limb suspension (40), and chronic bed rest (4,12,14). These conditions are associated with marked losses of skeletal muscle strength and function (21, 32), premature physical frailty (51), elevated health care costs, and an increased risk of mortality (36). Development of effective therapeutic strategies aimed at minimizing or preventing disuse atrophy will require a better understanding of the underlying molecular mechanisms that contribute to the loss of skeletal muscle mass. Maintenance of skeletal muscle mas...

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Section: Discussionmentioning

confidence: 60%

The mTORC1 signaling repressors REDD1/2 are rapidly induced and activation of p70S6K1 by leucine is defective in skeletal muscle of an immobilized rat hindlimb

Kelleher

Kimball

Dennis

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

118

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“…A recent study proved that Akt-induced phosphorylation triggers TSC2 de-localization from the nucleus to the cytoplasm through events at least partly dispensable from 14-3-3 binding [Rosner et al, 2007a]. Accordingly, in clone 3B kept at 338C TSC2 dephosphorylation at Thr 1462 following Akt inactivating de-phosphorylation in response to RAD 001 and IM association induced a significant increment of TSC2 nuclear expression ( P < 0.01) (Fig.…”

Section: Tsc2 De-phosphorylation and Release From 14-3-3 Contributes mentioning

confidence: 86%

“…Previous studies proved that Akt-induced phosphorylation of TSC2 creates 14-3-3 binding sites and thereby keeps TSC2 away from TSC1 at the cellular membranes, thereby hindering the TSC1/ TSC2 complex inhibitory function on mTORC1 [Liu et al, 2002;Cai et al, 2006]. Moreover, it promotes TSC2 de-localization from nuclear to cytoplasmatic compartments through events most likely at least partly independent from 14-3-3 ligand [Rosner et al, 2007a]. Here we showed that in clone 3B kept at 338C RAD 001 revokes Akt late re-phosphorylation in response to IM and thereby promotes a significant reduction of TSC2 phosphorylation at Thr 1462 (one of five Akt sites), release from 14-3-3 sigma and nuclear re-location (Figs.…”

Section: Discussionmentioning

confidence: 97%

“…The drug inhibitory effect on mTORC2 precluded Akt rephosphorylation at Ser 473 thereby preventing its late re-activation in response to IM. Such a RAD 001 ''high-dose effect'' on Akt reduced TSC2 phosphorylation at an Akt site (Ser 1462 ) allowing its release from 14-3-3 sigma (that restores its inhibitory function on mTORC1) and nuclear import (that drives the G 0 /G 1 arrest through functional interactions with CDK inhibitor p27 Kip1 ) [Liu et al, 2002;Rosner et al, 2007a]. RAD 001 effects on mTOR, Akt, and TSC2 were confirmed in CD34 þ hematopoietic progenitors purified from bone marrow samples of CML patients at diagnosis expressing the BCR-ABL gene.…”

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confidence: 99%

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RAD 001 (everolimus) prevents mTOR and Akt late re‐activation in response to imatinib in chronic myeloid leukemia

Mancini

Petta

Martinelli

et al. 2009

J of Cellular Biochemistry

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The mammalian target of rapamycin (mTOR) is one target of BCR-ABL fusion gene of chronic myeloid leukemia (CML). Moreover, it drives a compensatory route to Imatinib mesylate (IM) possibly involved in the progression of leukemic progenitors towards a drug-resistant phenotype. Accordingly, mTOR inhibitors are proposed for combined therapeutic strategies in CML. The major caveat in the use of mTOR inhibitors for cancer therapy comes from the induction of an mTOR-phosphatidylinositol 3 kinase (PI3k) feedback loop driving the retrograde activation of Akt. Here we show that the rapamycin derivative RAD 001 (everolimus, Novartis Institutes for Biomedical Research) inhibits mTOR and, more importantly, revokes mTOR late re-activation in response to IM. RAD 001 interferes with the assembly of both mTOR complexes: mTORC1 and mTORC2. The inhibition of mTORC2 results in the de-phosphorylation of Akt at Ser(473) in the hydrophobic motif of C-terminal tail required for Akt full activation and precludes Akt re-phosphorylation in response to IM. Moreover, RAD 001-induced inhibition of Akt causes the de-phosphorylation of tuberous sclerosis tumor suppressor protein TSC2 at 14-3-3 binding sites, TSC2 release from 14-3-3 sigma (restoring its inhibitory function on mTORC1) and nuclear import (promoting the nuclear translocation of cyclin-dependent kinase [CDK] inhibitor p27(Kip1), the stabilization of p27(Kip1) ligand with CDK2, and the G(0)/G(1) arrest). RAD 001 cytotoxicity on cells not expressing the BCR-ABL fusion gene or its p210 protein tyrosine kinase (TK) activity suggests that the inhibition of normal hematopoiesis may represent a drug side effect.

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“…Tuberin can be found at multiple sites within the cell including the cytosol, microsomes, cytoskeletal components and nucleus [6] . Whilst some studies have suggested that Akt activity influences tuberin levels [7,8] , other studies were unable to observe an affect [9,10] . Consistent with the latter, mitogenic stimulation induces Akt activity, whereas tuberin protein amounts remain constant [11,12] .…”

Section: Introductionmentioning

confidence: 96%

Tuberin: A Stimulus-Regulated Tumor Suppressor Protein Controlled by a Diverse Array of Receptor Tyrosine Kinases and G Protein-Coupled Receptors

Wu²,

Wong³

2006

Neurosignals

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Tuberin, a tumor suppressor protein, is involved in various cellular functions including survival, proliferation, and growth. It has emerged as an important effector regulated by receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). Regulation of tuberin by RTKs and GPCRs is highly complex and dependent on the type of receptors and their associated signaling molecules. Apart from Akt, the first kinase recognized to phosphorylate and inactivate tuberin upon growth factor stimulation, an increasing number of kinases upstream of tuberin have been identified. Furthermore, recruitment of different scaffolding adaptor components to the activated receptors appears to play an important role in the regulation of tuberin activity. More recently, the differential regulation of tuberin by various G protein family members have also been intensively studied, it appears that G proteins can both facilitate (e.g., G_i/o) as well as inhibit (e.g., G_q) tuberin phosphorylation. In the present review, we attempt to summarize our emerging understandings of the roles of RTKs, GPCRs, and their cross-talk on the regulation of tuberin.

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Akt regulates nuclear/cytoplasmic localization of tuberin

Cited by 55 publications

References 43 publications

The mTORC1 signaling repressors REDD1/2 are rapidly induced and activation of p70S6K1 by leucine is defective in skeletal muscle of an immobilized rat hindlimb

The mTORC1 signaling repressors REDD1/2 are rapidly induced and activation of p70S6K1 by leucine is defective in skeletal muscle of an immobilized rat hindlimb

RAD 001 (everolimus) prevents mTOR and Akt late re‐activation in response to imatinib in chronic myeloid leukemia

Tuberin: A Stimulus-Regulated Tumor Suppressor Protein Controlled by a Diverse Array of Receptor Tyrosine Kinases and G Protein-Coupled Receptors

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