Negative Regulation of AKT Activation by BRCA1

Tang, Xiang; Ohashi, Amiko; Huang, Yuping; Pandita, Tej K.; Ludwig, Thomas; Powell, Simon N.; Yang, Qin

doi:10.1158/0008-5472.can-08-3009

Cited by 113 publications

(110 citation statements)

References 20 publications

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“…CSE Causes Early Akt Phosphorylation and Later Akt Reduction-Phosphorylated (activated) Akt is known as a substrate for Akt E3 ligases (22,23), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and nicotine, cigarette smoke components, rapidly activate Akt through PI3K (27); thus, we FIGURE 1. CSE causes cell death and Akt degradation through the UPS in NHLFs.…”

Section: Cse Causes Cell Death and Akt Degradation Through Ups-mentioning

confidence: 99%

“…Therefore, Akt degradation is recognized as one of the Akt regulatory mechanisms; however, only limited information on E3 ligases for Akt is available. The breast cancer susceptibility gene 1 (BRCA1) (22) and tetratrico-peptide repeat domain 3 (TTC3) (23) are known to cause p-Akt ubiquitination and proteasomal degradation. Opposite to the negative regulatory role of BRCA1 and TTC3, TNF receptor-associated factor 6 (TRAF6) causes Akt ubiquitination in a different manner, enhancing membrane localization and subsequent activation of Akt (24).…”

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confidence: 99%

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Cigarette Smoke Induces Akt Protein Degradation by the Ubiquitin-Proteasome System

Kim

Lee

Huh

et al. 2011

Journal of Biological Chemistry

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Emphysema is one of the characteristic features of chronic obstructive pulmonary disease, which is caused mainly by cigarette smoking. Recent data have suggested that apoptosis and cell cycle arrest may contribute to the development of emphysema. In this study, we addressed the question of whether and how cigarette smoke affected Akt, which plays a critical role in cell survival and proliferation. In normal human lung fibroblasts, cigarette smoke extract (CSE) caused cell death, accompanying degradation of total and phosphorylated Akt (p-Akt), which was inhibited by MG132. CSE exposure resulted in preferential ubiquitination of the active Akt (myristoylated), rather than the inactive (T308A/S473A double mutant) Akt. Consistent with cytotoxicity, CSE induced a progressive decrease of phosphorylated human homolog of mouse double minute homolog 2 (p-HDM2) and phosphorylated apoptosis signal regulating kinase 1 (p-ASK1) with concomitant elevation of p53, p21, and phosphorylated p38 MAPK. Forced expression of the active Akt reduced both CSE-induced cytotoxicity and alteration in HDM2/p53/p21 and ASK1/p38 MAPK, compared with the inactive Akt. Of note, CSE induced expression of the tetratricopeptide repeat domain 3 (TTC3), known as a ubiquitin ligase for active Akt. TTC3 siRNAs suppressed not only CSE-induced Akt degradation but also CSE-induced cytotoxicity. Accordingly, rat lungs exposed to cigarette smoke for 3 months showed elevated TTC3 expression and reduced Akt and p-Akt. Taken together, these data suggest that cigarette smoke induces cytotoxicity, partly through Akt degradation via the ubiquitin-proteasome system, in which TTC3 acts as a ubiquitin ligase for active Akt.

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Section: Cse Causes Cell Death and Akt Degradation Through Ups-mentioning

confidence: 99%

mentioning

confidence: 99%

Cigarette Smoke Induces Akt Protein Degradation by the Ubiquitin-Proteasome System

Kim

Lee

Huh

et al. 2011

Journal of Biological Chemistry

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“…Because growth factor stimulation, such as IGF-1 treatment, strongly induces Akt HM site phosphorylation, we next determined whether Akt activation by IGF-1-treatment could also 35 S signal in each lane was normalized to the wild-type Akt with 10 min of pulse labeling, which is arbitrarily set to value 1. B, 293T cells were transfected with plasmids expressing HA-tagged Akt and Akt S473A mutant.…”

Section: Akt Ser-473 Phosphorylation Regulates the Stability Of Aktmentioning

confidence: 99%

mTOR Complex 2 Targets Akt for Proteasomal Degradation via Phosphorylation at the Hydrophobic Motif

Ouyang

Lazorchak

et al. 2011

Journal of Biological Chemistry

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The protein kinase Akt (also known as protein kinase B) is a critical signaling hub downstream of various cellular stimuli such as growth factors that control cell survival, growth, and proliferation. The activity of Akt is tightly regulated, and the aberrant activation of Akt is associated with diverse human diseases including cancer. Although it is well documented that the mammalian target of rapamycin complex 2 (mTORC2)-dependent phosphorylation of the Akt hydrophobic motif (Ser-473 in Akt1) is essential for full Akt activation, it remains unclear whether this phosphorylation has additional roles in regulating Akt activity. In this study, we found that abolishing Akt Ser-473 phosphorylation stabilizes Akt following agonist stimulation. The Akt Ser-473 phosphorylation promotes a Lys-48-linked polyubiquitination of Akt, resulting in its rapid proteasomal degradation. Moreover, blockade of this proteasomal degradation pathway prolongs agonist-induced Akt activation. These data reveal that mTORC2 plays a central role in regulating the Akt protein life cycle by first stabilizing Akt protein folding through the turn motif phosphorylation and then by promoting Akt protein degradation through the hydrophobic motif phosphorylation. Taken together, this study reveals that the Akt Ser-473 phosphorylation-dependent ubiquitination and degradation is an important negative feedback regulation that specifically terminates Akt activation.

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“…The E3 ligase controls the specificity of target-protein selection and the abundance of individual target proteins [16]. Although the molecular pathways and physiological roles of Akt ubiquitination have been recently studied [17][18][19][20][21][22], large aspects of Akt ubiquitination remain unclear. Here, we identify MULAN as a novel E3 ligase for Akt.…”

Section: Introductionmentioning

confidence: 99%