Akt-Mediated Regulation of Autophagy and Tumorigenesis Through Beclin 1 Phosphorylation

Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113 USA.
Science (Impact Factor: 31.48). 11/2012; 338(6109):956-959. DOI: 10.1126/science.1225967

ABSTRACT Aberrant signaling through the class I phosphatidylinositol 3-kinase (PI3K)–Akt axis is frequent in human cancer. Here, we
show that Beclin 1, an essential autophagy and tumor suppressor protein, is a target of the protein kinase Akt. Expression
of a Beclin 1 mutant resistant to Akt-mediated phosphorylation increased autophagy, reduced anchorage-independent growth,
and inhibited Akt-driven tumorigenesis. Akt-mediated phosphorylation of Beclin 1 enhanced its interactions with 14-3-3 and
vimentin intermediate filament proteins, and vimentin depletion increased autophagy and inhibited Akt-driven transformation.
Thus, Akt-mediated phosphorylation of Beclin 1 functions in autophagy inhibition, oncogenesis, and the formation of an autophagy-inhibitory
Beclin 1/14-3-3/vimentin intermediate filament complex. These findings have broad implications for understanding the role
of Akt signaling and intermediate filament proteins in autophagy and cancer.

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Available from: Govind Bhagat, Aug 19, 2015
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    • "Future clinical trials should evaluate whether the level of BECN1 expression predicts the response to specific chemotherapeutic regimens or whether strategies that increase BECN1 function might be therapeutic in patients with low BECN1 expression. Of note, the autophagy activity of Beclin 1 is inhibited by interaction with BCL- 2 family members (Pattingre et al., 2005; Maiuri et al., 2007), by oncogenic kinase AKT and EGFR-mediated Beclin 1 post-translational modifications (Wang et al., 2012; Wei et al., 2013), and by interactions with HER2 (Han et al., 2013). Thus, currently available Beclin 1/BCL-2 binding inhibitors, AKT inhibitors, EGFR inhibitors and HER2 inhibitors may act to increase Beclin 1 function in tumors with low BECN1 expression, and thereby, improve clinical outcomes. "
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    ABSTRACT: Both BRCA1 and Beclin 1 (BECN1) are tumor suppressor genes, which are in close proximity on the human chromosome 17q21 breast cancer tumor susceptibility locus and are often concurrently deleted. However, their importance in sporadic human breast cancer is not known. To interrogate the effects of BECN1 and BRCA1 in breast cancer, we studied their mRNA expression patterns in breast cancer patients from two large datasets: The Cancer Genome Atlas (TCGA) (n = 1067) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (n = 1992). In both datasets, low expression of BECN1 was more common in HER2-enriched and basal-like (mostly triple-negative) breast cancers compared to luminal A/B intrinsic tumor subtypes, and was also strongly associated with TP53 mutations and advanced tumor grade. In contrast, there was no significant association between low BRCA1 expression and HER2-enriched or basal-like subtypes, TP53 mutations or tumor grade. In addition, low expression of BECN1 (but not low BRCA1) was associated with poor prognosis, and BECN1 (but not BRCA1) expression was an independent predictor of survival. These findings suggest that decreased mRNA expression of the autophagy gene BECN1 may contribute to the pathogenesis and progression of HER2-enriched, basal-like, and TP53 mutant breast cancers.
    01/2015; 59(3). DOI:10.1016/j.ebiom.2015.01.008
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    • "The role of ubiquitination in selective autophagy provides further evidence of the connection between ubiquitination and autophagy [25] [26]. Studies with pharmacological inhibitors suggest that AKT can regulate autophagy [11]. Although the underlying molecular mechanisms are not fully understood, it is clear that ULK1 ( "
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    ABSTRACT: The serine threonine kinase AKT plays a central role in the regulation of cell survival in a variety of human neoplastic diseases. A series of studies have revealed a connection between AKT signaling and two important protein degradation pathways in mammalian cells: the ubiquitin-proteasome system and autophagy. Two distinct ubiquitination systems have been reported to regulate AKT signaling: K63-linked ubiquitination, which promotes the oncogenic activation of AKT, and K48-linked ubiquitination, which triggers the proteasomal degradation of phosphorylated AKT. Autophagy is an evolutionarily conserved mechanism for the gross disposal and recycling of intracellular proteins in mammalian cells. AKT signaling may play a regulatory role in autophagy; however, the underlying mechanisms have not been fully clarified. Recently, AKT was shown to phosphorylate key molecules involved in the regulation of autophagy. Furthermore, lysosomal co-localization of the AKT-Phafin2 complex is reportedly critical for the induction of autophagy. In this review, we will discuss the connection between AKT, a core intracellular survival regulator, and two major intracellular proteolytic signaling pathways in mammalian cells.
    Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 08/2014; 1846(2). DOI:10.1016/j.bbcan.2014.07.013 · 7.58 Impact Factor
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    • "t that , conversely , ULK1 also inhibits MTOR by phos - phorylation . This inhibition of MTORC1 by ULK1 may serve to amplify and stabilize initially small changes in nutrient signaling ( Chang et al . 2009 ; Jung et al . 2011 ) . Autophagy is also controlled by PKB . Short - term regu - lation occurs by PKB - dependent phosphorylation of Beclin1 ( Wang et al . 2012 ) ( Fig . 2 ) . Long - term regulation by PKB occurs by phosphorylation of FoxO3 , another transcription factor responsible for the synthesis of ATG proteins ( Mammucari et al . 2007 ) . This set of ATG proteins differs from that controlled by TFEB ( Settembre et al . 2011 ) ."
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    ABSTRACT: Amino acids not only participate in intermediary metabolism but also stimulate insulin-mechanistic target of rapamycin (MTOR)-mediated signal transduction which controls the major metabolic pathways. Among these is the pathway of autophagy which takes care of the degradation of long-lived proteins and of the elimination of damaged or functionally redundant organelles. Proper functioning of this process is essential for cell survival. Dysregulation of autophagy has been implicated in the etiology of several pathologies. The history of the studies on the interrelationship between amino acids, MTOR signaling and autophagy is the subject of this review. The mechanisms responsible for the stimulation of MTOR-mediated signaling, and the inhibition of autophagy, by amino acids have been studied intensively in the past but are still not completely clarified. Recent developments in this field are discussed.
    Amino Acids 06/2014; DOI:10.1007/s00726-014-1765-4 · 3.65 Impact Factor
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