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: 33.61). 11/2012; 338(6109):956-959. DOI: 10.1126/science.1225967


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, Oct 08, 2015
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    • "The autophagy protein microtubule-associated protein 1 light chain 3 (LC3) is present in the cytosol in the LC3-I form, until it is modified to a cleaved and lipidated membrane-bound form (LC3-II), which is localized to autophagosomes . Thus, in addition to p62 accumulation, another typical trait of autophagy inhibition consists of increased amounts of the cytosolic non-lipidated form of LC3 (LC3-I) and of total LC3 (Mizushima et al, 2010; Wang et al, 2012). As shown in Fig 1A, KRIT1 deficiency was associated with defective autophagy, displaying increased levels of p62 and total LC3. "
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    ABSTRACT: Cerebral cavernous malformation (CCM) is a major cerebrovascular disease affecting approximately 0.3-0.5% of the population and is characterized by enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhages. Cerebral cavernous malformation is a genetic disease that may arise sporadically or be inherited as an autosomal dominant condition with incomplete penetrance and variable expressivity. Causative loss-of-function mutations have been identified in three genes, KRIT1 (CCM1), CCM2 (MGC4607), and PDCD10 (CCM3), which occur in both sporadic and familial forms. Autophagy is a bulk degradation process that maintains intracellular homeostasis and that plays essential quality control functions within the cell. Indeed, several studies have identified the association between dysregulated autophagy and different human diseases. Here, we show that the ablation of the KRIT1 gene strongly suppresses autophagy, leading to the aberrant accumulation of the autophagy adaptor p62/SQSTM1, defective quality control systems, and increased intracellular stress. KRIT1 loss-of-function activates the mTOR-ULK1 pathway, which is a master regulator of autophagy, and treatment with mTOR inhibitors rescues some of the mole-cular and cellular phenotypes associated with CCM. Insufficient autophagy is also evident in CCM2-silenced human endothelial cells and in both cells and tissues from an endothelial-specific CCM3-knockout mouse model, as well as in human CCM lesions. Furthermore, defective autophagy is highly correlated to endothelial-to-mesenchymal transition, a crucial event that contributes to CCM progression. Taken together, our data point to a key role for defective autophagy in CCM disease pathogenesis, thus providing a novel framework for the development of new pharmacological strategies to prevent or reverse adverse clinical outcomes of CCM lesions.
    EMBO Molecular Medicine 09/2015; DOI:10.15252/emmm.201505316 · 8.67 Impact Factor
    • "Thus, in the presence of normal amounts of growth factors, autophagy is actively suppressed as cells receive adequate nutrient supplies, MTORC1 is activated, and BECN1 repressed. This implies that growth factor deprivation stimulates autophagy by (1) limiting the cellular intake of glucose via GLUT1 and GLUT4 (which results in AMPK-dependent MTORC1 inhibition, see below) (Leto and Saltiel, 2012); (2) unleashing the MTORC1-inhibitory activity of TSC2 (Inoki et al., 2002); and (3) allowing for the derepression of BECN1 (Wang et al., 2012; Wei et al., 2013). G protein-coupled receptor, class C, group 6, member A (GPRC6A), calcium-sensing receptor (CASR), gamma-aminobutyric acid B receptor 1 (GABBR1), heteromeric taste receptors, and various metabotropic glutamate receptors, all of which are activated by one or several amino acids, share the ability to repress autophagy in the presence of their ligands (Wauson et al., 2014). "
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    ABSTRACT: Autophagy constitutes a prominent mechanism through which eukaryotic cells preserve homeostasis in baseline conditions and in response to perturbations of the intracellular or extracellular microenvironment. Autophagic responses can be relatively non-selective or target a specific subcellular compartment. At least in part, this depends on the balance between the availability of autophagic substrates ("offer") and the cellular need of autophagic products or functions for adaptation ("demand"). Irrespective of cargo specificity, adaptive autophagy relies on a panel of sensors that detect potentially dangerous cues and convert them into signals that are ultimately relayed to the autophagic machinery. Here, we summarize the molecular systems through which specific subcellular compartments-including the nucleus, mitochondria, plasma membrane, reticular apparatus, and cytosol-convert homeostatic perturbations into an increased offer of autophagic substrates or an accrued cellular demand for autophagic products or functions. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular cell 08/2015; 59(4):522-539. DOI:10.1016/j.molcel.2015.07.021 · 14.02 Impact Factor
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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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