Article

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

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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    • "Atg9 serves as an important adapter molecule that recruits membranes and lipids to expand the isolation membrane (Mari et al., 2010; Orsi et al., 2012; Yamamoto et al., 2012). At a regulatory level, phosphorylation of beclin 1 by Akt inhibits autophagy (Wang et al., 2012b), while phosphorylation at a different residue by AMPK or ULK1 promotes its integration into the beclin 1-Atg14L-VPS34 kinase complex and initiates autophagy (Kim et al., 2013; Russell et al., 2013). Likewise, phosphorylation of Atg9 by ULK1 is required for the efficient recruitment of additional factors to the formation site and subsequent expansion of the isolation membrane (Papinski et al., 2014). "
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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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    • "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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