The Beclin 1–VPS34 complex – at the crossroads of autophagy and beyond

Funderburk, Sarah F.; Wang, Qing Jun; Yue, Zhenyu

doi:10.1016/j.tcb.2010.03.002

Cited by 683 publications

(626 citation statements)

References 55 publications

(108 reference statements)

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“…1 BCL2, an inhibitory factor in autophagy, binds to the BCL2-binding domain of BECN1 to suppress this complex. 26 In our study, SLC9A3R1 was found to reduce the integration between BECN1 and BCL2 via its interaction with BECN1 (Fig. 4).…”

Section: Discussionsupporting

confidence: 56%

SLC9A3R1 stimulates autophagy via BECN1 stabilization in breast cancer cells

Liu

et al. 2015

Autophagy

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Abbreviations: BCL2, B-cell CLL/lymphoma 2; CHX, cycloheximide; CQ, chloroquine; EGFR, epidermal growth factor receptor; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MTOR, mechanistic target of rapamycin (serine/threonine kinase); PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PIK3C3, phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4, phosphoinositide-3-kinase regulatory subunit 4; PTEN, phosphatase and tensin homolog; SLC9A3R1, solute carrier family 9, subfamily A (NHE3, cation proton antiporter 3), member 3 regulator 1; UB, ubiquitin.Autophagy, a self-catabolic process, has been found to be involved in abrogating the proliferation and metastasis of breast cancer. SLC9A3R1 (solute carrier family 9, subfamily A [NHE3, cation proton antiporter 3], member 3 regulator 1), a multifunctional scaffold protein, is involved in suppressing breast cancer cells proliferation and the SLC9A3R1-related signaling pathway regulates the activation of autophagy processes. However, the precise regulatory mechanism and signaling pathway of SLC9A3R1 in the regulation of autophagy processes in breast cancer cells remains unknown. Here, we report that the stability of BECN1, the major component of the autophagic core lipid kinase complex, is augmented in SLC9A3R1-overexpressing breast cancer MDA-MB-231 cells, subsequently stimulating autophagy by attenuating the interaction between BECN1 and BCL2. Initially, we found that SLC9A3R1 partially stimulated autophagy through the PTEN-PI3K-AKT1 signaling cascade in MDA-MB-231 cells. SLC9A3R1 then attenuated the interaction between BECN1 and BCL2 to stimulate the autophagic core lipid kinase complex. Further findings revealed that SLC9A3R1 bound to BECN1 and subsequently blocked ubiquitin-dependent BECN1 degradation. And the deletion of the C-terminal domain of SLC9A3R1 resulted in significantly reduced binding to BECN1. Moreover, the lack of C-terminal of SLC9A3R1 neither reduced the ubiquitination of BECN1 nor induced autophagy in breast cancer cells. The decrease in BECN1 degradation induced by SLC9A3R1 resulted in the activity of autophagy stimulation in breast cancer cells. These findings indicate that the SLC9A3R1-BECN1 signaling pathway participates in the activation of autophagy processes in breast cancer cells.

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Section: Discussionsupporting

confidence: 56%

SLC9A3R1 stimulates autophagy via BECN1 stabilization in breast cancer cells

Liu

et al. 2015

Autophagy

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“…The stratification can be viewed based on their interaction and stability: PIK3C3-PIK3R4-BECN1, the most stable and prevalent complex, constitutes the core; while ATG14 and UVRAG (UV radiation resistance associated) are combined with the core in PtdIns3K complex I (PtdIns3K-C1; ATG14-containing PtdIns3K complex) and PtdIns3K complex II (PtdIns3K-C2; UVRAG-containing PtdIns3K complex), respectively; 75-78 KIAA0226/Rubicon is a regulatory subunit that is thought to stably bind to UVRAGcontaining complexes; 77,78 AMBRA1, NRBF2 (nuclear receptor binding factor 2) and other accessory factors transiently or unstably interact with either BECN1 (e.g., AMBRA1) 79,80 or ATG14 (e.g., NRBF2), [81][82][83] thus comprising the peripheral components. 84,85 UVRAG also exists in a separate complex excluding ATG14, which holds an important role in the regulation of autophagy at the maturation step. 84,86 Atg14/ATG14 and Vps38/UVRAG are present exclusively in 2 Vps34/PIK3C3 complexes (PtdIns3K complex I and II in yeast, and class III PtdIns3K-C1 and PtdIns3K-C2 in mammalian cells, respectively), which are organized in similar V-shape conformations with Vps15/PIK3R4 at the base.…”

Section: Regulation Of Autophagy By Class III Ptdins3kmentioning

confidence: 99%

“…84,85 UVRAG also exists in a separate complex excluding ATG14, which holds an important role in the regulation of autophagy at the maturation step. 84,86 Atg14/ATG14 and Vps38/UVRAG are present exclusively in 2 Vps34/PIK3C3 complexes (PtdIns3K complex I and II in yeast, and class III PtdIns3K-C1 and PtdIns3K-C2 in mammalian cells, respectively), which are organized in similar V-shape conformations with Vps15/PIK3R4 at the base. 87 In yeast, PtdIns3K complex I and II play a role in autophagy and the vacuolar protein sorting pathway, respectively.…”

Section: Regulation Of Autophagy By Class III Ptdins3kmentioning

confidence: 99%

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

2015

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Abbreviations: 3-MA, 3-methyladenine; AMBRA1, autophagy/Beclin 1 regulator 1; ATG, autophagy related; ATM, ATM serine/threonine kinase; ATR, ATR serine/threonine kinase; BH3, Bcl-2 homology 3; CCD, coiled-coil domain; CDK, cyclin-dependent kinase; CISD2, CDGSH iron sulfur domain 2; class I/II PI3K, class I/II phosphoinositide 3-kinase; class III PtdIns3K, class III phosphatidylinositol 3-kinase; DAPK1, death-associated protein kinase 1; DDR, DNA damage response; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; ER, endoplasmic reticulum; FOXO, forkhead box O; FYCO1, FYVE and coiledcoil domain containing 1; GAP, GTPase-activating protein; HMGB1, high mobility group box 1; HSPA1A, heat shock 70kDa protein 1A; IR, ionizing radiation; MAPK8, mitogen-activated protein kinase 8; MEFs, mouse embryonic fibroblasts; MTMR, myotubularin-related protein; MTOR, mechanistic target of rapamycin (serine/threonine kinase); MTORC1, mechanistic target of rapamycin complex 1; MVBs, spherical multivesicular bodies; NRBF2, nuclear receptor binding factor 2; PAS, phagophore assembly site; PDPK1, 3-phosphoinositide dependent protein kinase 1; PE, phosphatidylethanolamine; PIKFYVE, phosphoinositide kinase, FYVE finger containing; PINK1, PTEN-induced putative kinase 1; PtdIns3K-C1, class III phosphatidylinositol 3-kinase complex I; PtdIns3K-C2, class III phosphatidylinositol 3-kinase complex II; PKB, protein kinase B; PRKA, protein kinase, AMP-activated; PRKD1, protein kinase D1; PRKDC, protein kinase, DNA-activated, catalytic polypeptide; PtdIns5P, phosphatidylinositol 5-phosphate; PtdIns4P, phosphatidylinositol 4-phosphate; PtdIns(4,5)P 2 , phosphatidylinositol 4,5-bisphosphate; PtdIns3P, phosphatidylinositol 3-phosphate; PtdIns(3,5)P 2 , phosphatidylinositol 3,5-bisphosphate; PtdIns(3,4,5)P 3 , phosphatidylinositol 3,4,5-trisphosphate; RHEB, Ras homolog enriched in brain; RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1; SQSTM1, sequestosome 1; TECPR1, tectonin b-propeller repeat containing 1; TFEB, transcription factor EB; TRIM28, tripartite motif containing 28; TSC, tuberous sclerosis; UV, ultraviolet; UVRAG, UV radiation resistance associated; WDFY3, WD repeat and FYVE domain containing 3; WIPI, WD repeat domain, phosphoinositide interacting; ZFYVE1, zinc finger, FYVE domain containing 1.Autophagy is an evolutionarily conserved and exquisitely regulated self-eating cellular process with important biological functions. Phosphatidylinositol 3-kinases (PtdIns3Ks) and phosphoinositide 3-kinases (PI3Ks) are involved in the autophagic process. Here we aim to recapitulate how 3 classes of these lipid kinases differentially regulate autophagy. Generally, activation of the class I PI3K suppresses autophagy, via the well-established PI3K-AKT-MTOR (mechanistic target of rapamycin) complex 1 (MTORC1) pathway. In contrast, the class III PtdIns3K catalytic subunit PIK3C3/Vps34 forms a protein complex with BECN1 and PIK3R4 and produces phosphatidylinositol 3-phosphate (PtdIns3P), which is required for the initiati...

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“…6 This conserved complex consists of vacuolar protein sorting 34 (Vps34; also known as Pik3c3), Atg6/Becn1 (also known as Vps30 in yeast), and the serine-threonine kinase Vps15/ird1 (p150 in mammals; also known as Pik3r4). 7,8 Localized production of PI3P by Vps34 can act to recruit proteins containing PX or FYVE domains to membrane compartments, such as the autophagosome isolation membrane. 9 Vps34 is also required more broadly for several vesicular trafficking processes such as the sorting of hydrolytic enzymes to the yeast vacuole and mammalian lysosome, and endocytic trafficking.…”

mentioning

confidence: 99%

Vps15 is required for stress induced and developmentally triggered autophagy and salivary gland protein secretion in Drosophila

Anding

Baehrecke

2014

Cell Death Differ

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Autophagy is a catabolic process used to deliver cellular material to the lysosome for degradation. The core Vps34/class III phosphatidylinositol 3-kinase (PI3K) complex, consisting of Atg6, Vps15, and Vps34, is highly conserved throughout evolution, critical for recruiting autophagy-related proteins to the preautophagosomal structure and for other vesicular trafficking processes, including vacuolar protein sorting. Atg6 and Vps34 have been well characterized, but the Vps15 kinase remains poorly characterized with most studies focusing on nutrient deprivation-induced autophagy. Here, we investigate the function of Vps15 in different cellular contexts and find that it is necessary for both stress-induced and developmentally programmed autophagy in various tissues in Drosophila melanogaster. Vps15 is required for autophagy that is induced by multiple forms of stress, including nutrient deprivation, hypoxia, and oxidative stress. Furthermore, autophagy that is triggered by physiological stimuli during development in the fat body, intestine, and salivary gland also require the function of Vps15. In addition, we show that Vps15 is necessary for efficient salivary gland protein secretion. These data illustrate the broad importance of Vps15 in multiple forms of autophagy in different animal cells, and also highlight the pleiotropic function of this kinase in multiple vesicle-trafficking pathways. Cell Death and Differentiation ( Autophagy is an evolutionarily conserved process in which cytoplasmic proteins or organelles are packaged into lysosomes for degradation. This process can be initiated by a variety of stimuli, such as high levels of starvation or stress, to provide nutrients to the cells or to clear the cell of damaged organelles or protein aggregates. 1 In some circumstances, autophagy can promote an alternative form of cell death, such as in the clearance of larval tissues in Drosophila melanogaster. 2 As defects in autophagy have been implicated in several physiological and pathological conditions, such as cancer, neurodegenerative diseases, and aging, 3,4 it is important to obtain a complete understanding of the molecular mechanisms controlling autophagy.The induction of autophagy is regulated by the Atg1/Ulk1 complex, and this complex is regulated by mechanistic target of rapamycin (mTOR). 5 Vesicle nucleation is controlled by the class III phosphoinositide 3-kinase (PI3K) complex that generates phosphatidylinositol 3-phosphate (PI3P). 6 This conserved complex consists of vacuolar protein sorting 34 (Vps34; also known as Pik3c3), Atg6/Becn1 (also known as Vps30 in yeast), and the serine-threonine kinase Vps15/ird1 (p150 in mammals; also known as Pik3r4). 7,8 Localized production of PI3P by Vps34 can act to recruit proteins containing PX or FYVE domains to membrane compartments, such as the autophagosome isolation membrane. 9 Vps34 is also required more broadly for several vesicular trafficking processes such as the sorting of hydrolytic enzymes to the yeast vacuole and mammalian lysosome, and endocytic tra...

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The Beclin 1–VPS34 complex – at the crossroads of autophagy and beyond

Cited by 683 publications

References 55 publications

SLC9A3R1 stimulates autophagy via BECN1 stabilization in breast cancer cells

SLC9A3R1 stimulates autophagy via BECN1 stabilization in breast cancer cells

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

Vps15 is required for stress induced and developmentally triggered autophagy and salivary gland protein secretion in Drosophila

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