Targeting autophagy in breast cancer

Table 1 Some autophagy-related proteins and other proteins implicated in autophagy mentioned in the text and their autophagy-independent functions

Protein	Role in autophagy	Autophagy-independent roles
ULK1/2	Protein kinase involved in autophagy induction and phagophore biogenesis[105]
Atg2	Interacts with Atg18, possibly involved in phagophore biogenesis[105].	Regulation of lipid droplet morphology and dispersion[106]
Atg3	E2-like enzyme for Atg8/LC3 ubiquitin-like conjugation system. Involved in phagophore expansion[105]	Atg12-Atg3 complex formation does not affect starvation-induced autophagy, increases mitochondrial mass and inhibits cell death mediated by mitochondrial pathways[107]
Atg4	Cysteine protease involved in Atg8/LC3 processing (removal of amino acid residues to expose the C-terminal glycine for lipidation) and in lipid removal from Atg8/LC3-PE (lipidated LC3 or LC3II). Involved in phagophore expansion[105]
Atg5	Atg12-Atg5 conjugation system, involved in phagophore expansion[105]	Its expression increases during DNA damage induced by chemotherapy. It induces cell cycle arrest and mitotic catastrophe[108]
Atg6/beclin 1	Component of the class III PI3K complex, involved in the induction of autophagy and phagophore biogenesis[105]	Interacts with Bcl-2 family proteins. Regulates the stability of USP10 and USP13 thus controlling p53 levels[32]
Atg7	E1 (ubiquitin-activating)-like enzyme for the two ubiquitin-like conjugation systems (Atg12-Atg5 and Atg8/LC3)[105]	Binds p53 and regulates cell cycle arrest upon metabolic stress[109]
Atg8/LC3	Ubiquitin-like protein that is conjugated to PE. It is involved in cargo recruitment into, biogenesis of autophagosomes and phagophore expansion[105]
Atg9	Transmembrane protein that may act as lipid carrier for phagophore expansion[105]
Atg10	E2 (ubiquitin-conjugating)-like enzyme for the Atg12-Atg5 ubiquitin-like conjugation system[105]
Atg12	Ubiquitin-like protein that gets covalently linked to Atg5 in the Atg12-Atg5 conjugation system. Involved in phagophore expansion[105]	Atg12-Atg3 complex formation does not affect starvation-induced autophagy, increases mitochondrial mass and inhibits cell death mediated by mitochondrial pathways[107]
Atg13	Binding partner and regulator of ULK1/2, involved in induction of autophagy and phagophore biogenesis[105]
Atg14/ATG14L	Component of the class III PI3K complex, involved in induction of autophagy and phagophore biogenesis[105]
Atg16	Associates with Atg12-Atg5 and acts as an E3 ligase to direct LC3 lipidation, involved in phagophore expansion[105]
Atg17/FIP200	Binding partner and regulator of ULK1/2 involved in induction of autophagy and phagophore biogenesis[105]
Atg18/WIPIs	PI3P-binding proteins possibly involved in phagophore biogenesis[105]	Retrograde transport from the vacuole to the Golgi complex. Regulation of PI(3,5)P2 synthesis[105]
mTORC1	Serine/threonine kinase rapamycin-sensitive complex, main down-regulator of autophagy that responds to growth factor and nutrient availability[105]	Regulates cell growth (accumulation of cell mass) through coordination of protein anabolism, nucleotide biosynthesis, lipogenesis, glycolysis and autophagy[110]
Vps34	Class III PI3K, produces PI3P and allows recruitment of PI3P-binding proteins WIPI1/2 and of the two ubiquitin-like conjugation systems[105]	Regulation of vesicular trafficking in the endosomal/lysosomal system. Regulates signaling by recruiting proteins that bind PI3P[111]
Vps15	Regulatory kinase subunit of the class III PI3K[105]
p62	Selective substrate of autophagy that functions as an adaptor protein that links ubiquitinated proteins to LC3[105]	Serves as a scaffold to promote NFκB signaling in TNFR, IL-1βR or NGFR signaling by binding RIP1 or TRAF6. Can bind caspase-8 and stimulate apoptosis. Binds mTORC1 and Rag GTPases on the lysosomal surface to signal amino acid availability[112]. Activates transcription factor Nrf2, which drives expression of antioxidant and detoxifying enzymes by competitively binding to Keap1, its ubiquitin ligase[113]
NBR1	(Neighbor of BRCA1 gene 1), selective substrate of autophagy with structural similarity to p62[105]	Negatively regulates receptor tyrosine kinase endocytic traffic[114]
AMPK	(AMP-activated protein kinase), a sensor of energy that is activated by an increase in the AMP/ATP ratio[105,115]	AMPK regulates metabolism, decreases energy expenditure, mediates cell cycle checkpoints, inhibits pro-survival growth pathways and modulates mitotic progression[115]
Bcl-2/Bcl-XL	Members of the Bcl-2 family of proteins that inhibit macroautophagy (by binding beclin 1) and pro-apoptotic BH3-only proteins[105]	Antiapoptotic proteins that inhibit pro-apoptotic BH3-only proteins (BNIP3, Bad, Bik, Noxa, Puma and BimEL)[105]
Survivin	Interacts with beclin-1[103]	Member of the Inhibitor of Apoptosis (IAP) family of proteins that inhibits caspases. It is also involved in chromosome segregation during cell division[116]
PINK1	(PTEN-induced kinase 1/PARK6), mitochondrial protein that spans the outer mitochondrial membrane upon mitochondrial depolarization, recruiting Parkin to facilitate mitophagy[105]	Mitochondrial protein (mutated in some forms of Parkinson disease) that is processed in a membrane potential-dependent manner to maintain mitochondrial function[105]
VMP1	(vacuole membrane protein 1), localizes to the plasma membrane of the ER. Interacts with beclin 1 and is required for autophagy[105]	Required for protein secretion and Golgi organization, regulates cell proliferation, anchorage-independent growth and secretory membrane transport. It is a component of initial cell-cell contacts and tight junctions[117]
DAPK	Death associated protein kinase, it phosphorylates beclin 1 to activate autophagy by causing dissociation from Bcl-2[105]	Regulates cell death, inhibits cell motility and adhesion, promotes membrane blebbing and stress fiber formation[118]
Bif-1	Bax-interacting factor 1)/endophilin B1, protein that interacts with beclin 1 via UVRAG and is required for macroautophagy[105]. It has membrane curvature-inducing activity, indicating that it may play a role in biogenesis of isolation membranes[119].	Involved in mitochondrial fission and coat protein complex I (COPI)-vesicle formation[119]. Regulates receptor degradation and cytokinesis when present in a class III PI3K subcomplex containing Vps15, Vps34, beclin 1 and UVRAG[120]
UVRAG	UV irradiation resistance-associated gene, component of the class III PI3K complex that activates autophagy. It disrupts beclin 1 dimers and forms a heterodimer that activates autophagy. It binds Bif-1 to activate class III PI3K and competes with Atg14L for binding to beclin 1, directing class III PI3K to function in the maturation step of autophagy[105]	Regulates receptor degradation and cytokinesis when present in a class III PI3K subcomplex containing Vps15, Vps34, beclin 1 and Bif-1[120]. Regulates coat protein complex I (COPI)-vesicle tethering in the ER[121]
Ambra1	Activating molecule in beclin 1-regulated autophagy, binds beclin 1 and positively regulates autophagy[105]. Regulates ULK1 stability and kinase activity and is phosphorylated and inactivated by mTOR, inhibiting its action on ULK1[122]. Also, changes in its subcellular localization are important during autophagosome formation[123]
HMGB1	High mobility group box 1, a chromatin-associated nuclear protein that translocates to the cytoplasm in response to stress. Binds to beclin 1, displacing Bcl-2 and promoting autophagy. Autophagy also promotes the release of HMGB1 from the nucleus and the cell which further induces autophagy[105]	In the nucleus it is a DNA chaperone, sustains nucleosome dynamics and chromosome stability, modulates gene transcription, recombination and participates in DNA repair and telomere maintenance. It regulates mitochondrial function and when secreted regulates inflammation, immunity, migration, proliferation, metabolism and apoptosis[124]
NAF-1	Nutrient-deprivation autophagy factor-1, integral membrane component of the IP3 receptor complex. It binds Bcl-2 at the ER and is required for Bcl-2 to bind beclin 1, resulting in the inhibition of autophagy[105]	Required for Bcl-2 dependent regulation of the IP3 channel at the ER and regulates Ca2+ homeostasis[125]