Targeting autophagy in breast cancer

Figure 2 Beclin 1, its protein interactions and its role in autophagy. Beclin 1 has been found to form part of different class III phosphatidylinositol 3-kinase (PI3K) complexes. Each complex consists of beclin 1, Vps34, Vps15 and Ambra1. ATG14L activates the complex and induces the formation of autophagosomes. UVRAG and ATG14L are present in mutually exclusive class III PI3K complexes and UVRAG and Bif-1 have been shown to activate the complex. UVRAG has also been shown to function in autophagosome maturation and endocytic trafficking possibly independent from its interaction with beclin 1. Rubicon has also been shown to bind beclin 1 and can inhibit autophagosome formation and maturation. TAB1/2, two upstream activators of the TAK1-IKK signaling pathway interact with beclin 1 and their dissociation seems to be necessary for autophagy induction. GAPR-1 can also bind beclin 1 and inhibit autophagy probably through beclin 1 tethering in the Golgi apparatus. Bcl-2/Bcl-XL can bind beclin 1 and inhibit autophagy. JNK1 phosphorylates Bcl-2 while DAPK phosphorylates beclin 1 and disrupt their interaction. Additionally, BH3-only proteins (tBid, Bad, BNIP3) or BH3 mimetics (ABT737) bind Bcl-2 and release beclin 1. Beclin 1 has also been found to be a substrate of caspases-3, 7 and 8 during apoptosis, in which cleavage of beclin 1 suppresses autophagy. Other beclin 1 interacting proteins that induce autophagy are PINK1 and VMP1. TRAF6 and USP13 have been shown to regulate beclin 1 ubiquitination. Survivin, an anti-apoptotic protein can also bind beclin 1 and regulate TRAIL induced apoptosis. NAF-1, a component of the IP3 receptor complex contributes to the interaction of Bcl-2 with beclin 1 at the ER[32,99-104]. Proteins and drugs shown are color-coded according to their effect on autophagy. Red: Inhibits autophagy; Green: Induces autophagy; Yellow: Unknown.