Fig. 3.

Signaling machinery upstream and downstream of the PtdIns3K class III complex. The PtdIns3K class III core complex consists of the catalytic subunit VPS34, the adaptor VPS15 (p150), and Beclin 1 (ATG6). Beclin 1 binds to additional regulatory proteins, including ATG14, NRBF2, UBRAG, Rubicon, AMBRA1, BCL2, and several others (reviewed in [172–175]). Furthermore, there exists considerable crosstalk between the ULK1-complex and the PtdIns3K class III complex (for details see “The PtdIns3K class III complex”). ULK1 phosphorylates Beclin 1, AMBRA1, and VPS34. In turn, AMBRA1 regulates ULK1 stability and activation. Next to ULK1 itself, several ULK1-regulating kinases—such as mTORC1, AMPK, and AKT—also regulate the PtdIns3K class III complex. The product of the PtdIns3K class III catalytic activity is phosphatidylinositol 3-phosphate (PtdIns3P) (red circles). PtdIns3P then recruits the downstream effectors DFCP1 and proteins of the WIPI-family. For simplicity, the mutually exclusive interactions of ATG14 or UVRAG with Beclin 1 are shown within one complex