Abstract
The occurrence of cancer is often associated with a dysfunction in one of the three central membrane-involution processes—autophagy, endocytosis or cytokinesis. Interestingly, all three pathways are controlled by the same central signaling module: the class III phosphatidylinositol 3-kinase (PI3K-III) complex and its catalytic product, the phosphorylated lipid phosphatidylinositol 3-phosphate (PtdIns3P). The activity of the catalytic subunit of the PI3K-III complex, the lipid-kinase VPS34, requires the presence of the membrane-targeting factor VPS15 as well as the adaptor protein Beclin 1. Furthermore, a growing list of regulatory proteins associates with VPS34 via Beclin 1. These accessory factors define distinct subunit compositions and thereby guide the PI3K-III complex to its different cellular and physiological roles. Here we discuss the regulation of the PI3K-III complex components by ubiquitination and SUMOylation. Especially Beclin 1 has emerged as a highly regulated protein, which can be modified with Lys11-, Lys48- or Lys63-linked polyubiquitin chains catalyzed by distinct E3 ligases from the RING-, HECT-, RBR- or Cullin-type. We also point out other cross-links of these ligases with autophagy in order to discuss how these data might be merged into a general concept.
Highlights
The occurrence of cancer is often associated with a dysfunction in one of the three central membrane-involution processes—autophagy, endocytosis or cytokinesis
This review focuses on phosphatidylinositol 3-phosphate (PtdIns3P), which is mainly generated by the lipid kinase VPS34 through the phosphorylation of PtdIns at the 3-hydoxyl group of the inositol ring (Figure 1A)
The upstream and downstream events in the phosphatidylinositol 3-kinases (PI3Ks)-I centered signaling pathway are in many cases associated with tumorigenesis because it is often found to be upregulated caused by hyperactivated receptor tyrosine kinases (RTKs), loss-of-function mutations in the gene encoding PTEN or presence of oncogenic forms of the small GTPase RAS [9,10,11]
Summary
The phosphorylated derivatives of phosphatidylinositol (PtdIns) are called phosphoinositides and are regarded as important signaling molecules. The class C Vps—bound UVRAG complex enhances endosome-endosome fusion events, resulting in rapid degradation of endocytic cargo [59] It regulates the trafficking of the essential autophagy factor Atg9 [60]. It is important to note, that USP10 has been identified as a deubiquitinating enzyme for p53 [95], especially as the interaction of p53 and Beclin 1 has been suggested to regulate the cellular decision on the induction of apoptosis or, alternatively, autophagy in embryonal carcinoma cells [96] These potential functional links between the RALB-EXO84-ULK1-assembly, as well as USP10, p53 and VPS34-Beclin 1—complexes strongly suggests the existence of a regulatory network that governs the dynamic interplay of these different signaling hubs
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