Ubiquitination and phosphorylation of Beclin 1 and its binding partners: Tuning class III phosphatidylinositol 3-kinase activity and tumor suppression.
The class III phosphatidylinositol 3-kinase (PI3K-III) complex and its phosphorylated lipid product phosphatidylinositol 3-phosphate (PtdIns3P) control the three topologically related membrane-involution processes autophagy, endocytosis, and cytokinesis. The activity of the catalytic unit of PI3K-III complex, the Vacuolar sorting protein 34 (VPS34), depends on the membrane targeting unit Vacuolar sorting protein 15 (VPS15), and the tumor suppressor protein Beclin 1. It is established that the overall activity of VPS34 is positively regulated by Beclin 1, whose positive influence is further controlled through the association with a set of Beclin1 interacting components, which stimulate or inhibit VPS34. The interaction between Beclin 1 and Beclin 1-associated components are controllable and is regulated by phosphorylation in a context-dependent manner. Here, we focus on an emerging concept whereby the activity of the PI3K-III complex is controlled by ubiquitination of Beclin 1 or Beclin 1-associated molecules. In summary, at least three different ubiquitin ligases can affect the positive regulatory function of Beclin 1 towards VPS34, suggesting that ubiquitination is an important and physiologically relevant event in tuning the tumor suppressor function of Beclin 1.
Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, 0310 Oslo, Norway. hilde.abrahamsen@rr-research.no
Hilde
H
Abrahamsen
Harald
H
Stenmark
Harald W
HW
Platta
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000071186:Beclin-1; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation; D054875:Ubiquitination
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D058546:Class III Phosphatidylinositol 3-Kinases; D058539:Phosphatidylinositol 3-Kinase