Negative Regulation of Vps34 by Cdk Mediated Phosphorylation

SummaryVacuolar protein sorting 34 (Vps34) complexes, the class III PtdIns3 kinase, specifically phosphorylate the D3 position of PtdIns to produce PtdIns3P. Vps34 is involved in the control of multiple key intracellular membrane trafficking pathways including endocytic sorting and autophagy. In mammalian cells, Vps34 interacts with Beclin 1, an ortholog of Atg6 in yeast, to regulate the production of PtdIns3P and autophagy. We show that Vps34 is phosphorylated on Thr159 by Cdk1, which negatively regulates its interaction with Beclin 1 during mitosis. Cdk5/p25, a neuronal Cdk shown to play a role in Alzheimer's disease, can also phosphorylate Thr159 of Vps34. Phosphorylation of Vps34 on Thr159 inhibits its interaction with Beclin 1. We propose that phosphorylation of Thr159 in Vps34 is a key regulatory mechanism that controls the class III PtdIns3 kinase activity in cell-cycle progression, development, and human diseases including neurodegeneration and cancers.

Graphical AbstractFigure optionsDownload high-quality image (170 K)Download as PowerPoint slideHighlights▸ Vps34 is phosphorylated by Cdk1 during mitosis and upon Cdk5 activation ▸ Phosphorylation of Vps34 by Cdks leads to inhibition of its lipid kinase activity ▸ Phosphorylation of T159 on Vps34 interferes its binding with Beclin 1, and T159A Vps34 mutant is hyperactive in its lipid kinase activity ▸ T668 of Vps34 is required for its lipid kinase activity