Phosphatidylinositol 3-Kinase Class III
PI3K Protein Family
Phosphatidylinositol 3-kinase (PI3K) class III (PI3KcIII) is a member of the PI3K protein family of enzymes that are employed in various cellular processes in organisms ranging from plants and fungi to mammals including humans. PI3K proteins work by phosphorylating the inositol cyclic group of phosphatidylinositol (PtdIns), and thus regulating the signalling cascades in, amongst others, cell motility, differentiation and growth [1].
Figure 2. The association of the PI3K class III protein complex.
Discovery, Function, Structure
PI3KcIII was first discovered in yeast (Saccharomyces cerevisiae), as a vacuolar protein sorting protein, vps34. This protein was shown to accommodate protein transport to vacuolar compartments (the yeast-equivalent of lysosomes) for digestion [4].
PI3KcIII, also known as vps34, acts by phosphorylating specifically phosphatidylinositol (PI) from cell membranes into phosphatidylinositol 3-phosphate (PI3P). In order to do this, vps34 must associate with a serine-threonine protein kinase, vps15 in yeast, or the mammalian equivalent, p150 [5]. The PI3KcIII protein complex that is essential for the process of autophagy is formed by the association of vps34, vps15, Atg6 (Beclin-1 in mammals) and Atg14 (or UV-radiation resistance-associated gene protein, UVRAG) [3]. The complex has been showed to be necessary for the initiation of autophagosome creation, and also for the fusing of the autophagosome and lysosome [6], however the exact mechanism in which the phosphorylated product, PI3P accommodates this remains unclear.
As well as its vital role in autophagy, the PI3KcIII complex has kinase and transferase roles in cell division, facilitates membrane traffic activity, and regulates the movement of proteins from the Golgi apparatus to either the vacuole or lysosome, depending on the organism [7]. Vps34 is the catalytic subunit of this protein complex, while vps15 is a regulatory subunit, as it recruits cytoplasmic vps34 to the Golgi complex or the endosome, where the formation of PI3P is needed for protein transport [5]. As vps34 has been found in the majority of species as diverse as Arabidposis plants, yeast, fruit fly, mouse and human, it is assumed that it is vital for protein movement within the cell and has thus been conserved through evolution.
Website
This website draws specific focus to vps34, the catalytic subunit of the PI3KcIII protein complex. The structure, amino acid sequences and all further analysis, therefore, refer to vps34 exclusively.
Autophagy
When cells are deprived of nutrients due to, for example, elevated stress, neurodegenerative problems, cancer formation or other infection, they are likely to initiate a pathway of self-conservation known as autophagy. This is a catabolic cellular process by which the cell essentially digests itself (either entirely or only the excess components) in order to preserve valuable degradation by-products [2].
In mammals, autophagy commences with the formation of an autophagosome double-membrane, which eventually engulfs a nutrient-rich area of the cytosol. Nucleation takes place, initially forming the autophagosome, and then elongates around a portion of the cell to be digested. This novel compartment then fuses to lysosomes; cytoplasmic organelles containing digestive enzymes and toxic elements needed for breakdown. In yeast, vacuole organelles accommodate autophagy in a similar way to lysosomes [3].
References:
1. T., K. 1999. Synergistic activation of a family of phosp... [Chem Phys Lipids. 1999] - PubMed - NCBI. [online] Available at: http://www.ncbi.nlm.nih.gov/pubmed/10358930 [Accessed: 1 Mar 2014].
2. Petkova, D. S., Viret, C. and Faure, M. 2012. IRGM in autophagy and viral infections. Frontiers in immunology, 3.
3. Medical and Biological Laboratories Co., LTD. n.d. What is Autophagy?. [online] Available at: http://ruo.mbl.co.jp/e/product/protein/autophagy/autophagy.html [Accessed: 27 Feb 2014].
4. Herman, P. K., Stack, J. H. and Emr, S. D. 1992. An essential role for a protein and lipid kinase complex in secretory protein sorting. Trends in cell biology, 2 (12), pp. 363-368.
5. Vanhaesebroeck, B. and Waterfield, M. 1999. Signaling by distinct classes of phosphoinositide 3-kinases. Experimental cell research, 253 (1), pp. 239-254.
6. Juhász, G., Hill, J. H., Yan, Y., Sass, M., Baehrecke, E. H., Backer, J. M. and Neufeld, T. P. 2008. The class III PI (3) K Vps34 promotes autophagy and endocytosis but not TOR signaling in Drosophila. The Journal of cell biology, 181 (4), pp. 655-666.
7. Wurmser, A. E., Gary, J. D. and Emr, S. D. 1999. Phosphoinositide 3-kinases and their FYVE domain-containing effectors as regulators of vacuolar/lysosomal membrane trafficking pathways. Journal of Biological Chemistry, 274 (14), pp. 9129-9132.
Figure 3. PI3KcIII complex (circled) role in the autohpagy signalling pathway.
Figure 1. Cellular processes of autophagy. Note PI3KcIII (vps34) complex circled.