THE NOVEL PRESENCE AND ROLE OF INOSITOL POLYPHOSPHATE 4-PHOSPHATASE TYPE I IN THE NUCLEUS AND EXTRACELLULAR MILIEU

Abstract

Phosphoinositides are phospholipids bearing phosphorylated inositol rings. They are small lipid secondary messengers which together, through their synchronized consortium, bring about complex intracellular cascades which are involved in the regulation of cell metabolism, endocytosis & exocytosis, membrane trafficking, cytoskeleton re-arrangements, nuclear events, cell proliferation & differentiation. The regulators of phosphoinositides i.e. Kinases and phosphatases can transform Phosphatidylinositol by phosphorylating or de-phosphorylating it at three positions 3’, 4’ & 5’-OH in an alternate manner and can produce seven different species of phosphoinositides. Every phosphoinositides & its specific regulator have a definitive organelle to which they localize and are involved in maintaining distinct roles in various intracellular cascades. Phosphoinositides are known to impart organelle identity. Hence, their location is in co-ordination with their role. PI3Kinase signalling pathway is one pathway involving various phosphoinositides and their kinases and phosphatases, all mediating a cascade regulating diverse cellular functions including metabolism, growth, proliferation, survival, transcription and protein synthesis. The key mediators of this pathway are PI3kinase, AKT, PDK1, INPP5, INPP4A/INPP4B, and PTEN. This pathway is the most mutated pathway associated with cancer pathogenesis. Many key mediators (i.e. some classes of PI3kinase, PTEN, AKT and PDK1) and phosphoinositides (i.e. PtdIns(3,4,5)P3, PtdIns(3,4)P2 ) involved in PI3K signalling pathway have already been found in the nucleus and their dynamic presence in nucleus has been 2 associated with the regulation of cell’s proliferation and differentiation. PTEN which is emerging as a cellular regulator with multiple functions has already been found in cytoplasm, nucleus and secreted out of the cells classically and in nano-sized vesicles called exosomes. Its role as a tumour suppressor and its significance in maintaining cell proliferation and differentiation at all the locations has been validated. In this thesis, another key mediator of PI3K pathway, which also plays a crucial role in endosomes/phagosomes formation and neurological pathologies i.e. INPP4A has been reported for the first time to be present inside the nucleus as well as in the cell’s extracellular milieu. Nuclear INPP4A was found to have a higher molecular weight than its cytoplasmic counterpart. Overexpression studies revealed an inhibitory role of nuclear INPP4A on cell’s proliferation rate. The translocation of INPP4A in the nucleus increases on serum starvation and its presence in nucleus is highest in G0/G1 phase. The secreted INPP4A is glycosylated and is secreted via non-classical pathway of secretion. These findings are novel and will likely have implications in tumor biology.