IPMK is a novel PI3k essential for mTORC2 activation and cell migration

PROJECT SUMMARY IPMK is a novel PI3K crucial for AKT activation and cell migration. Our previous research demonstrated that the loss of IPMK's PI3K activity impairs PDK1's membrane localization, disrupting PDK1-mediated AKT phosphorylation. To achieve complete AKT activation, phosphorylation by mTORC2 is essential. Interestingly, mTORC2 activation relies on PIP3. The essential PI3K responsible for generating PIP3 required for mTORC2 activation remains unidentified. Our investigation is focused on understanding the mechanism behind the activation of mTORC2 by PI3K IPMK. We aim to decipher the impact of IPMK's PI3K activity on mTORC2 activation. We will also explore whether IPMK's PI3K activity affects cell migration by activating mTORC2 or through an independent pathway. Furthermore, we will delve into how IPMK's PI3K activity influences the organization of the actin cytoskeleton, a critical element in the process of cell migration. The following aims will be explored to investigate the hypothesis: “IPMK is a novel PI3k essential for mTORC2 activation and cell migration.” Specific Aim 1: Mechanism of IPMK-Mediated mTORC2 Activation. In this aim, we will elucidate the molecular mechanism underlying IPMK-mediated mTORC2 activation. Specific Aim 2: Impact of Phosphorylation on IPMK's PI3k Activity. We will identify the specific phosphorylation sites in IPMK necessary for its PI3K activity and investigate how phosphorylation-deficient mutants of IPMK affect downstream functions such as AKT activation, mTORC2 activation, and cell migration. Specific Aim 3: Regulation of Cell Migration by IPMK and its PI3K Activity. This aim will assess how IPMK and its PI3K activity influence actin polymerization, a crucial factor in cell migration. Mechanistically, we will determine whether IPMK-mediated cell migration relies on mTORC2 or operates independently. By addressing these specific aims, we aim to shed light on the intricate roles of IPMK's PI3K activity in mTORC2 activation and cell migration, contributing to our understanding of this novel pathway and its potential implications.