| Activation of the lipid kinase phosphoinositide 3-kinase (PI3K) results in the formation of 3' phosphorylated inositol lipids. These lipids have long been suspected to function as second messengers, since PI3K activity has been shown essential to many cellular processes, including cell cycle control, cell survival and cell metabolism. Together with Dr. Paul Coffer I discovered the serine/threonine protein kinase PKB as a target for PI3K signalling, and this has provided the basis for our current understanding as to how this signalling pathway regulates many of these cellular processes. Regulation of gene expression is one of the main mechanisms whereby a cellular process is regulated, and in this respect we have identified a sub-family of the Forkhead transcription factors as targets in transcriptional control by PI3K and PKB. The importance and variety of PI3K signalling in normal cellular responses is also reflected by the observation that deregulated PI3K signalling is, at least in part, causative to the emergence of many different types of disease, including cancer, diabetes and Alzheimer. Also, the Forkhead family of transcription factors is involved in the regulation of many fundamental biological processes and genetic alterations are responsible for a variety of human diseases. Therefore the understanding of this signal transduction pathway is essential to enable drug target discovery for these diseases. The main objective of this proposal is to further understand the molecular details of this pathway, to create model systems (genetically modified cell lines, transgenic mice etc.) and to further our knowledge on the physiological role of this pathway. Thus the current research proposal aims at understanding the role of the PI3K/PKB/Forkhead pathway in cell cycle control, cell survival and cell metabolism, the mechanism(s) by which these responses are integrated, and the role of deregulated signalling in the evolvement of disease. |
