Molecular Mechanisms of Cell Signaling

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Summary/Abstract The overall vision of our research is to gain a comprehensive understanding of the molecular mechanisms driving the function of two major brakes to cell survival signaling, protein kinas C (PKC) and the PH domain Leucine-rich repeat Protein Phosphatase (PHLPP, pronounced `flip'). The PKC family has been intensely investigated in the context of cancer since the discovery in the early 1980s that it is a receptor for the tumor-promoting phorbol esters. This led to the dogma that activation of PKC by phorbol esters promotes carcinogen- induced tumorigenesis. Nonetheless, PKC has been an elusive chemotherapeutic target despite decades of research. We recently established that, contrary to conventional thinking, PKC is a tumor suppressor, not an oncogene, thus explaining why 30+ years of clinical trials with PKC inhibitors have not only failed but, in some cases, worsened patient outcome. We are now challenged with understanding the molecular mechanisms by which PKC isozymes, generally, serve as the brakes to oncogenic signaling. Our work on PKC led to the discovery of PHLPP, a phosphatase that, by different mechanisms, also brakes oncogenic signaling but about which considerably less is known regarding its structure, function, and regulation. We aim to tackle key gaps in our understanding of the molecular mechanisms that control the amount, activity, and location of PHLPP in the cell. Uncovering the molecular details of how PKC and PHLPP control cell signaling will pave the way for novel therapies.