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 a major brake to cell survival signaling, protein kinase C (PKC), and its negative regulator, the PH domain Leucine-rich repeat Protein Phosphatase (PHLPP). 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. In 2015 we reversed a major paradigm by showing that PKC generally suppresses, rather than enhances, oncogenic signaling. This proposal aims to 1] understand the downstream substrates and molecular mechanisms by which PKC isozymes brake oncogenic signaling and 2] establish ways to restore PKC in cancer. Furthermore, we aim to understand the regulatory mechanisms of its negative regulator, PHLPP, which we discovered in a targeted search for a phosphatase that would dephosphorylate a conserved site on PKC and related kinases such as Akt. PHLPP functions both as a tumor suppressor and as an oncogene and whereas much is known about its substrates, downstream signaling pathways, and function, comparatively little is known about its own regulatory mechanisms. This proposal aims to understand the structure and regulatory mechanisms of PHLPP in order to inhibit target-specific roles of PHLPP, especially as a way to restore PKC. The overarching challenge of the proposed research is to fill gaps in our knowledge of the molecular mechanisms governing the regulation of, and signaling by, PKC and PHLPP in order to leverage this understanding to develop effective therapies when these mechanisms are disrupted in disease.