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Currently the lab is focusing on a stress-induced cell death pathway mediated by a scaffold protein known as POSH (Plenty of SH3s). To date this pathway has been most characterized in neurons, though POSH is expressed at low levels in a wide variety of cell types. Over expression of POSH induces cell death in neurons and other cells via a kinase cascade leading to JNK activation and apoptosis. More physiologically, the POSH apoptotic pathway has been shown to be induced when neurons are starved of growth factors such as NGF.
We are interested in the details of how POSH functions and how POSH is regulated within the cell. We have recently shown that the pro-survival protein kinase Akt can phosphorylate POSH and block its ability to induce apoptosis.
In addition to acting as a scaffold in this stress-induced apoptotic pathway, POSH appears to play another role in unstressed cells as a ubiquitin protein ligase (E3). The ubiquitin ligase activity of POSH was recently found to be required for budding of HIV from infected cells, though POSH E3 enzymatic activity is not required for apoptosis. Although several POSH ubiquitin ligase substrates have been identified, a clear understanding of the cellular role of POSH E3 activity has not yet emerged.
Although our focus is primarily on the role of POSH in apoptotic signaling, we are engaged in a variety of studies of POSH function including in vitro and in vivo studies of POSH ubiquitin ligase activity, and identification of POSH binding proteins in stressed and unstressed cells using both yeast two hybrid and proteomic approaches.