Membranes are sites of intense signaling activity in eukaryotic cells. Essential processes such as autophagy, cytokinesis, exo- and endo- cytosis, and cytoskeletal remodeling depend on signal propagation at cellular membranes. Dysregulation of signal transduction at these sites is the cause of a number of hereditary and non-hereditary diseases, including Coffin-Lowry syndrome, spinocerebellar ataxia, myotonic dystrophy, and various cancers. Over 500 kinases and 130 phosphatases regulate signal transduction by phosphorylating or dephosphorylating their target proteins. Of the more than 500 kinases, 54 contain known lipid-binding or membrane-interacting domains, and whilst much is known about how these proteins are targeted to cellular membranes, very little is known about how membrane engagement is coupled to signal transduction. We are using a spectrum of biophysical (including X-ray crystallography), biochemical, and cell biological techniques to address two questions central to signal transduction at membranes.

One of the most important consequences of the activation of cell surface receptors is the generation of small molecule second messengers. In addition to the freely diffusible second messengers such as cAMP and inositol triphosphate (IP₃), a number of cellular second messengers are lipids. Despite being of fundamental importance to the exquisite spatial and temporal regulation of many cellular processes, the molecular mechanisms of lipid-mediated signal transduction are not well understood. Our goal is to understand how lipid second messengers can turn on signaling pathways at the membrane. Many of the lipid responsive human protein kinases belong to the AGC family of kinases, of which the paradigmatic lipid-regulated kinase is protein kinase C (PKC). We would like to understand how lipid-engagement by these protein kinases is coupled to their activation at the molecular level. Ultimately, we hope to elucidate common principles of the molecular mechanisms that govern lipid-mediated signal transduction.

The second question relates to how signal transduction pathways are organized. Scaffolding of signaling proteins in the same pathway enhances specificity, promotes signal amplification by reducing noise, and, ultimately, improves signal propagation through the pathway. Membranes act as the scaffolds for many signaling reactions, including those involved in visual signaling in Drosophila and those involved in regulating cellular growth processes. Our studies are aimed at understanding how diverse signals are integrated, how substrate specificity is encoded not just at the kinase level, and the influence of the membrane environment on multi-component signaling hubs. This is an exciting area of research with frontiers in ageing, cancer, metabolic diseases such as diabetes, and obesity.

We are focused on signaling by the mammalian target of rapamycin (mTOR) pathway, which regulates growth processes, including PKC signaling, from yeast to mammals. The mTOR kinase is particularly interesting because it forms two antagonistic complexes with distinct substrate profiles in the same cell.