Enzymology of PIP lipid modifying enzymes
PIP lipids control cellular organization
The ability of cells to regulate the localization of molecules in both time and space is a hallmark of cellular organization. In the case of polarized cell migration, cell surface receptors relay signals across the plasma membrane to spatially control the activation of signaling molecules, including phosphatidylinositol phosphate (PIP) lipid kinases and phosphatases. Depending on the nature of the signal, cells can generate transient, polarized, or oscillatory patterns in PIP lipid phosphorylation reactions. Since PIP lipids function as master regulators of signal transduction, misregulation of PIP lipid kinases and phosphatases can negatively impact cellular homeostasis, morphogenesis, and differentiation.
Despite the importance of PIP lipid kinases and phosphatases in biology, many questions remain unanswered regarding their function in cells. What regulates the strength and duration of PIP lipid phosphorylation reactions on intracellular membranes? How are micron length scale asymmetries in PIP lipid composition established and maintained by opposing lipid kinases and phosphatases? To answer these questions, I’m building an interdisciplinary team of researchers that leverage biochemistry, quantitative cell biology, material science, and theoretical approaches to define the molecular mechanisms of membrane signaling events. We have established methods to characterize the enzymology of PIP lipid kinases and phosphatases with single molecule resolution both in vitro and in living cells. Learning molecular details about individual proteins is the first step towards understanding complex emergent properties, such as signal adaptation and spatial pattern formation. Overall, we want to understanding of how membrane signaling reactions are orchestrated in cells and how these processes are perturbed in human disease.
PIP lipid modifying enzymes
We are currently trying to understand how signaling events that occur upstream and downstream of phosphatidylinositol phosphate-5-kinase (PIP5K) and phosphoinositide 3-kinase (PI3K) activation and down-regulation (i.e. signaling adaptation). These lipid kinases function in redundant and overlapping signaling pathways that are difficult to biochemically understand using traditional genetic and cell biological approaches. For this reason, we take a reductionist approach to biochemically reconstitute minimal sets of signaling molecules that control this complex signaling pathway. Below are some of the tools we use to biochemically reconstitute membrane proximal signaling events.