Affiliation: UCSD SOM
Professor of Pharmacology, Cellular $ Molecular Medicine, and Chemistry & Biochemistry
B.A., University of California, Los Angeles
Ph.D., University of California, Santa Barbara
Postdoc, University of California, San Diego
Cells are highly responsive to signals from their environment. These signals include growth factors, neuronal firing, or even the presence of a bacteria or pathogen that has invaded the body. The sensing and processing of these signals are carried out by molecular circuits within the cell which detect, amplify and integrate these signals into a specific response. One of the most widely utilized cellular responses to environmental signals is to change the phosphorylation strategy of specific proteins. The level of protein phosphorylation is controlled by two families of enzymes known as protein kinases and phosphatases. My laboratory is interested in deciphering the role of the phosphatases in various cellular paradigms, as phosphatases play key roles in the ontogeny of cancer as well as the processes of axonal pathfinding and bacterial pathogenesis. Because we have studied the function of protein phosphatases in some detail, I will review some of our findings in this area and briefly outline our current research interests.
We have cloned, expressed and characterized a number of Protein Tyrosine Phosphatases (PTPases) showing that this entire family of enzymes proceeds via a unique phosphoenzyme intermediate. Our laboratory also identified the first dual specific phosphatase which dephosphorylates Ser/Thr as well as Tyr phosphoproteins. This family now includes major regulators of growth cycle such as p80cdc25 as well as phosphatases which regulate the mitogen-activated protein kinase pathway. In collaboration with Mark Saper, we have determined the X-ray structure of a PTPase and a dual specific phosphatase. Several projects in the laboratory focus on further defining the structures and functions of PTPases.
Because PTPases can potentially reverse the action of oncogenes such as v-src, several research projects currently under investigation in the laboratory focus on the anti-transformation activity of the phosphatases and their role in cancer. We have demonstrated that a tumor suppressor gene known as PTEN, which has sequence identity to the PTPases, specifically dephosphorylates phosphatidylinositol 3,4,5-triphosphate. This was the first reported example of a PTPase which functions to dephosphorylate a lipid second messenger and it also established the biological function of PTEN. Understanding the function of PTEN also provides a rationale for why the loss of this gene plays a key role in oncogenesis.
PTPases have recently been shown to play critical roles in guiding neuronal axons to specific targets. Thus far these phosphatases all belong to the receptor-like subfamily of PTPases. Our work has identified an interaction between a non-receptor PTPase and an adaptor protein which is critical for axonal guidance in Drosophila. Interestingly, this adaptor protein, called Dock, also interacts with a number of proteins involved in rearrangements of the actin cytoskeleton. We are currently identifying additional Dock associated proteins and determining how they participate in the transmission of guidance signals. Our studies may provide a direct link between the acquisition of guidance signals and directed axonal growth.
We have demonstrated that certain pathogenic bacteria also have PTPase activity. This is remarkable because bacteria are not thought to contain any proteins that are phosphorylated on tyrosine. The bacteria that have the tyrosine phosphatase activity are from the genus Yersinia. This genus of bacteria is responsible for the plague (or "Black Death"), and we have shown that the PTPase is essential for Yersinia pathogenesis. We have been able to demonstrate that the Yersinia PTPase can enter a macrophage and inhibit cellular processes essential for antigen presentation, thus disarming the body's immune response to the pathogen. This finding has stimulated our interest in attempting to understand the function of other Yersinia proteins which function in bacterial pathogenesis by disrupting eukaryotic signal transduction pathways in both plants and animal hosts. These projects utilize biochemical methods, protein-protein interactions, molecular genetics, bioinformatics and function genomics to determine the mechanisms by which these Yersinia virulence proteins inhibit key functions of the immune system to prevent detection and destruction of the invading bacteria.
References From PubMed (NCBI)