Dr. Dixon spends approximately 3 weeks each month at the Howard Hughes Medical Institute -- serving as Vice-President and Chief Scientific Officer. One week each month he is at his laboratory at UCSD.


Research Overview

Cells are highly responsive to signals from their environment. These signals include growth factors, neuronal firing, or even the presence of bacteria or pathogens that have invaded the body. The sensing and processing of these signals are carried out by molecular circuits within the cell that detect, amplify, and integrate the signals into a specific response. One of the most widely used cellular responses to environmental signals is to change the phosphorylation state of specific proteins. The level of phosphorylation of a protein is governed by two families of enzymes: protein kinases and protein phosphatases. My laboratory is interested in deciphering the role of protein phosphatases in various cellular paradigms, as phosphatases play key roles in processes such as the development of cancer, axonal pathfinding, and bacterial pathogenesis. Following is a review of some of our findings in the phosphatase area and a brief presentation of our current research interests.

The Dixon lab has 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.

Structure of Protein Tyrosine Phosphatase. Denu, J.M., Stuckey, J.A., Saper, M.A., Dixon, J.E. (1996) Cell 87(3): 361-364

Cover photo: Molecular Diversity of Axon Guidance Receptors. Schmucker, D., Clemens, J.C., Shu, H., Worby, C.A., Xiao, J., Muda, M., Dixon, J.E.,and Zipursky, S.L. (2000) Cell 101(6): 671-684

We have also demonstrated that certain pathogenic bacteria encode proteins with PTPase activity. This is remarkable because bacteria generally do not contain proteins that are phosphorylated on tyrosine. The bacteria that have the PTPases are from the genus Yersinia, which includes the species responsible for plague, or “Black Death”. We demonstrated 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 stimulated our interest in understanding the function of other Yersinia proteins which function in bacterial pathogenesis by disrupting signal transduction pathways. A second recent observation is the identification of a novel protein phosphatase which is associated with the proteosome. The proteosome is known to be phosphorylated, but the function of its phosphorylation is poorly understood. We have also found that this phosphatase regulates proteosome activity both in vitro and in vivo. This opens a completely new area of research in understanding the role of reversible phosphorylation in regulating proteosome function.

Finally, our interest in pathogenesis has lead to the identification of the function of a novel domain found in thousands of proteins. This domain, termed the Fic domain and defined by a core HPFxxxGNGR motif, had no previously-known function. We have now shown that the Fic domain regulates host cell signaling by adenylylation. Fic domains catalyze reversible adenylylation of a conserved tyrosine residue in Rho GTPases. This modification requires the conserved His of the Fic motif and renders the Rho GTPases inactive. We have also shown that the only human protein to contain a Fic domain, huntingtin yeast-interactive protein E (HYPE), adenylylates Rho GTPases in vitro. Thus we have shown that Fic domain-containing proteins are a class of adenylylating enzymes that mediate bacterial pathogenesis as well as a previously unrecognized eukaryotic post-translational modification that may regulate key signaling events (Worby and Mattoo et al., Mol. Cell, 2009). We also sought to understand how Fic domain-containing enzymes function at the molecular level. In order to accomplish this goal we have solved the X-ray structure of an inactive Fic domain complexed with the GTPase substrate in the presence of ATP (Xiao et al., Nature Structural Biology, in press). The structure provides a detailed understanding of the mechanism employed by this novel family of catalysts, which is likely common to all Fic domain-containing proteins. Diagram: Schematic view of the domain composition of all members of the four PTP families. A. Alonso, J. Sasin, N. Bottini, I. Friedberg, A. Osterman, A. Godzik, T. Hunter, J. Dixon, T. Mustelin. (2004) Cell 117 (699-711) We continue to be interested in this family of protein tyrosine phosphatases and recently we have identified most, if not all, of the PTPases in the human genome. There appears to be 107 genes in the human genome that encode members of the PTP families.

Photo: (Top) Effect of Fic domain expression in HeLa cells. (Bottom) Mechanism of Fic mediated adenylylation. Worby and Mattoo et al. (Mol Cell. 2009 Apr 10;34(1):93-103.) Photo: Crystal structure of Fic in complex with its substrate CDC42. Xiao J et al. (Nat Struct Mol Biol. 2010 Aug;17(8):1004-10.)