Gary Thomas, Ph.D.

Background

Gary Thomas received his Ph.D. in Biochemistry from the Biozentrum at the University of Basel, Switzerland, in 1984 after earning his B.S. at Boise State University. He did his postdoctoral fellowship at the University of Oregon and at the Vollum Institute. Thomas has been a faculty member in the Vollum since 1987 and was promoted to senior scientist in 1999. He is also a professor of Cell and Developmental Biology in the School of Medicine.

Summary of Current Research

Mammalian cells represent highly dynamic and adaptable information processing centers. They receive and integrate messages from neighboring or distant cells and interpret these signals to effect responses ranging from the control of organ homeostasis to the regulation of cellular proliferation and differentiation or to executing cell death. These manifold responses rely on the ability of the membrane trafficking machinery to sort and localize a diverse complement of proteins, lipids and various small molecules.

To accommodate the communication between the secretory and endocytic pathways with mitochondria to maintain organ homeostasis, mammalian cells have evolved elaborate membrane sorting systems and employ trafficking proteins not found in lower eukaryotes. The Thomas lab discovered one family of mammalian trafficking proteins—the phosphofurin acidic cluster sorting (PACS) proteins—which combine to integrate secretory pathway traffic with ER-mitochondria communication and the regulation of apoptotic programs. In addition, expression of the PACS genes are misregulated in diseases ranging from polycystic kidney disease to cancer, and the PACS proteins are also targeted by pathogenic viruses to mediate processes ranging from virus assembly to receptor downregulation and immunoevasion.

Current projects in our lab are to determine 1) how PACS-1 and PACS-2 combine to regulate the localization of polycystin-2 between the endoplasmic reticulum and the cell surface, thereby regulating the compartmental activity of the calcium channel; 2) the structural basis for the control of cargo binding of the PACS proteins by the reversible phosphorylation of an autoregulatory domain; 3) how the survival kinase Akt/PKB collaborates with 14-3-3 proteins to regulate the apoptotic activity of PACS-2 and how this pathway is disrupted in colorectal cancer; 4) how HIV-1 misregulates the PACS-1 and PACS-2 sorting pathways to evade immune surveillance; and 5) the in vivo roles of the PACS proteins in regulating organ homeostasis and apoptosis and how these sorting proteins enable HIV-1 Nef to cause AIDS-like disease.

Selected Publications

Aslan, J.E., You, H., Williamson, D.M., Endig, J., Youker, R.T., Thomas, L., Shu, H., Du, Y., Milewski, R.L., Brush, M.B., Possemato, A., Sprott, K., Fu, H., Greis, K.D., Runckel, D.N., Vogel, A., and Thomas, G (2009) Akt and14-3-3 control a PACS-2 homeostatic switch that integrates membrane traffic with TRAIL-induced apoptosis. Mol. Cell 34:497-509. PMID:19481529

You, H. and Thomas, G. (2009) A homeostatic switch in PACS-2 links membrane traffic to TRAIL-induced apoptosis. Cell Cycle 8:2679-2680. PMID:19690460

Youker, R.T., Shinde, U., Day, R., and Thomas, G. (2009) At the crossroads of homeostasis and disease: Roles of the PACS proteins in membrane traffic and apoptosis. Biochem. J. 421:1-15. PMID:19505291

Aslan, J.E. and Thomas, G. (2009) Death by committee: Organellar trafficking and communication in apoptosis Traffic 10:1390-1404. PMID:19566895

Jenkins, P.M., Zhang, L., Thomas, G., and Martens, J.R. (2009) PACS-1 mediates phosphorylation-dependent ciliary trafficking of the cyclic-nucleotide-gated channel in olfactory sensory neurons. J. Neurosci. 29:10541-10551. PMID:19710307

Atkins, K.M., Thomas, L., Youker, R.T., Harriff, M.J., Pissani, F., You, H., and Thomas, G. (2008) HIV-1 Nef binds PACS-2 to assemble a multikinase cascade that triggers major histocompatibility complex class I (MHC-I) downregulation: analysis using short interfering RNA and knock-out mice. J. Biol. Chem. 283:11772-11784. PMID:18296443

Hung, C.H., Thomas, L., Ruby, C.E., Atkins, K.M., Morris, N.P., Knight, Z.A., Scholz, I., Barklis, E., Weinberg, A.D., Shokat, K.M., and Thomas, G. (2007) HIV-1 Nef assembles a Src family kinase-ZAP-70/Syk-PI3K cascade to downregulate cell-surface MHC-I. Cell Host Microbe 1:121-133. PMID:18005690

Jiao, G.S., Cregar, L., Wang, J., Millis, S.Z., Tang, C., O’Malley, S., Johnson, A.T., Sareth, S., Larson, J., and Thomas, G. (2006) Synthetic small molecule furin inhibitors derived from 2,5-dideoxystreptamine. Proc. Natl. Acad. Sci. USA 103:19707-19712. PMID:17179036

Scott, G.K., Fei, H., Thomas, L., Medigeshi, G.R., and Thomas, G. (2006) A PACS-1, GGA3 and CK2 complex regulates CI-MPR trafficking. EMBO J. 25:4423-4435. PMID:16977309

Feliciangeli, S.F., Thomas, L., Scott, G.K., Subbian, E., Hung, C.H., Molloy, S.S., Jean, F., Shinde, U., and Thomas, G. (2006) Identification of a pH sensor in the furin propeptide that regulates enzyme activation. J. Biol. Chem. 281:16108-16116. PMID:16601116

Simmen, T., Aslan, J.E., Blagoveshchenskaya, A.D., Thomas, L., Wan, L., Xiang, Y., Feliciangeli, S.F., Hung, C.H., Crump, C.M., and Thomas, G. (2005) PACS-2 controls ER-mitochondria communication and Bid-mediated apoptosis. EMBO J. 24:717-729. PMID:15692567

Köttgen, M., Benzing, T., Simmen, T., Tauber, R., Buchholz, B., Feliciangeli, S., Huber, T.B., Schermer, B., Kramer-Zucker, A., Höpker, K., Simmen, K.C., Tschucke, C.C., Sandford, R., Kim, E., Thomas, G., and Walz, G. (2005) Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation. EMBO J. 24:705-716. PMID:15692563

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