A major area of research explores signaling pathways that utilize cell surface receptors and membrane associated GTP-binding proteins (G proteins). These G proteins mediate hormonal regulation of intracellular enzymes, which produce various second messengers and their sequelae. Examples of G protein regulated systems include production of cAMP and several lipid-derived second messengers such as the phosphoinositides. In addition, the G proteins can more directly regulate a variety of signaling proteins such as ion channels, protein kinases and exchange factors for other GTPases. Major goals have been identification of the participants in these pathways, elucidation of the circuitry which defines interaction among the various components and definition of the molecular mechanisms by which regulation is achieved.
A specific focus in this area has been the mechanisms for regulation of guanine nucleotide exchange factors for RhoA (RhoGEFs) by the heterotrimeric G12 and G13 proteins. This finding represents the first direct regulatory link between the receptor coupled G proteins and the monomeric GTPases. Besides the hormonal regulation of Rho-dependent cytoskeletal regulation and gene transcription, this pathway offers a unique paradigm for regulation in that the RhoGEF acts bi-directionally as both a recipient for activation by the G proteins as well as a facilitator of inactivation of the G proteins. Current studies focus on elucidating the mechanisms of these regulatory actions, determining their in vivo relevance and discovery of other similar regulatory paradigms that link G protein coupled receptors to the monomeric GTPases. This is being accomplished through the pursuit of traditional biochemical approaches, determination of molecular structures for the individual proteins and their active complexes, development of fluorescent biosensors to detect the activated states of pathway components in vivo, and selective perturbation of specific pathway components to assess physiological impact.
A focus of the Alliance for Cellular Signaling is to assess the complexity of interactions among multiple signaling pathways impinging on single cells. Thus in a macrophage cell line, non-additivity in the regulation of secreted cytokines can be observed with up to four ligands that utilize unique regulatory paradigms. The identification of numerous interactions among ligands for G protein coupled receptors that regulate intracellular calcium and cyclic-AMP has provided the basis for more specific studies to determine the mechanisms of these interactions and associated development of mathematical models at the molecular level to explain and predict the behavior of these signaling pathways. The Dallas group focuses largely on development and implementation of sensors to measure pathway activities in vivo as well as discovery of pathway components and mechanisms.
RESEARCH INTERESTS
Integration of Hormone Signaling Pathways
Mechanisms of G protein-mediated Signaling
Structures of Signaling Molecules
Regulation of Rho GTPases
Fluorescent Sensors to measure in vivo activities
RECENT PUBLICATIONS
Jiang, L.I., Collins, J., Davis, R., Lin, K-M., DeCamp, D., Roach, T., Hsueh, R., Rebres, R.A., Ross, E.M., Taussig, R., Fraser, I., Sternweis, PC., "Use of a cAMP BRET sensor to characterize a novel regulation of cAMP by the sphingosine 1-phosphate/G13 pathway." J. Biol. Chem., 282:10576-84, April 2007
Chen, Z., Singer, W.D., Sternweis, P.C., Sprang, S.R., "Structure of the p115RhoGEF rgRGS domain-Galpha13/i1 chimera complex suggests convergent evolution of a GTPase activator." Nat. Struct. Mol. Biol., 12:191-7, February 2005
Wells,C.D., Liu, M-Y., Jackson, M., Gutowski, S., Sternweis, P.M., Rothstein, J.D., Kozasa, T., and Sternweis, P.C., "Mechanisms for reversible regulation between G13 and Rho exchange Factors." J. Biol. Chem, 277:1174-1181, 2002
Chen, Z., Singer, W.D., Wells, C.D., Sprang, S.R., Sternweis, P.C., "Mapping the Ga13 Binding Interface of the rgRGS Domain of p115RhoGEF." J Biol Chem., 278:9912-9919, 2003
Wang, Q., Liu, M., Kozasa, T., Rothstein, J.D., Sternweis, P.C., Neubig, R.R., "Thrombin and lysophosphatidic acid receptors utilize distinct rhoGEFs in prostate cancer cells." J. Biol. Chem., 279:28831-4, July 2004
SIGNIFICANT PUBLICATIONS
Hart, M.J., Jiang, X., Kozasa, T., Roscoe, W., Singer, W.D., Gilman, A.G., Sternweis, P.C., and Bollag, G., "Direct Stimulation of the Guanine Nucleotide Exchange Activity of p115 RhoGEF by Ga13." Science, 280:2112-2114, 1998
Kozasa, T., Jiang, X., Hart, M.J., Sternweis, P.M., Singer, W.D., Gilman, A.G., Bollag, G. and Sternweis, P.C., "p115 RhoGEF, a GTPase Activating Protein for Ga12 and Ga13." Science, 280:2109-2111, 1998
Natarajan, M., Lin, K-M., Hsueh, R.C., Sternweis, P.C., Ranganathan, R., "A global analysis of cross-talk in a mammalian cellular signalling network." Nat. Cell Biol., 8:571-80, June 2006
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