Paul C. Sternweis
Board Member: 1993 - 1996
G-Protein Mediated Signalling
A major focus 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, detection of light, and modulation several lipid-derived second messengers such as the phosphoinositides and products of arachidonic acid metabolism. 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 represented 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 second specific focus, in collaboration with Li Jiang at UT-Southwestern, is the elucidation of interacting G protein pathways that regulate cAMP in macrophages. In these cells, all four major G proteins intersect to synergistically modulate the activity of a specific adenylyl cyclase isoform, AC7. Efforts are directed at determining the molecular mechanisms of this synergistic regulation and the role of this specific cyclase in the immune system. Approaches include direct biochemical dissection of the system and physiolgical characterization of mice lacking AC7.