Gender	Female
E-mail	jeanne.hirsch@mssm.edu

Hirsch Laboratory

signal transduction pathways

The research program of this laboratory is aimed at understanding signal transduction pathways mediated by heterotrimeric G proteins in the yeast Saccharomyces cerevisiae. Sequencing of the entire yeast genome has revealed that it contains two genes that encode G protein alpha-subunits. We are studying novel aspects of the signal transduction pathways mediated by each of these alpha-subunits. Because the mechanism of G protein activation is conserved in all eukaryotes, information obtained from the yeast system is likely to have broad implications for signaling pathways in a wide variety of systems.

G proteins are composed of alpha-, beta-, and gamma-subunits, and they transmit intracellular signals through regulated exchange of guanine nucleotides on the alpha-subunit. Activation of a G protein occurs after it interacts with ligand-bound receptor at the cell surface. Transmission of the signal to downstream components can be carried out by either the GTP-bound alpha-subunit or the free beta-gamma complex.

One of the signal transduction pathways that we work on is involved in nutrient regulation of growth through extracellular signals. In yeast, growth and morphology are regulated by both Ras proteins and the alpha-subunit of a G protein. These two signaling components work in parallel to activate downstream kinases and perhaps function to integrate different nutrient signals into an overall growth rate. We have recently cloned a G protein-coupled receptor that functions upstream of the alpha-subunit. Current work is aimed at identifying the ligand for the receptor and at elucidating the mechanism by which the alpha-subunit activates its downstream target. The other signal transduction pathway being investigated mediates the response of haploid yeast cells to mating pheromones via two cell type-specific G protein-coupled receptors. The pheromone signal results in induction of specific gene expression, cell cycle arrest, and morphological changes that prepare the cell for mating. In this system, the beta-gamma complex propagates the signal after it is released from the alpha-subunit. We have uncovered a novel interaction between the G protein beta-subunit and its associated receptor. This interaction causes inhibition of the signaling pathway when it is necessary for the cell to re-enter the cell cycle. Inhibition of signaling correlates with re-localization of the beta-subunit from the plasma membrane to an internal compartment. Specific mutations in the beta-subunit have been isolated that abolish its ability to inhibit signaling but do not affect its ability to promote signaling. Current work is aimed at elucidating the mechanism by which the beta-subunit can uncouple from its signaling function and move to a different subcellular location.

For more information, please visit the Hirsch Laboratory website.

Niranjan T, Guo X, Victor J, Lu A, Hirsch JP. Kelch Repeat Protein Interacts with the Yeast G{alpha} Subunit Gpa2p at a Site That Couples Receptor Binding to Guanine Nucleotide Exchange. J Biol Chem 2007 Aug 17; 282(33): 24231-24238.

Lu A, Hirsch JP. Cyclic AMP-Independent Regulation of Protein Kinase A Substrate Phosphorylation by Kelch Repeat Proteins. Eukaryot Cell 2005 Nov; 4(11): 1794-800.

Peng L, Mirshahi T, Zhang H, Hirsch JP, Logothetis DE. Critical determinants of the G protein gamma subunits in the Gbetagamma stimulation of G protein-activated inwardly rectifying potassium (GIRK) channel activity. J Biol Chem 2003 Dec 12; 278(50): 50203-11.

Battle M, Lu A, Green DA, Xue Y, Hirsch JP. Krh1p and Krh2p act downstream of the Gpa2p G(alpha) subunit to negatively regulate haploid invasive growth. J Cell Sci 2003 Feb 15; 116(Pt 4): 701-10.

Kim J, Bortz E, Zhong H, Leeuw T, Leberer E, Vershon AK, Hirsch JP. Localization and signaling of G-beta subunit Ste4p are controlled by a-factor receptor and the a-specific protein Asg7p. Mol Cell Biol 2000 Dec; 20(23): 8826-8835.

Lorenz MC, Pan X, Harashima T, Cardenas ME, Xue Y, Hirsch J, Heitman J. The G protein-coupled receptor Gpr1 is a nutrient sensor that regulate pseudohyphal differentiation in Saccharomyces cerevisiae. Genetics 2000 Feb; 154(2): 609-22.

Kim J, Couve A, Hirsch JP. Receptor inhibition of pheromone signaling is mediated by the Ste4p Gbeta subunit. Mol Cell Biol 1999 Jan; 19(1): 441-9.

Yu Y, Yussa M, Song J, Hirsch J, Pick L. A double interaction screen identifies positive and negative ftz gene regulators and ftz-interacting proteins. Mech Dev 1999 May; 83(1-2): 95-105.

Kim J, Hirsch JP. A nucleolar protein that affects mating efficiency in Saccharomyces cerevisiae by altering the morphological response to pheromone. Genetics 1998 Jun; 149(2): 795-805.

Xue Y, Battle M, Hirsch JP. GPR1 encodes a putative G protein-coupled receptor that associates with the Gpa2p Galpha subunit and functions in a Ras-independent pathway. EMBO J 1998 Apr 1; 17(7): 1996-2007.