Regulation of G Protein–Initiated Signal Transduction in Yeast: Paradigms and Principles

Abstract

All cells have the capacity to evoke appropriate and measured responses to signal molecules (such as peptide hormones), environmental changes, and other external stimuli. Tremendous progress has been made in identifying the proteins that mediate cellular response to such signals and in elucidating how events at the cell surface are linked to subsequent biochemical changes in the cytoplasm and nucleus. An emerging area of investigation concerns how signaling components are assembled and regulated (both spatially and temporally), so as to control properly the specificity and intensity of a given signaling pathway. A related question under intensive study is how the action of an individual signaling pathway is integrated with (or insulated from) other pathways to constitute larger networks that control overall cell behavior appropriately. This review describes the signal transduction pathway used by budding yeast (Saccharomyces cerevisiae) to respond to its peptide mating pheromones. This pathway is comprised by receptors, a heterotrimeric G protein, and a protein kinase cascade all remarkably similar to counterparts in multicellular organisms. The primary focus of this review, however, is recent advances that have been made, using primarily genetic methods, in identifying molecules responsible for regulation of the action of the components of this signaling pathway. Just as many of the constituent proteins of this pathway and their interrelationships were first identified in yeast, the functions of some of these regulators have clearly been conserved in metazoans, and others will likely serve as additional models for molecules that carry out analogous roles in higher organisms.

Identification of Novel Membrane-binding Domains in Multiple Yeast Cdc42 Effectors

“…It regulates multiple mitogen-activated protein kinase (MAPK) pathways that control mating, filamentous growth, and osmotic stress response and also is involved in cell polarity and cell cycle control (Leberer et al, 1992;Liu et al, 1993;Cvrckova et al, 1995;O'Rourke and Herskowitz, 1998;Holly and Blumer, 1999;Raitt et al, 2000;Hofken and Schiebel, 2002). In the mating pathway, Ste20 activates MAPK cascade signaling when mating pheromones bind to membrane receptors (Dohlman and Thorner, 2001). The receptor-activated G␤␥ dimer binds Ste20 (Leeuw et al, 1998) and recruits the scaffold protein Ste5 to the plasma membrane (Pryciak and Huntress, 1998), allowing Ste20 to phosphorylate the first in a chain of Ste5-associated kinases that eventually trigger cell cycle arrest, transcription of mating genes, and polarized morphogenesis.…”

The KlSTE2 and KlSTE3 genes encode MATα‐ and MATa‐specific G‐protein‐coupled receptors, respectively, which are required for mating of Kluyveromyces lactis haploid cells

“…Although the primary sequences of the pheromone receptors do not show similarity, all GPCRs share parallelism in their topological arrangement in the plasma membrane, consisting of seven hydrophobic and potentially α-helical segments that span the lipid bilayer (Dohlman and Thorner, 2001). The N-terminus of these receptors is located extracellularly and, along with portions of extracellular loops, forms the binding pocket for pheromone (Naider and Becker, 2004).…”

Accessibility of Cysteine Residues Substituted into the Cytoplasmic Regions of the α-Factor Receptor Identifies the Intracellular Residues That Are Available for G Protein Interaction

“…post-translational modifications that regulate receptor desensitization and endocytosis (3). Ste2 activates a heterotrimeric G protein in which the α subunit shows about 45% identity with mammalian Gα proteins and is most closely related to the Gi subfamily (4).…”