Regulation of Yeast G Protein Signaling by the Kinases That Activate the AMPK Homolog Snf1

Abstract

Extracellular signals, such as nutrients and hormones, cue intracellular pathways to produce adaptive responses. Often, cells must coordinate their responses to multiple signals to produce an appropriate outcome. We showed that components of a glucose-sensing pathway acted on components of a heterotrimeric guanine nucleotide–binding protein (G protein)–mediated pheromone signaling pathway in the yeast Saccharomyces cerevisiae. We demonstrated that the G protein α subunit Gpa1 was phosphorylated in response to conditions of reduced glucose availability and that this phosphorylation event contributed to reduced pheromone-dependent stimulation of mitogen-activated protein kinases, gene transcription, cell morphogenesis, and mating efficiency. We found that Elm1, Sak1, and Tos3, the kinases that phosphorylate Snf1, the yeast homolog of adenosine monophosphate–activated protein kinase (AMPK), in response to limited glucose availability, also phosphorylated Gpa1 and contributed to the diminished mating response. Reg1, the regulatory subunit of the phosphatase PP1 that acts on Snf1, was likewise required to reverse the phosphorylation of Gpa1 and to maintain the mating response. Thus, the same kinases and phosphatase that regulate Snf1 also regulate Gpa1. More broadly, these results indicate that the pheromone signaling and glucose-sensing pathways communicate directly to coordinate cell behavior.

Direct Modulation of Heterotrimeric G Protein-coupled Signaling by a Receptor Kinase Complex

“…By precedent, the yeast G␣ subunit is phosphorylated by a non-receptor kinase in response to changes in the cell cycle (48) and is also phosphorylated in response to the limited availability of glucose (49). Also, in the membranes of human leukemia HL-60 cells during activation of G proteins, the G␤ subunit is phosphorylated (50).…”

Guanine Nucleotide-binding Protein (Gα) Endocytosis by a Cascade of Ubiquitin Binding Domain Proteins Is Required for Sustained Morphogenesis and Proper Mating in Yeast

“…(26), polyubiquitination (SCF/Cdc4) (29), deubiquitination (Ubp12) (25), phosphorylation (Elm1, Tos1, Sak3) (30,31,66), and dephosphorylation (Reg1) (66) as well as the seven UBD proteins identified here. We conclude that the ubiquitination domain likely evolved to serve a unique trafficking function and that this function is wholly separate from the regulation of G protein catalytic activity.…”

Cross-regulation between CDK and MAPK control cellular fate

“…For instance, Mitogen-Activated Protein Kinase (MAPK) pathways are central nodes in the signaling network of eukaryotic cells, because they relay extracellular cues such as growth factors or stresses 1,2 . The metabolic state, the cellular morphology or the cell cycle phase of individual cells can be integrated by the MAPK cascade to finely tune the cellular response [3][4][5] . However, the molecular mechanisms that allow these signal integrations are generally unknown.…”

“…The budding yeast MAPK network is composed of four main pathways active in haploid cells 6 . Multiple instances of signal integration have been documented in this model system: the cross-inhibition between two MAPK pathways 5 , the limitation of signal transmission in low nutrient conditions 3,7 and the tight coupling between cell cycle regulation and MAPK activity 4,[8][9][10][11][12] . In this study, we will focus on the interplay between the cell cycle and the mating pathway.…”