G Protein Signaling

G Protein Signaling Is Not a Done Deal

Science Signaling  29 Jun 2010:
Vol. 3, Issue 128, pp. ec191
DOI: 10.1126/scisignal.3128ec191

Do we have a relatively complete parts list for understanding cellular signaling? A systematic exploration of genes essential for viability in yeast for their potential roles in signaling indicates that perhaps we do not. Cappell et al. focused on essential genes (which are more likely than the average yeast gene to have human orthologs) and used a library of strains in which the promoter of individual essential genes can be acutely repressed by treating the yeast cells with tetracycline. Screening for genes required for proper signaling through the heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors that recognize mating hormones identified 92 such essential genes and some unanticipated regulatory components of the pheromone signaling pathway. Several genes encoding proteins that function in ubiquitin-dependent degradation of proteins were identified, and the authors confirmed that the Cdc34 protein, a ubiquitin-conjugating enzyme, could directly ubiquitinate Gpa1, the yeast G protein α subunit. The ubiquitin ligase complex SCFCdc4 and Cdc34 appear to function in promoting pheromone signaling by enhancing degradation of Gpa1, thus preventing it from sequestering G protein β-γ subunits. Also implicated in signaling were the phosphatidylinositol 4-kinases Pik1 and Stt4. Generation of monophosphorylated phosphoinositides appeared to be required for activation of the mitogen-activated protein kinase Fus3. The authors predict that there are in fact “many new pathway components to be found.”

S. D. Cappell, R. Baker, D. Skowyra, H. G. Dohlman, Systematic analysis of essential genes reveals important regulators of G protein signaling. Mol. Cell 38, 746–757 (2010). [PubMed]