| Title: | Specific alpha-arrestins negatively regulate Saccharomyces cerevisiae pheromone response by down-modulating the G-protein-coupled receptor Ste2 |
| Author(s): | Alvaro CG; O'Donnell AF; Prosser DC; Augustine AA; Goldman A; Brodsky JL; Cyert MS; Wendland B; Thorner J; |
| ISSN/ISBN: | 1098-5549 (Electronic) 0270-7306 (Print) 0270-7306 (Linking) |
| Abstract: | "G-protein-coupled receptors (GPCRs) are integral membrane proteins that initiate responses to extracellular stimuli by mediating ligand-dependent activation of cognate heterotrimeric G proteins. In yeast, occupancy of GPCR Ste2 by peptide pheromone alpha-factor initiates signaling by releasing a stimulatory Gbetagamma complex (Ste4-Ste18) from its inhibitory Galpha subunit (Gpa1). Prolonged pathway stimulation is detrimental, and feedback mechanisms have evolved that act at the receptor level to limit the duration of signaling and stimulate recovery from pheromone-induced G1 arrest, including upregulation of the expression of an alpha-factor-degrading protease (Bar1), a regulator of G-protein signaling protein (Sst2) that stimulates Gpa1-GTP hydrolysis, and Gpa1 itself. Ste2 is also downregulated by endocytosis, both constitutive and ligand induced. Ste2 internalization requires its phosphorylation and subsequent ubiquitinylation by membrane-localized protein kinases (Yck1 and Yck2) and a ubiquitin ligase (Rsp5). Here, we demonstrate that three different members of the alpha-arrestin family (Ldb19/Art1, Rod1/Art4, and Rog3/Art7) contribute to Ste2 desensitization and internalization, and they do so by discrete mechanisms. We provide genetic and biochemical evidence that Ldb19 and Rod1 recruit Rsp5 to Ste2 via PPXY motifs in their C-terminal regions; in contrast, the arrestin fold domain at the N terminus of Rog3 is sufficient to promote adaptation. Finally, we show that Rod1 function requires calcineurin-dependent dephosphorylation" |
| Keywords: | "Arrestins/*metabolism Calcineurin/metabolism Carrier Proteins/genetics/*metabolism Cell Cycle Endosomal Sorting Complexes Required for Transport/genetics/*metabolism Gene Expression Regulation, Fungal Mating Factor Membrane Proteins/genetics/*metabolism P;" |
| Notes: | "MedlineAlvaro, Christopher G O'Donnell, Allyson F Prosser, Derek C Augustine, Andrew A Goldman, Aaron Brodsky, Jeffrey L Cyert, Martha S Wendland, Beverly Thorner, Jeremy eng R01 GM021841/GM/NIGMS NIH HHS/ R01 GM48729/GM/NIGMS NIH HHS/ R01 GM21841/GM/NIGMS NIH HHS/ GM07276/GM/NIGMS NIH HHS/ T32 GM007276/GM/NIGMS NIH HHS/ GM07232/GM/NIGMS NIH HHS/ R01 GM75061/GM/NIGMS NIH HHS/ R01 GM075061/GM/NIGMS NIH HHS/ R01 DA014204/DA/NIDA NIH HHS/ R01 GM048729/GM/NIGMS NIH HHS/ T32 GM007232/GM/NIGMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2014/05/14 Mol Cell Biol. 2014 Jul; 34(14):2660-81. doi: 10.1128/MCB.00230-14" |
