Chapter Two - Heterotrimeric G Protein Ubiquitination as a Regulator of G Protein Signaling

Ubiquitin-mediated regulation of G proteins has been known for over 20 years as a result of discoveries made independently in yeast and vertebrate model systems for pheromone and photoreception, respectively. Since that time, several details underlying the cause and effect of G protein ubiquitination have been determined-including the initiating signals, responsible enzymes, trafficking pathways, and their effects on protein structure, function, interactions, and cell signaling. The collective body of evidence suggests that Gα subunits are the primary targets of ubiquitination. However, longstanding and recent results suggest that Gβ and Gγ subunits are also ubiquitinated, in some cases impacting cell polarization-a process essential for chemotaxis and polarized cell growth. More recently, evidence from mass spectrometry (MS)-based proteomics coupled with advances in PTM bioinformatics have revealed that protein families representing G protein subunits contain several structural hotspots for ubiquitination-most of which have not been investigated for a functional role in signal transduction. Taken together, our knowledge and understanding of heterotrimeric G protein ubiquitination as a regulator of G protein signaling-despite 20 years of research-is still emerging.