G proteins and RGS proteins: Linking trafficking and signaling

Protein trafficking and signal transduction are intimately intertwined. Vesicular trafficking is regulated by signaling molecules (Rabs, Arfs, phosphoinositides), and signaling is controlled in time and space by trafficking and translocation of signaling molecules to specific cellular sites where signals are initiated and propagated. G proteins are well known to function in relaying signals from liganded GPCR receptors to intracellular effectors. G proteins are also present on intracellular membranes such as those of the ER, Golgi and endosomes, but their function on intracellular membranes has remained elusive. It has been suggested they function in vesicle budding, vesicle fusion, assembly of vesicle coats or protein sorting during vesicular trafficking. More recently, a number of novel regulatory proteins for heterotrimeric G proteins (RGS proteins, GoLoco proteins, Ric‐8) have been found on intracellular compartments, implying that G proteins are active and that their activity can be regulated at intracellular sites. The characterization of these new G protein binding proteins has implicated G proteins in a variety of cell processes from endocytosis to cell division. In this lecture I will be review work on the characterization and functions of G proteins and their binding proteins that has provided insights into their functions on intracellular compartments. Analysis of RGS‐PX1 has been particularly fruitful, as this protein serves as both a GAP for G[alpha]s through its RGS domain and a SNX through its PX domain and regulates trafficking at early endosomes. G[alpha]s and RGS‐PX‐1 form a protein complex with components of the sorting machinery that control down‐regulation of the EGF receptor at early endosomes. This scenario may provide a wider paradigm as to how G proteins and their regulatory proteins connect signaling. to vesicle trafficking and protein sorting.