Award Lecture 2006
Marilyn G. Farquhar, PhD
Department of Cellular and Molecular Medicine, Uni of California San Diego, La Jolla, CA
To be Presented April 4, 2006, ASBMB Annual Meeting, San Francisco, CA,
2006 FASEB Experimental Biology Symposium
"G proteins and RGS proteins: Linking Trafficking and Signaling"
It has become apparent that protein trafficking and signaling are intimately intertwined. Vesicular trafficking is regulated by signaling molecules such as small GTPases (Rabs, Arfs) and phosphoinositides, and signal transduction is controlled in time and space by trafficking and translocation of signaling molecules such as receptors, G proteins and kinases to specific cellular sites where signals are initiated and propagated.
Heterotrimeric G proteins are well known to be anchored to the inner surface of the cell membrane where they function in relaying signals from liganded, seven transmembrane domain, G protein coupled receptors to intracellular effectors. More than ten years ago G proteins were also discovered to be present on intracellular membranes such as those of the endoplasmic reticulum, Golgi and endosomes, but their function on intracellular membranes has remained elusive. It has been variously suggested that they function in vesicle budding, vesicle fusion, assembly of vesicle coats and protein sorting during vesicular trafficking. More recently, a number of novel regulatory proteins for heterotrimeric G proteins such as RGS proteins which are GAPs that turn off G protein signaling, the GoLoco (AGS/LGN) proteins that serve as GDI’s, and Ric-8 a GEF that activates G proteins were also found to be associated with intracellular compartments, implying that G proteins on intracellular membranes are active and that their activity can be regulated at intracellular sites. A number of additional proteins including calnuc and GIV were also found to bind G proteins at intracellular sites. The characterization of these new G protein binding proteins has implied involvement of G proteins in a wide variety of cell processes from endocytic trafficking to cell division.
In this lecture I will review work to date on the characterization and functions of G proteins and their binding proteins on intracellular membranes which has provided insights into functions of G proteins on intracellular compartments. Work on RGS-PX1 has been particularly fruitful as this protein serves as both a GAP for Gas through its RGS domain and a SNX protein through its PX domain and regulates trafficking at the early endosome. Moreover, Gas and RGS-PX-1 form a protein complex with components of the sorting machinery that control down-regulation of growth factor receptors and perhaps other receptors at the early endosome. This scenario may provide a wider paradigm as to how heterotrimeric G proteins and their regulatory proteins connect G protein signaling to vesicle trafficking and protein sorting.