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Marilyn G.
Farquhar, Ph.D.
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.
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