Research in this laboratory focuses on the area of
transmembrane signaling mediated through guanine nucleotide-binding
regulatory proteins (G proteins). Many of these signaling
pathways are involved in control of cell growth; this
property is highlighted by discoveries over the past
decade that mutations in G proteins can lead to cell
transformation. There are two major areas of research
ongoing in the lab. The first is the covalent modification
of G proteins by isoprenoid lipids and the role this
modification, termed protein prenylation, plays in
the membrane targeting and function of G proteins.
Prenylation plays a crucial role oncogenic transformation
by one class of G proteins, the Ras proteins. The
enzymes that catalyze these modifications have been
isolated and cloned and are being used to develop
in vitro systems to both define the enzymes structures
and molecular mechanisms and elucidate the role of
prenylation in G protein function. The importance
of this work is highlighted by the fact that several
of these enzymes, most notably protein farnesyltransferase
(FTase) and geranylgeranyltransferase (GGTase-1),
a prenyl protein-specific protease termed Rce1, and
a specific methyltransferase termed Icmt have become
major targets in the development of anti-cancer therapeutics.
The second general area of research involves identification
of the signaling pathways controlled by specific types
of G proteins. One such protein, termed Gz, exhibits
very limited tissue distribution that includes primarily
neuronal and neuroendocrine cells. Gz exhibits several
biochemical properties that suggest that this protein
controls a unique signaling pathway, and we have recently
linked Gz to two distinct pathways using molecular
genetic and biochemical approaches. We have also have
a program to identify molecular targets of G12 proteins.
This is the least understood of all G protein families,
but evidence has been accumulating that the two members
of this family play critical roles in cell growth
and stress responses. We have recently linked the
G12 proteins to cell-surface cadherins, and have obtained
evidence that the interaction of G12 with the cytoplasmic
tail of cadherins affects multiple functions of these
molecules.
