molecular
basis of exocytosis and cell morphogenesis
Exocytosis is a basic membrane traffic event mediated
by transport, docking, and fusion of secretory vesicles carrying
proteins and lipids to the plasma membrane. Through exocytosis,
hormones and neurotransmitters can be released. Also through
exocytosis, membrane proteins and lipids can be incorporated
into specific domains of plasma membrane for cell surface expansion,
cell growth, morphogenesis, and cell migration. Our research
aims to address two fundamental questions in cell and developmental
biology: (1) what is the molecular basis for exocytosis; and
(2) how do the secretory machinery functions in concert with
cytoskeleton and small-GTP-binding proteins during cell polarization,
morphogenesis, and cancer cell metastasis.
Our research focuses
on an evolutionarily conserved multi-protein complex, named the
exocyst. The exocyst consists of eight components:
Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70 and Exo84. All play
essential roles in secretory vesicle targeting and docking at
the plasma membrane for exocytosis. The exocyst is specifically
localized to sites of active exocytosis and polarized cell growth.
In budding yeast, the exocyst proteins are localized to the tip
of the budding daughter cells (bud tip), a region of active exocytosis
and cell surface expansion. In developing neurons, the exocyst
is localized to the tips of growing neurites. In epithelial cells,
the exocyst is concentrated near the adherens junction, a region
of active basolateral membrane addition. The exocyst complex
is a downstream effector of small GTPases including Rab, Rho,
and Ral. Through interacting with this multiprotein exocyst complex,
these small G-proteins can spatially and kinetically regulate
exocytosis and membrane morphology. Besides the small GTPases,
the exocyst also interact with cytoskeleton and other signaling
molecules in the cell. The assembly of the exocyst complex therefore
integrates various sources of cellular information to ensure
the accuracy of exocytosis and morphogenesis.
Our goal is to
understand how this important secretory machinery works using
a combination of biochemistry, molecular biology,
genetics, and cell biology approaches. Furthermore, through studying
the exocyst complex, we aim to learn how multiple cellular machines
are coordinated to carry out important biological functions such
as morphogenesis and cell migration. We study the exocyst in
both yeast and mammalian cells: the budding yeast Saccharomyces
cerevisiae grows asymmetrically by "budding", a seemingly
simple process that requires sophisticated mechanisms that coordinate
membrane traffic, cell polarity and cell cycle progression. This
property, in combination with its facile genetics and well-characterized
genomics, makes the budding yeast a powerful model system for
our research. We also study the exocyst in mammalian cells, in
which we investigate the role of the exocyst in morphogenesis
and cell migration. Taking advantage of these two different eukaryotic
systems in parallel, we wish to elucidate the basic mechanisms
of exocytosis and cell morphogenesis and their involvement in
cancer, polycystic kidney diseases, and diabetes.
Zhang, X., Orlando, K., He, B., Xi, F., Zhang, J., Zajac, A.,
and Guo, W. Membrane association and functional regulation of
Sec3 by phospholipids and Cdc42. J. Cell Biol. (in press).
Liu, J., Zuo, X., Yue, P., and Guo, W. Phosphatidylinositol
4, 5-bisphosphate mediates the targeting of the exocyst to the
plasma membrane for exocytosis in mammalian cells. Mol. Biol.
Cell. (2007) 18(11):4483-4492.
He, B., Xi, F., Zhang,
X., Zhang, J., and Guo, W. Exo70 interacts with phospholipids
and mediates the targeting of the exocyst
to the plasma membrane. EMBO J. (2007) 26, 4053-4065.
He, B., Xi, F., Zhang, J., TerBush D., Zhang, X., and
Guo, W. Exo70 mediates the secretion of specific exocytic
vesicles at
early stages of cell cycle for polarized cell growth. J.
Cell Biol. (2007) 176(6):771-777.
Zuo, X., Zhang, J., Zhang, Y., Hsu,
S., Zhou, D., and Guo, W. Exo70 interacts with the Arp2/3
complex and regulates cell migration.
Nature-Cell Biology (2006) 8(12):1383-1388.
Zhang, X., Wang,
P., Gangar, A., Zhang, J., Brennwald, P., TerBush, D.,
and Guo, W. (2005) The yeast Lgl protein interacts
with the
exocyst complex and is involved in polarized exocytosis.
J. Cell Biol. 170(2):273-83.
Zhang, X., Zajac, A., Zhang,
J., Wang, P., Li, M., Murray, J. TerBush, D., Guo,
W.
(2005) The critical role of Exo84p
in the
organization and polarized localization of the exocyst
complex. J. Biol. Chem 280(21), 20356-20364.
Zajac, A.,
Sun, X., Zhang, J. and Guo, W. (2005) Cyclical Regulation
of the Exocyst and Cell Polarity Determinants
for Polarized
Growth. Mol. Biol. Cell 16(3), 1500-1512.
Hsu, S-C, TerBush,
D., Abraham, M, and Guo, W. (2004) The Exocyst Complex
in Polarized Exocytosis. International
Review of Cytology 233:243-265.
Guo, W and Novick P. (2004) The exocyst
meets the translocon: a regulatory circuit for secretion
and protein synthesis?
Trends in Cell Biol. 14 (2), 61-63.
EauClaire, S.F.
and Guo, W. (2003) Conservation and specialization:
the role of the exocyst in neuronal
exocytosis. Neuron 37, 369-374.
Novick. P. and Guo, W. (2002) Ras family
therapy: Rab, Rho and Ral talk to the exocyst. Trends
in
Cell Biol.
12 (6),
247-249.
Zhang, X., Bi, E., Novick, P., Du, L.,
Kozminski, K.G., Lipschultz, J., and Guo, W. (2001)
Cdc42 interacts with the exocyst and
regulates polarized exocytosis J. Biol.
Chem. 276, 46745-46750.
Guo, W. Tamanoi, F., and Novick,
P. (2001) Spatial regulation of the exocyst complex
by Rho1 GTPase.
NATURE-Cell Biology 3(4):353-360.
Guo, W., Sacher, M., Barrowman,
J., S. Ferro-Novick, and P. Novick. (2000) Protein complexes
in
transport vesicle
targeting.
Trends
in Cell Biol. 10:251-255.
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