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.
Membrane traffic, exocytosis, cell migration, morphogenesis, exocyst, cell polarity, actin cytoskeleton, small GTPases, Rab, Rho, cancer, metastasis, polycycstic kidney diseases.
Lu, H., Liu, J., Liu, S. Zeng, J., Ding, D., Carstens, R., Cong, Y., Xu, X., Guo, W. Exo70 isoform switching upon epithelial-mesenchymal transition regulates cancer cell invasion. Developmental CELL (2013) 27:560-573
Liu, J., Yang, C., Capraro, B., Baumgart, T., Bradley, R.P., Ramakrishnan, N.,
Xu, X. Radhakrishnan, R., Svitkina, T., Guo,
W. Exo70 generates membrane curvature for
morphogenesis and cell migration. Developmental
CELL (2013) 26, 266-278.
Luo, G., Zhang, J., Luca, F., Guo, W. Mitotic phosphorylation of Exo84 disrupts exocyst assembly and arrests cell growth. J. Cell Biol. (2013) 202 (1): 97-111.
Liu, J., Zhao, Y., Sun, Y., Yang, C., He, B., Goldman Y., Svitkina, T., Guo, W. Exo70 stimulates actin branching for lamellipodia formation and cell migration. Current Biology (2012) 22:1510-1515.
Ren, J. and Guo, W. ERK1/2 regulates post-Golgi exocytosis through phosphorylation of the exocyst component Exo70. Developmental CELL (2012) 22(5):967-978.
Feng, S, Knödler A, Zhang, J., Zhang, X., Huang, S., Peränen, J., Guo, W. A Rab8 GEF-effector interaction network regulates primary ciliogenesis. J. Biol. Chem. (2012) 287:15602-15609.
Sakamori, R, Das, S, Feng, S, Stypulkowski, E, Harada, A., Brakebusch, C., Guo, W., Gao N. Cdc42 and Rab8a control stem cell division, survival, and differentiation in mouse intestine. J Clin Invest. (2012) 122(3):1052-65.
Das, A. and Guo, W. Rabs and exocyst in ciliogenesis, lumenogenesis and beyond. Trends in Cell Biol. (2011) 21(7) 383-386.
Orlando, K., Sun, X. Zhang, J. Lu, T., Yokomizo, L., Wang, P. and Guo, W. Exo-endocytic trafficking and the septin-based diffusion barrier are required for the maintenance of Cdc42p polarization during budding yeast asymmetrical growth. Mol. Biol. Cell (2011) 22:624-633.
Knödler, A., Feng, S., Zhang, X., Zhang, J., Das, A., Peränen, J. Guo, W. Coordination of Rab11 and Rab8 in primary ciliogenesis. PNAS (2010) 107 (14) 6346-6351.
Baek, K., Knödler, A., Lee, S., Zhang, X., Orlando, K., Zhang, J., Foskett, T.J., Guo, W*., Dominguez, D*. Structural basis for membrane and GTPase-binding by Sec3. J. Biol. Chem. (2010) 285(14):10424-33. (*co-corresponding authors).
Zhao, Y. and Guo, W. Secure nanotubes with the exocyst and RaIA. NATURE-Cell Biology (2009) 11(12): 1396-1397.
Liu, J., Yue, P., Artym V.V., Mueller S.C. and Guo, W. The roles of the exocyst in MMP secretion and actin dynamics during tumor cell invadopodia formation. Mol. Biol. Cell. (2009) 20:3763-3771.
He, B. and Guo, W. The exocyst complex in polarized exocytosis. Curr. Opin. Cell Biol. (2009) 21(4):537-42
Orlando, K., Zhang, J., Zhang, X., Yue, P., Chiang, T., Bi, E., and Guo, W. Regulation of Gic2 function by PI(4,5)P2 and Cdc42. J. Biol. Chem. (2008). 283:14205-14212.
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. (2008) 180(1): 145-158.
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.
- BIOL 202 (Biochemistry and Cell Biology)
- BIOL 480 / CAMB 480 (Advanced Cell Biology)
Honors and Awards:
- Pew Scholar in Biomedical Sciences
- American Cancer Society Research Scholar
- American Heart Association Established Investigator Award
- Biology Department Teaching Award (2008)