Molecular basis of exocytosis, cell migration, and tumor invasion
Exocytosis is a basic cell biological process 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 three fundamental questions in cell biology: (1) what is the molecular basis for exocytosis; (2) how do the secretory machinery functions in concert with cytoskeleton and small-GTP-binding proteins during cell polarization and cell migration; (3) how the basic cell biolgical processes mentioned above become malfunctional in diseases such as cancer and diabetes.
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, and plays essential roles in secretory vesicle targeting and docking at the plasma membrane during exocytosis. The exocyst is specifically localized to sites of active exocytosis and polarized cell growth, and is a downstream effector of many small GTPases including Rab, Rho, and Ral. In addition, the exocyst is a direct target of many kinases in the cell. Under the control of these signaling proteins, the exocyst coordinates with cytoskeletons in processes such as cytokinesis, ciliogeneisis, and cell migration.
A combination of biochemistry, molecular biology, genetics, and cell biology approaches are used in our research. We sue both yeast and mammalian cells in our study. 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 cell migration and tumor invasion. Taking advantage of these two different eukaryotic systems in parallel, we wish to elucidate the basic mechanisms of exocytosis and cell migration, and their involvement in tumor metastasis and diabetes.
Membrane traffic, exocytosis, cell migration, morphogenesis, exocyst, cell polarity, actin cytoskeleton, small GTPases, Rab, Rho, cancer, metastasis.
(selected from >70 publications; after 2005)
Lu, H., Liu, S., Zhang, G., Kwong L., Zhu, Y., Miller, J.P., Hu, Y., Zhong, W., Zeng, J., Wu, L., Krepler, C., Sproesser, K., Xiao, M., Xu, W., Karakousis, G.C., Schuchter, L., Field, J., Zhang, P.J., Herlyn, M., Xu, X., and Guo, W. Oncogenic BRAF-mediated melanoma cell invasion. CELL REPORTS (2016) 15: 2012-2024.
Wu, B., Guo, W. The Exocyst at a Glance. J. Cell Science (2015) 128(16):2957-64.
Wang, J., Ren, J., Wu, B., Feng, S., Cai, G., Tuluc, F., Peränen, J., and Guo, W. Activation of Rab8 guanine nucleotide exchange factor Rabin8 by ERK1/2 in response to EGF signaling. PNAS (2015) 112(1):148-153.
Luo, G., Zhang, J. and Guo, W. The Role of Sec3p in secretory vesicle targeting and exocyst assembly. Mol. Biol. Cell. (2014) 25(23):3813.
Das, A., Gajendra, S. Falenta, K., Oudin, O., Peschard, P. Feng, S. Wu, B., Marshall, C.J., Doherty, P.., ·Lalli, G., ·Guo, W. RalA promotes a direct exocyst-Par6 interaction to regulate polarity in neuronal development. (·co-corresponding authors). J. Cell Science (2014) 127: 686-699
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.
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.
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.
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 205 (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)