Cell migration is important for a wide range of physiological processes from chemotaxis and wound healing, to neuron development and embryogenesis. Cell migration requires the dynamic assembly of the actin network and remodeling of the membrane. How actin dynamics and membrane activities are coordinated during cell migration is a fundamental question in the field. The exocyst, a multiprotein complex consisting of Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70 and Exo84, mediates exocytosis and polarized cell surface expansion. Recently, the exocyst emerges as an important player in cell migration. The exocyst component Exo70 directly interacts with, and kinetically stimulates, the Arp2/3 complex for actin polymerization and branching. In addition, Exo70 induces membrane curvature to generate surface protrusions. Exo70 therefore couples actin dynamics with membrane remodeling for protrusion formation and cell migration. Here we propose to examine the molecular mechanisms by which Exo70 promotes membrane curvature induction and the Arp2/3 complex-mediated actin remodeling. Furthermore, we will investigate the coordinated actions of the exocyst complex, the Arp2/3 complex, and the EHD family of """"""""pinchases"""""""" in the generation of secretory vesicles from the sorting endosome that mediates integrins recycling to the leading edge for migration. We take a multi-disciplinary approach combining biochemistry, biophysics, microscopic imaging, and molecular dynamics simulation to address important emerging questions in the field. These studies will help us to elucidate the molecular mechanisms of cell migration, and contribute t our understanding of a number of diseases such neurological disorders and cancer.

Public Health Relevance

Directional cell migration is fundamental to many physiological processes such as chemotaxis, embryogenesis, and neuronal development. Studying the molecular basis of cell migration will help us understand these physiological processes and shed light on the etiologies of diseases such as neurological disorders and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM085146-06
Application #
8711489
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Nie, Zhongzhen
Project Start
2009-06-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Lu, Hezhe; Liu, Shujing; Zhang, Gao et al. (2016) Oncogenic BRAF-Mediated Melanoma Cell Invasion. Cell Rep 15:2012-24
Wu, Bin; Guo, Wei (2015) The Exocyst at a Glance. J Cell Sci 128:2957-64
Das, Amlan; Gajendra, Sangeetha; Falenta, Katarzyna et al. (2014) RalA promotes a direct exocyst-Par6 interaction to regulate polarity in neuronal development. J Cell Sci 127:686-99
Yu, Shiyan; Yehia, Ghassan; Wang, Juanfei et al. (2014) Global ablation of the mouse Rab11a gene impairs early embryogenesis and matrix metalloproteinase secretion. J Biol Chem 289:32030-43
Zhao, Yuting; Liu, Jianglan; Yang, Changsong et al. (2013) Exo70 generates membrane curvature for morphogenesis and cell migration. Dev Cell 26:266-78
Lu, Hezhe; Liu, Jianglan; Liu, Shujing et al. (2013) Exo70 isoform switching upon epithelial-mesenchymal transition mediates cancer cell invasion. Dev Cell 27:560-73
Cai, Bishuang; Giridharan, Sai Srinivas Panapakkam; Zhang, Jing et al. (2013) Differential roles of C-terminal Eps15 homology domain proteins as vesiculators and tubulators of recycling endosomes. J Biol Chem 288:30172-80
Luo, Guangzuo; Zhang, Jian; Luca, Francis C et al. (2013) Mitotic phosphorylation of Exo84 disrupts exocyst assembly and arrests cell growth. J Cell Biol 202:97-111
Ren, Jinqi; Guo, Wei (2012) ERK1/2 regulate exocytosis through direct phosphorylation of the exocyst component Exo70. Dev Cell 22:967-78
Liu, Shujing; Kumar, Suresh M; Lu, Hezhe et al. (2012) MicroRNA-9 up-regulates E-cadherin through inhibition of NF-κB1-Snail1 pathway in melanoma. J Pathol 226:61-72

Showing the most recent 10 out of 17 publications