Many eukaryotic cells undergo chemotaxis, directed movement towards a soluble ligand. This process is necessary for many biological functions, including wound healing, axonal guidance, and the aggregation of Dictyostelium cells. Chemotaxis also plays a role in disease states such as arthritis, cancer, and multiple sclerosis. Directional cell movement requires a defined cell polarity in which components of the cytoskeleton are differentially localized at the leading edge of a migrating cell as well as its retracting posterior. This polarization can be initiated by the chemoattractant binding of heterotrimeric G protein-coupled membrane- bound receptors, and subsequent activation of downstream signal transduction pathways direct reorganization of the actin and myosin cytoskeleton. Our previous studies suggested that a polarized actin cytoskeleton is achieved by concentrating regulators of actin assembly such as WASP and WIP in subdomains at the cell cortex. The goal of this study is to understand how the subcellular localization and activation of WASP is regulated during chemotaxis. We hypothesize that a complex interplay between PCH family proteins, CLP1/2, and RacC leads to polarized trafficking of WASP and ACA, resulting in cell polarity establishment via the polarized organization of actin cytoskeleton and asymmetric distribution of ACA during Dictyostelium chemotaxis. To test this hypothesis, we propose the following specific aims: 1) To elucidate the role of PCH family proteins, CLP1/2 and RacC in controlling function and localization of WASP during vesicle formation. 2) To investigate roles of CLP1/2, RacC, and Unc104 in the trafficking of WASP- and ACA-vesicles. 3) To study how polarized trafficking of WASP- and ACA-vesicles contribute to establish cell polarity during chemotaxis. It is anticipated that these studies will serve not only to provide new insights on how exocytic vesicle formation from Golgi is controlled, but also to understand how cellular polarity can be achieved b vesicle trafficking during chemotaxis.

Public Health Relevance

Many cells in our body undergo chemotaxis, directed movement toward a chemical compound which is necessary for many biological functions including wound healing and the development of the nervous system. Chemotaxis also plays a role in disease states such as arthritis, cancer, and multiple sclerosis. Our proposed research would help us understand how cells maintain cell polarity and directed cell movement when they migrate directionally toward a directional cue.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cell Structure and Function (CSF)
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Gaillard, Shawn R
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Vanderbilt University Medical Center
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Lee, Sang-Hyun; Sud, Neetu; Lee, Narae et al. (2016) Regulation of Integrin ?6 Recycling by Calcium-independent Phospholipase A2 (iPLA2) to Promote Microglia Chemotaxis on Laminin. J Biol Chem 291:23645-23653
Wang, C; Jung, D; Cao, Z et al. (2015) Adenylyl cyclase localization to the uropod of aggregating Dictyostelium cells requires RacC. Biochem Biophys Res Commun 465:613-9
Chung, Chang Y; Feoktistov, Alexander; Hollingsworth, Ryan J et al. (2013) An attenuating role of a WASP-related protein, WASP-B, in the regulation of F-actin polymerization and pseudopod formation via the regulation of RacC during Dictyostelium chemotaxis. Biochem Biophys Res Commun 436:719-24
Lee, Sang-Hyun; Hollingsworth, Ryan; Kwon, Hyeok-Yil et al. (2012) ýý-arrestin 2-dependent activation of ERK1/2 is required for ADP-induced paxillin phosphorylation at Ser(83) and microglia chemotaxis. Glia 60:1366-77
Lee, Sang-Hyun; Schneider, Claus; Higdon, Ashlee N et al. (2011) Role of iPLA(2) in the regulation of Src trafficking and microglia chemotaxis. Traffic 12:878-89
Gruver, J Scott; Potdar, Alka A; Jeon, Junhwan et al. (2010) Bimodal analysis reveals a general scaling law governing nondirected and chemotactic cell motility. Biophys J 99:367-76
Lin, Wan-Hsin; Nelson, Sharon E; Hollingsworth, Ryan J et al. (2010) Functional roles of VASP phosphorylation in the regulation of chemotaxis and osmotic stress response. Cytoskeleton (Hoboken) 67:259-71
Lee, S; Chung, C Y (2009) Role of VASP phosphorylation for the regulation of microglia chemotaxis via the regulation of focal adhesion formation/maturation. Mol Cell Neurosci 42:382-90
Lee, S; Han, J W; Leeper, L et al. (2009) Regulation of the formation and trafficking of vesicles from Golgi by PCH family proteins during chemotaxis. Biochim Biophys Acta 1793:1199-209
Gruver, J S; Wikswo, J P; Chung, C Y (2008) 3'-phosphoinositides regulate the coordination of speed and accuracy during chemotaxis. Biophys J 95:4057-67

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