Chemotaxis, a process in which cells migrate toward higher concentrations of chemoattractants, is important for a variety of physiological events such as axon guidance, wound healing, and tissue morphogenesis. Inappropriate chemotaxis leads to many human diseases including tumor metastasis, asthma, arthritis and atherosclerosis. The long-term goal of our research is to reveal the molecular mechanism of chemotaxis and to understand the pathogenesis of chemotaxis- related human diseases. Using Dictyostelium discoideum as our experimental model system, we have demonstrated that phosphatidylinositol 3,4,5 triphosphate (PIP3) plays a critical role for intracellular signaling in chemotaxis. PIP3 is highly enriched at the leading edge of cells and activates downstream signaling events such as remodeling of the actin cytoskeleton. We have demonstrated that the intracellular level and localization of PIP3 are regulated by a lipid phosphatase, PTEN. PTEN is located at the rear end of chemotaxing cells and restricts the production of PIP3 at the leading edge. The local accumulation of PIP3 stimulates actin polymerization to extend pseudopods toward the source of chemoattractant. To date, it is unknown how the localization and activity of PTEN are regulated, and how PIP3 signaling is translated into reorganization of the actin cytoskeleton. In this research proposal, we will use a combination of genetics, biochemistry, cell biology and proteomics to achieve the following specific aims: 1) To determine how phosphorylation regulates the localization and activity of PTEN;2) To define the functions of two proteins required for chemotaxis - Huntingtin and GxcT, a novel guanine nucleotide exchange factor for Rho GTPases;3) To identify novel components that link PIP3 signaling and the actin cytoskeleton using proteomic approaches as well as genome-wide characterization of PH-domain containing proteins. The outcomes of our research are expected to provide novel insights into molecular mechanisms of chemotaxis and may lead to development of chemotaxis-based treatments for cancer and inflammation.

Public Health Relevance

We study chemotaxis, a process in which cells sense extracellular chemical compounds and move toward the source of chemicals. Chemotaxis is highly relevant to development and maintenance of healthy human body as well as the pathogenesis of many diseases such as cancer, asthma, arthritis and atherosclerosis. The long-term goal of our study is to understand how chemotaxis works and how defects in chemotaxis cause human diseases using a variety of approaches including genetics, biochemistry, cell biology and proteomics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084015-04
Application #
8325132
Study Section
Cell Structure and Function (CSF)
Program Officer
Nie, Zhongzhen
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$305,399
Indirect Cost
$119,180
Name
Johns Hopkins University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Nguyen, Hoai-Nghia; Yang, Jr-Ming; Afkari, Yashar et al. (2014) Engineering ePTEN, an enhanced PTEN with increased tumor suppressor activities. Proc Natl Acad Sci U S A 111:E2684-93
Zhang, Qiang; Tamura, Yasushi; Roy, Madhuparna et al. (2014) Biosynthesis and roles of phospholipids in mitochondrial fusion, division and mitophagy. Cell Mol Life Sci 71:3767-78
Itoh, Kie; Tamura, Yasushi; Iijima, Miho et al. (2013) Effects of Fcj1-Mos1 and mitochondrial division on aggregation of mitochondrial DNA nucleoids and organelle morphology. Mol Biol Cell 24:1842-51
Itoh, Kie; Nakamura, Ken; Iijima, Miho et al. (2013) Mitochondrial dynamics in neurodegeneration. Trends Cell Biol 23:64-71
Tamura, Yasushi; Onguka, Ouma; Hobbs, Alyson E Aiken et al. (2012) Role for two conserved intermembrane space proteins, Ups1p and Ups2p, [corrected] in intra-mitochondrial phospholipid trafficking. J Biol Chem 287:15205-18
Chen, Chun-Lin; Wang, Yu; Sesaki, Hiromi et al. (2012) Myosin I links PIP3 signaling to remodeling of the actin cytoskeleton in chemotaxis. Sci Signal 5:ra10
Zhang, Zhongyan; Wakabayashi, Nobunao; Wakabayashi, Junko et al. (2011) The dynamin-related GTPase Opa1 is required for glucose-stimulated ATP production in pancreatic beta cells. Mol Biol Cell 22:2235-45
Tang, Ming; Iijima, Miho; Kamimura, Yoichiro et al. (2011) Disruption of PKB signaling restores polarity to cells lacking tumor suppressor PTEN. Mol Biol Cell 22:437-47
Wang, Yu; Steimle, Paul A; Ren, Yixin et al. (2011) Dictyostelium huntingtin controls chemotaxis and cytokinesis through the regulation of myosin II phosphorylation. Mol Biol Cell 22:2270-81
Wang, Yu; Chen, Chun-Lin; Iijima, Miho (2011) Signaling mechanisms for chemotaxis. Dev Growth Differ 53:495-502

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