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
Yang, Jr-M; Schiapparelli, P; Nguyen, H-N et al. (2017) Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization. Oncogene 36:3673-3685
Yamada, Tatsuya; Adachi, Yoshihiro; Fukaya, Masahiro et al. (2016) Dynamin-Related Protein 1 Deficiency Leads to Receptor-Interacting Protein Kinase 3-Mediated Necroptotic Neurodegeneration. Am J Pathol 186:2798-2802
Yamada, Tatsuya; Adachi, Yoshihiro; Iijima, Miho et al. (2016) Making a Division Apparatus on Mitochondria. Trends Biochem Sci 41:209-10
Senoo, Hiroshi; Cai, Huaqing; Wang, Yu et al. (2016) The novel RacE-binding protein GflB sharpens Ras activity at the leading edge of migrating cells. Mol Biol Cell 27:1596-605
Senoo, Hiroshi; Sesaki, Hiromi; Iijima, Miho (2016) A GPCR Handles Bacterial Sensing in Chemotaxis and Phagocytosis. Dev Cell 36:354-6
Roy, Madhuparna; Itoh, Kie; Iijima, Miho et al. (2016) Parkin suppresses Drp1-independent mitochondrial division. Biochem Biophys Res Commun 475:283-8
Adachi, Yoshihiro; Itoh, Kie; Yamada, Tatsuya et al. (2016) Coincident Phosphatidic Acid Interaction Restrains Drp1 in Mitochondrial Division. Mol Cell 63:1034-43
Yang, Jr-Ming; Nguyen, Hoai-Nghia; Sesaki, Hiromi et al. (2015) Engineering PTEN function: membrane association and activity. Methods 77-78:119-24
Roy, Madhuparna; Kageyama, Yusuke; Iijima, Miho et al. (2015) PARK2/Parkin becomes critical when DNM1L/Drp1 is absent. Autophagy 11:573-4
Nguyen, H-N; Yang Jr, J-M; Rahdar, M et al. (2015) A new class of cancer-associated PTEN mutations defined by membrane translocation defects. Oncogene 34:3737-43

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