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 #
5R01GM084015-02
Application #
7937803
Study Section
Cell Structure and Function (CSF)
Program Officer
Deatherage, James F
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$308,484
Indirect Cost
Name
Johns Hopkins University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kriebel, Paul W; Majumdar, Ritankar; Jenkins, Lisa M et al. (2018) Extracellular vesicles direct migration by synthesizing and releasing chemotactic signals. J Cell Biol 217:2891-2910
Yamada, Tatsuya; Murata, Daisuke; Adachi, Yoshihiro et al. (2018) Mitochondrial Stasis Reveals p62-Mediated Ubiquitination in Parkin-Independent Mitophagy and Mitigates Nonalcoholic Fatty Liver Disease. Cell Metab 28:588-604.e5
Igarashi, Atsushi; Itoh, Kie; Yamada, Tatsuya et al. (2018) Nuclear PTEN deficiency causes microcephaly with decreased neuronal soma size and increased seizure susceptibility. J Biol Chem 293:9292-9300
Adachi, Yoshihiro; Iijima, Miho; Sesaki, Hiromi (2018) An unstructured loop that is critical for interactions of the stalk domain of Drp1 with saturated phosphatidic acid. Small GTPases 9:472-479
Yamada, Tatsuya; Adachi, Yoshihiro; Yanagawa, Toru et al. (2018) p62/sequestosome-1 knockout delays neurodegeneration induced by Drp1 loss. Neurochem Int 117:77-81
Kameoka, Shoichiro; Adachi, Yoshihiro; Okamoto, Koji et al. (2018) Phosphatidic Acid and Cardiolipin Coordinate Mitochondrial Dynamics. Trends Cell Biol 28:67-76
Itoh, Kie; Adachi, Yoshihiro; Yamada, Tatsuya et al. (2018) A brain-enriched Drp1 isoform associates with lysosomes, late endosomes, and the plasma membrane. J Biol Chem 293:11809-11822
Tellios, Nikoleta; Belrose, Jillian C; Tokarewicz, Alexander C et al. (2017) TGF-? induces phosphorylation of phosphatase and tensin homolog: implications for fibrosis of the trabecular meshwork tissue in glaucoma. Sci Rep 7:812
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
Adachi, Yoshihiro; Itoh, Kie; Iijima, Miho et al. (2017) Assay to Measure Interactions between Purified Drp1 and Synthetic Liposomes. Bio Protoc 7:

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