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.
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.
|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|
Showing the most recent 10 out of 34 publications