Research Topic:  Lipid Signaling Chemotaxis

Mechanisms of gradient sensing and chemotaxis are conserved in mammalian leukocytes and Dictyostelium amoebae. Both cells use G protein linked signaling pathways.  PH domains specific for PtdIns(3,4)P2 and PtdIns(3,4,5)P3 bind to the membrane at the leading edge of the chemotaxing cell. This suggests that the local production of  these phosphoinositides are regulated by PI3Ks and PTEN phosphatases and are a key component of directional sensing. The translocation of specific PH domain containing proteins at the leading edge likely regulates actin polymerization and pseudopud formation. Phosphoinositide secondary messengers may include members of the small GTPase Rho family, which have dramatic effects on the organization of the actin cytoskeleton. These GTPases are activated by guanine nucleotide exchange factors (GEFs). The GEFs for Rho/Rac/cdc42 each contain a PH domain and a catalytic Dbl homology domain, some of which have been shown to bind to the PIP3.

In order to make a further connection between signaling events and directional movement, we have identified 17 new PH domain-containing proteins in addition to 10 previously known genes in the Dictyostelium cDNA and genome database. Five of these genes contain both the Dbl and the PH domains, suggesting these proteins are involved in actin polymerization. A PTEN homologue has been also identified in Dictyostelium that is highly conserved with the human gene. We are disrupting all of these genes and studying their roles in chemotaxis.

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Selected Publications

Tang, M., Iijima, M., and Devreotes, P. Generation of cells that ignore the effects of PIP3 on cytoskeleton.  Cell Cycle. (2011). In press.

Wang, Y., Steimle, P.A., Ren, Y., Ross, C.A., Robinson, D.N., Egelhoff, T.T., Sesaki, H., and Iijima, M. Dictyostelium huntingtin controls chemotaxis and cytokinesis through the regulation of myosin II phosphorylation. Mol. Biol. Cell. (2011). 22: 2270-2281

Wang, Y., Chen, C-L., and Iijima, M. Signaling mechanisms for chemotaxis. Development Growth and Differentiation (2011). 53: 495-502

Zhang, Z., Wakabayashi, N., Wakabayashi, J., Tamura, Y., Song, W.J., Sereda, S., Clerc, P., Polster, B.M., Aja, S.M., Pletnikov, M.V., Kensler, T.W., Shirihai, O.S., Iijima, M., Hussain, M.A., and Sesaki H. The dynamin-related GTPase Opa1 is required for glucose-stimulated ATP production in pancreatic beta cells. Mol. Biol. Cell. (2011). 22: 2235-2245.

Tang, M., Iijima, M., Kamimura, Y., Chen, L., Long, Y., and Devreotes, P. Disruption of PKB signaling restores polarity to cells lacking tumor suppressor PTEN. Mol. Biol. Cell. (2011). 22: 437-47.

Zhang, P., Wang, Y., Sesaki, H. and Iijima, M. Proteomic identification of PtdIns(3,4,5)P3-binding proteins in D. discoideum. Proc. Natl. Acad. Sci. USA. (2010). 107: 11829-11834.

Tamura, Y., Iijima, M., and Sesaki, H. Mdm35p imports Ups proteins into the mitochondrial intermembrane space by functional complex formation. EMBO J. (2010). 29: 2875-2887.

Wakabayashi, J., Zhang, Z., Wakabayashi, N., Tamura, Y., Fukaya, M., Kensler, T.W., Iijima, M., and Sesaki, H. The dyanmin-related GTPase Drp1 is required for embryonic and brain development in mice. J. Cell Biol. (2009). 186: 805-816.

Pramanik, M.K., Iijima, M., Iwadate, Y., and Yumura, S.  PTEN is a mechanosensing signal transducer for myosin II localization in Dictyostelium cells. Genes to Cells. (2009). 14: 821-34.

Tamura, Y., Endo, T., Iijima, M., and Sesaki, H. Ups1p and Ups2p antagonistically regulate cardiolipin metabolism in mitochondria. J. Cell Biol. (2009). 185: 1029-1045.

Yoshino, R., Morio, T., Yamada, Y., Kuwayama, H., Sameshima, M., Tanaka, Y., Sesaki, H., and Iijima, M., Regulation of ammonia homeostasis by the ammonium transporter AmtA in Dictyostelium, Eukaryot Cell.  (2007) 6: 2419-2428.

Chen, L., Iijima, M., Tang, M., Landree, M.A. Huang, Y.E.,  Xiong, Y., Iglesias, P.A., Devreotes, P.N. PLA2 and PI3K/PTEN pathways act in parallel to mediate chemotaxis.
Dev. Cell. (2007) 12: 603-614.

Somesh, B.P., Vlahou, G., Iijima, M., Insall, R.H., Devreotes, P.N., Rivero, F. RacG regulates morphology, phagocytosis and chemotaxis. Eukaryot Cell. (2006) 5:1648-1663.

Somesh, B.P., Neffgen, C., Iijima, M., Devreotes, P.N., Rivero, F. Dictyostelium RacH regulates endocytic vesicular trafficking and is required for localization of vacuolin. Traffic. (2006) 7:1194-1212.

Sesaki, H., Dunn, C.D., Iijima, M., Shepard, K.A., Yaffe, M.P., Machamer, C.E., and Jensen, R.E. Ups1p, a conserved intermembrane space protein, regulates mitochondrial shape and alternative topogenesis of Mgm1p. J. Cell Biol. (2006) 173:651-658.

Matsuoka, S., Iijima, M., Watanabe, T.M., Kuwayama, H., Yanagida, T., Devreotes, P.N., and Ueda, M. Single-molecule analysis of chemoattractant-stimulated membrane recruitment of a PH-domain-containing protein. J Cell Sci. (2006) 119:1071-1079.

Janetopoulos, C., Borleis, J., Vazquez, F., Iijima, M., and Devreotes, P.N. Temporal and spatial regulation of phosphoinositide signaling mediates cytokinesis. Dev. Cell. (2005) 8: 467-477.

Iijima, M., Huang, Y.E., Luo, H.R., Vazquez, F., Devreotes, P.N. Novel mechanism of PTEN regulation by its phosphatidylinositol 4,5-bisphosphate binding motif is critical for chemotaxis.
J. Biol. Chem. (2004) 16: 16606-16613.

Chen, L., Janetopoulos, C., Huang, Y.E., Iijima, M., Borleis, J., Devreotes, P.N. Two phases of actin polymerization display different dependencies on PI(3,4,5)P3 accumulation and have unique roles during chemotaxis. Mol. Biol. Cell. (2003) 12: 5028-5037.

Luo, H.R., Huang, Y.E., Chen, J.C., Saiardi, A., Iijima, M., Ye, K., Huang, Y., Nagata, E., Devreotes, P.N., Snyder, S.H. Inositol Pyrophosphates Mediate Chemotaxis in Dictyostelium via Pleckstrin Homology Domain-PtdIns(3,4,5)P3 Interactions. Cell (2003) 114: 559-572.

Huang, Y.E., Iijima, M., Parent, C.A., Funamoto, S., Firtel, R.A., Devreotes, P.N. Receptor-mediated Regulation of PI3Ks Confines PI(3,4,5)P3 to the Leading Edge of Chemotaxing Cells.
Mol. Biol. Cell. (2003) 5:1913-1922.

Iijima, M., Huang, Y.E., Devreotes, P.N. Temporal and spatial regulation of chemotaxis.
Dev. Cell (2002) 4; 469-478.

Iijima, M., and Devreotes, P.N. Tumor suppressor PTEN mediates sensing of chemoattractant gradients. Cell (2002) 109; 599-610 (Cover page picture).