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, Dr. Iijima and her team 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. They are disrupting all of these genes and studying their roles in chemotaxis.
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Wang, Y., Senoo, H., Sesaki, H. and Iijima, M. (2013). Rho GTPases orient gradient sensing in chemotaxis. Proc. Natl. Acad. Sci. USA. 110: E4723-32
Nguyen, H-N., Yang, J.M., Afkari, Y., Park, B.H., Sesaki, H., Devreotes, P.N. and Iijima, M. (2014). Engineering ePTEN: an enhanced PTEN with increased tumor suppressor activities. Proc. Natl. Acad. Sci. USA. 111: E2684-2693
Yang, J.M., Schiapparelli, P., Nguyen, H-N., Igarashi, A., Zhang, Q., Abbadi, S., Amzel, L.M., Sesaki, H., Quiñones-Hinojosa, A., and Iijima, M. (2017). Characterization of PTEN mutations in brain cancer reveals that PTEN mono-ubiquitination promotes protein stability and nuclear localization. Oncogene. 36: 3673-3685
Igarashi, A., Itoh, K., Yamada, T., Adachi, Y., kato, T., Murata, D., Sesaki, H., and Iijima, M. (2018). Nuclear PTEN deficiency causes microcephaly with decreased neuronal soma size and increased seizure susceptibility. J. Biol. Chem. 5;293: 9292-9300
Senoo H, Kamimura K, Kimura R, Nakajima A, Sawai S, Sesaki H, Iijima M. (2019). Phosphorylated Rho-GDP directly activates mTORC2 Kinase toward AKT through dimerization with Ras-GTP to regulate cell migration. Nat. Cell Biol. 21: 867-878