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Signal transduction is indispensable for organ development and homeostasis. Hormones, neurotransmitters induce a variety of cell responses mediated through membrane receptors and intracellular signaling pathways. Impairment of the signal transduction often causes disease. Many drugs targeted at the signal components are widely used today. Our laboratory is interested in cellular signaling systems with special emphasis through heterotrimeric G proteins. In our laboratory, faculty and graduate students are dedicated to cutting-edge scientific research and work towards a better understanding of how the human body functions and to alleviate human disease.
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1 ) Regulatory mechanisms and functions of G protein signaling
Heterotrimeric GTP-binding regulatory protein (G protein) consists of α, β and γ subunits, and is activated by seven-span transmembrane receptors, G protein-coupled receptors (GPCRs). G proteins transduce extracellular signals to downstream effecter molecules and are involved in many aspects of cellular physiology. Recently, a small molecule and several gene products that regulate the G protein signaling have been discovered. We try to clarify the new regulatory mechanisms and functions of G protein signaling using these molecules. Cross talk and interaction between different signaling pathways are also studied.
2 ) Molecular mechanisms for regulation of migration, self-renewal, differentiation of neural stem cells
Neural stem cell that can differentiate into neuron and glia exist in not only embryo but also adult brain. However, the mechanism for self- renewal, asymmetric cell division and migration during brain development remains obscure. Using slice culture, neurosphere culture and in ovo microinjection with virus-vectors, we attempt to understand the molecular mechanisms. More recently, we found the dual regulation of neuronal progenitor cell migration by distinct G protein signals mediated through dynamic cytoskeleton rearrangements.
3 ) Monoclonal antibodies against orphan adhesion GPCRs
More than 200 members of GPCRs are orphan receptors that miss endogenous ligands. We prepared the monoclonal antibodies against adhesion GPCR, GPR56, and obtained the functional antibody that acts as an agonist. This antibody inhibits cancer cell migration in vitro system. Using newly identified antibodies, we analyze the function and activation mechanism of orphan adhesion GPCRs, and approach the drug development.
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- Nishimura A. et al., Proc. Natl. Acad. Sci. USA, 107, 13666, 2010
- Tago K. et al., J. Biol. Chem, 285, 30622, 2010
- Nagai Y. et al., J. Biol. Chem, 285, 11114, 2010
- Nakata A. et al., EMBO Rep., 10, 622-628, 2009
- Mizuno N. & Itoh H., Neurosignals 17, 42, 2009
- Iguchi T. et al., J. Biol. Chem, 283, 14469, 2008
- Urano D et al., Cell Signal, 20, 1545, 2008
- Sugawara et al., Cell Signal, 19, 1301, 2007
- Nishimura A. et al., Gene Cells, 11, 487, 2006
- Mizuno N. et al., Proc. Natl. Acad. Sci. USA, 102, 12365, 2005
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Fig. 1 Signal transduction mediated by G protein- coupled receptor
Fig. 2 G protein/PKA signal-regulated dynamics of cytoskeleton in neuronal progenitor cells
Fig. 3 Monoclonal antibody against orphan GPCR as a tool for signal analysis
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