Laboratories and faculty

Molecular Signal Transduction

Outline of Research and Education

Signal transduction is indispensable for organ development and homeostasis. Hormones and neurotransmitters induce a variety of cell responses mediated through membrane receptors and intracellular signaling pathways. Impairment of the signal transduction often causes disease. And with this, many drugs targeting these signal components are widely used today. Our laboratory is interested in cellular signaling systems with special emphasis on 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 the alleviation of human disease.

Major Research Topics

Cellular functions and regulatory mechanisms 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.

Monoclonal antibodies against orphan adhesion GPCRs involved in tumorigenesis and neural function

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.

Role of adhesion GPCRs in breast cancer

Adhesion GPCRs equip characteristic extra cellular domains putatively involved in Cell-ECM interaction that underlies migration and invasion of cancer. We identified several adhesion GPCRs required for formation of invasive-like structure of breast cancer cells by using 3-D culture system. Our goal is to uncover mechanistic roles of these GPCRs in development and progression of breast cancer in vitro and in vivo.

Formation and function of primary cilia

Primary cilium, a tiny protrusion from cell surface, functions as the cellular antennae to sense extracellular environments and transduce signals to the cell body. Defects in the organelle associate with a wide spectrum of genetic diseases and cancers. We study to elucidate molecular mechanisms that underlie assembly and function of primary cilia in mammals, thereby approaching human disorders and drug development.

Fig. 1
Fig.1 Signal transduction mediated by G protein- coupled receptor
Fig. 2
Fig.2 G protein/PKA signal-regulated dynamics of a cytoskeleton in neuronal progenitor cells
Fig. 3
Fig.3 Monoclonal antibody against orphan GPCR as a tool for signal analysis

References

  1. Dateyama I. et al., J Cell Sci, 132, jcs224428, 2019
  2. Kobayashi T. et al., Cell Cycle, 16, 817, 2017
  3. Kobayashi T. et al., EMBO Rep., 18, 334, 2017
  4. Ohta S. et al., Biol. Pharm. Bull., 38, 59, 2015
  5. Kobayashi T. et al., J. Cell Biol., 204, 215, 2014
  6. Jenie RI. et al., Genes Cells, 18, 1095, 2013
  7. Toriyama M. et al., J. Biol. Chem, 287,12691, 2012
  8. Kobayashi T. et al., Cell, 145, 914, 2011
  9. Kobayashi T. et al., J. Cell Biol., 193, 435, 2011
  10. Nishimura A. et al., Proc. Natl. Acad. Sci. USA, 107, 13666, 2010
  11. Tago K. et al., J. Biol. Chem, 285, 30622, 2010
  12. Nagai Y. et al., J. Biol. Chem, 285, 11114, 2010
  13. Nakata A. et al., EMBO Rep., 10, 622, 2009
  14. Mizuno N. & Itoh H., Neurosignals, 17, 42, 2009
  15. Iguchi T. et al., J. Biol. Chem, 283, 14469, 2008
  16. Urano D. et al., Cell Signal, 20, 1545, 2008
  17. Sugawara Y. et al., Cell Signal, 19, 1301, 2007
  18. Nishimura A. et al., Genes Cells, 11, 487, 2006
  19. Mizuno N. et al., Proc. Natl. Acad. Sci. USA, 102, 12365, 2005