Summary of Research Project Results under JSPS FY2001
"Research for the Future Program"

1.Research Institution Nagoya University
2.Research Area Life Sciences
3.Research Field Cellular Signaling
4.Term of Project FY 1997 〜 FY 2001
5.Project Number 97L00302
6.Title of Project Regulation of Cytoskeletons by Intracellular Signals

7.Project Leader
Name Institution,Department Title of Position
Kozo, Kaibuchi Nagoya University, Graduate School of Medicine Professor

8.Core Members

Names Institution,Department Title of Position
Masaki, Inagaki Aichi Cancer Center Research Institute Director
Sinya, Yamanaka Nara Institute of Science and Technology, Graduate School of Biological Sciences Assistant Professor

9.Summary of Research Results

Research interest of our group is to understand the molecular mechanism underlying the regulation of cytoskeleton and cell adhesion through the Rho family GTPases by intracellular signals. However, how the Rho family GTPases regulate the various functions was largely unknown until recently. We previously identified Rho-kinase and MBS, as effectors of Rho, and found that Rho-kinase together with MBS regulate contractility of non-muscle cells and smooth muscle, and stress fiber and focal adhesion formation through the phosphorylation of myosin light chain. In this project, we have found the following results.
(1) Cytoskeleton: We have identified various substrates of Rho-kinase, such as adducin, ERM family protein, intermediate filaments, and CRMP-2. We have found that the phosphorylation of adducin, ERM family protein, and CRMP-2 by Rho-kinase are important for cell migration, cytoskeletal reorganization, and growth cone collapse, respectively. We have also shown that the Rho/Rho-kinase pathway is involved in the pathogenesis of vasospasm and arteriosclerosis, and is a potent target of new therapies for these diseases. Moreover, we have shown that CRMP-2 plays critical roles in determination of axon/dendrite fate.
(2) Cell adhesion: We have found that IQGAP1, as a effector of Rac1 and Cdc42, negatively regulates E-cadherin-mediated cell-cell adhesion by interacting with β-catenin, causing the dissociation ofα -catenin from the cadherin-catenin complex. Activated Rac1 and Cdc42 positively regulate cadherin-mediated cell-cell adhesion by inhibiting the interaction of IQGAP1 withβ-catenin. Moreover, we have shown that Rac1/Cdc42/IQGAP1 system functions in cell scattering, which is thought to be a model system for dispersal of cancer cells. Our results indicate that the Rho family GTPases and their effectors regulate rearrangements of cytoskeletons and cell adhesions.

10.Key Words

(1)Signal transduction、(2)Neuroscience、(3)Brain/Neuron
(4)Cytoskeleton/Cell adhesion、(5)Arteriosclerosis、(6)Nervous system regeneration
(7)Small GTPases、(8)Rho-kinase、(9)CRMP-2