Faculty Profile, National Health Research Institutes, Taiwan

Faculty Profiles


Isao Matsuura, Ph.D.

Assistant Investigator
Institute of Molecular and Genomic Medicine
imatsuura@nhri.org.tw

EDUCATION

- M.Sc. & Ph.D., Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, Japan, 1992
- B.Sc., Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, Japan, 1987

PROFESSIONAL EXPERIENCES

- Assistant Investigator, Division of Molecular and Genomic Medicine, National Health Research Institutes, Taiwan (2006-present)
- Research Associate, Center for Advanced Biotechnology & Medicine, Rutgers University, USA (2003- present)
- Postdoctoral Fellow, Center for Advanced Biotechnology & Medicine, Rutgers University, USA (1999-2003)
- Research Associate, Kresge Eye Institute, Wayne State University, USA (1997-1999)
- Exchange Scholar, Department of Biochemistry & Molecular Biology, University of Melbourne, Australia (1996-1997)
- Research Assistant, Department of Biochemistry, Hong Kong University of Science & Technology, Hong Kong (1995-1997)
- Research Fellow, Department of Medical Biochemistry, Faculty of Medicine, University of Calgary, Canada(1992-1995)

RESEARCH INTERESTS

Transforming growth factor-b (TGF-β) is a multifunctional cytokine and plays important roles in cancer development. In normal cells it works as a growth inhibitor whereas it is a tumor promoter in some cancer cells. It signals from cell surface to nucleus through its major effecter proteins, Smads, and other pathways that involve phosphorylation events of many cellular proteins.

TGF-β signal ultimately leads to gene regulation, and differential spectrum of genes regulated by TGF-β in normal and cancer cells may account for its conflicting dual role in cancer development. Understanding the molecular mechanisms by which TGF-β switch its property during cancer development will have important implications for cancer therapeutics.

A number of studies have suggested that major downstream effecters, Smads, switch their property during cancer progression. Although this "dual function" model seems to be widely accepted, the molecular basis of how the same signaling pathway play opposite roes in cancer development is poorly understood.

Smad2/3 contain several serine or threonine residues followed by proline (prolinedirected sites) that are phosphorylated in vivo. Interested in the role of this phosphorylation in modulation of Smad activity, Dr. Matsuura is searching for a novel Smad-binding protein(s) that interacts with Smads in a proline-directed phosphorylation-sensitive manner. Identification of such proteins may reveal novel Smad-mediated pathway(s) in cancer development.TGF-β induces phosphorylation of many intracellular proteins (non-Smad pathways). Using new phosphoproteomic techniques, Dr. Matsuura is also analyzing TGF-β-mediated changes in phosphoproteomes of normal and cancer cells. The information from the study will provide new insight into the role of TGF-β signaling in cancer.

RESEARCH ACTIVITIES & ACCOMPLISHMENTS

Smad3, a major mediator of TGF-β sinnaling, contains several serine or threonine residues followed by proline (proline-directed sites) that are phosphorylated in vivo. Using a series of phospho-specific antibodies, we have demonstrated multiple sites in Smad3, Thr8, T178 and Ser212, can be phosphorylated by G1 CDKs, CDK4 and CDK2. Mutation of these sites to nonphosphorylatable residues augmented Smad3 activity: downregulating c-Myc, upregulating p15, and inhibiting cell growth. Thus CDK-catalyzed phosphorylation negatively regulates antiproliferative function of Smad3. This finding established a novel negative feedback mechanism in the Smad3-mediated cytostatic pathway. Erk MAP kinases can also phosphorylate Smad3 at partially overlapped sites (Thr178, Ser203 and Ser207) to inhibit its activity. Because cancer cells often contain elevated levels of G1 CDK activity as well as Erk activity, increased Smad3 phosphorylation in those cells may contribute to the resistance to TGF-β-mediated growth inhibition and to tumorigenesis.

HONORS & AWARDS

- 2005 New Jersey Cancer Research Award for Scientific Excellence

SELECTED PUBLICATIONS

  1. Matsuura, I., Wang G., He, D., and Liu, F. Identification and characterization of MAP kinase phosphorylation sites in Smad3. Biochemistry 44:12546-12553, 2005.
  2. Liu, F. and Matsuura, I. Inhibition of Smad antiproliferative function by CDK phosphorylation. Cell Cycle 4:1, 63-66, 2005.
  3. Wang, G., Long, J., Matsuura, I., He, D., and Liu, F. The Smad3 linker-region contains a transcriptional activation domain. Biochem. J. 386: 29-34, 2005.
  4. Long, J., Wang, G., Matsuura, I., He, D., and Liu, F. Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3). Proc. Natl. Acad. Sci. USA 101: 99-104, 2004.
  5. Matsuura, I., Denissova, N.G., Wang, G., Long, J., He, D., and Liu, F. Cyclin-dependent kinases regulate the antiproliferational function of Smads.* Nature 430: 226-231, 2004. (*selected in top ten articles of the month)
  6. Long, J., Matsuura, I., He, D., Wang, G., Shuai, K., and Liu, F. Repression of Smad transcriptional activity by PIASy, an inhibitor of activated STAT. Proc. Natl. Acad. Sci. USA 100: 9791-9796, 2003.
  7. Yamazaki, A., Yu, H., Yamazaki, M., Honkawa, H., Matsuura, I., Usukura, J., and Yamazaki, R.K. A critical role for ATP in the stimulation of retinal guanylyl cyclase by guanlyly cyclase-activating proteins. J. Biol. Chem. 278: 33150-33160, 2003.