Summary of Research Project Results Under the JSPS FY2000
"Research for the future Program"



1.Research Institution@Japanese Foundation for Cancer Research (JFCR)
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2.Research Area@Life Science
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3.Research Field@Cellular Signaling
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4.Term of Project@FY1996`FY2000
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5.Project Number@96L00304
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6.Title of Project@Study on the Signal Transduction by Serine-Threonine Kinase Receptors

7.Projetct Leader
Name Institution,Department Title of Position
Kohei Miyazono JFCR Cancer Inst., Biochemistry Chief

8.Core Members

Names Institution,Department Title of Position
Masahiro Kawabata JFCR Cancer Inst., Biochemistry Ass. Member
Takeshi Imamura JFCR Cancer Inst., Biochemistry Ass. Member
Tetsuo Noda JFCR Cancer Inst., Cell Biology Chief

9.Cooperating Researchers

Names Institution,Department Title of Position
Mitsuyasu Kato JFCR Cancer Inst., Biochemistry Ass. Member
Makiko Fujii JFCR Cancer Inst., Biochemistry Post-doc
Hideyuki Beppu JFCR Cancer Inst., Biochemistry Post-doc

10.Summary of Research Results

We studied the signaling mechanisms of serine-threonine kinase receptors, which are the receptors for members of transforming growth factor- (TGF-) superfamily. We studied: 1) signaling mechanisms of serine-threonine kinase receptors in invertebrates, e.g. Drosophila, 2) signaling mechanisms of serine-threonine kinase receptors in mammalian cells, and 3) studies on signaling by serine-threonine kinase receptors using gene targeting in mice.
We first isolated Smad6, an inhibitory Smads in mammals, and proposed that Smads can be classified into three subtypes, i.e. receptor-regulated Smads, common-partner Smads, and inhibitory Smads. We demonstrated several proteins interacting Smads, including Runx and Ski. We also showed biological activities of Smads, e.g. their effects on bone and cartilage formation, using adenoviral vector systems.
In Drosophila melanogaster, we reported severla proteins involved in erine-threonine kinase receptor signaling. These include DIAP1, Dad, Medea, dSmad2, and Schnurri.
We further prepared mice lacking Smad2 and BMP type II receptor. The BMP type II receptor is responsible for the pathogenesis of human primary pulmonary hypertension. We were able to show some biochemical evidence that the mutations of the BMP type II receptor block signaling activity of BMPs.

11.Key Words

(1)TGF-A(2)BMPA(3)serine-threonine kinase
(4)receptorA(5)SmadA(6)Drosophila
(7)adenovirus vectorA(8)gene targetingA(9)signal transduction

12.References

[Reference Articles]
Author Title of Article
Heldin, C. -H., et al. TGF- signalling from cell membrane to nucleus via Smad proteins
Journal Volume Year Pages Concerned
Nature 390 1997 465-471

Author Title of Article
Nakao, A., et al. TGF- receptor-mediated signalling through Smad2, Smad3 and Smad4
Journal Volume Year Pages Concerned
EMBO J. 16 1997 5353-5362

Author Title of Article
Imamura T., et al. Smad6 inhibits signalling by the TGF- superfamily
Journal Volume Year Pages Concerned
Nature 389 1997 622-626

Author Title of Article
Shimizu, A., et al. Identification of receptors and Smad proteins involved in activin signaling in a human epidermal keratinocyte cell line
Journal Volume Year Pages Concerned
Genes Cells 3 1998 125-134

Author Title of Article
Oeda, E., et al. Interaction of Drosophila inhibitors of apoptosis with Thick veins, a type I serine/threonine kinase receptor for Decapentaplegic
Journal Volume Year Pages Concerned
J. Biol. Chem. 273 1998 9353-9356

Author Title of Article
Inoue, H., et al. Interplay of signal mediators of Decapentaplegic (Dpp): Molecular characterization of Mothers aganst dpp, Medea, and Daughters against Dpp
Journal Volume Year Pages Concerned
Mol. Biol. Cell 9 1998 2145-2156

Author Title of Article
Kawabata, M., et al. Smad proteins exist as monomers in vivo and undergo homo- and hetero- oligomerization upon activation by serine/threonine kinase receptors
Journal Volume Year Pages Concerned
EMBO J. 17 1998 4056-4065

Author Title of Article
Nishihara, A., et al. Role of p300, a transcriptional coactivator, in signaling of TGF-
Journal Volume Year Pages Concerned
Genes Cells 3 1998 613-623

Author Title of Article
Yagi, K., et al. Alternatively-spliced variand of Smad2 lacking exon 3: Comparison with wild-type Smad2 and Smad3
Journal Volume Year Pages Concerned
J. Biol. Chem. 274 1999 703-709

Author Title of Article
Yanagisawa. J., et al. Convergence of transforming growth factor- and vitamin D signaling pathways on SMAD transcriptional coactivators
Journal Volume Year Pages Concerned
Science 283 1999 1317-1321

Author Title of Article
Nakashima, K., et al. Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300
Journal Volume Year Pages Concerned
Science 284 1999 479-482

Author Title of Article
Nishihara, A., et al. E1A inhibits transforming growth factor- signaling through binding to Smad proteins
Journal Volume Year Pages Concerned
J. Biol. Chem. 274 1999 28716-28723

Author Title of Article
Ebisawa, T., et al. Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation
Journal Volume Year Pages Concerned
J. Cell Sci. 112 1999 3519-3527

Author Title of Article
Fujii, M., et al. Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblastic and chondroblastic differentiation
Journal Volume Year Pages Concerned
Mol. Biol. Cell 10 1999 3801-3813

Author Title of Article
Ishida, W., et al. Smad6 is a Smad1/5-induced Smad inhibitor: Characterization of bone morphogenetic protein-responsive element in the mouse Smad6 promoter
Journal Volume Year Pages Concerned
J. Biol. Chem. 275 2000 6075-6079

Author Title of Article
Udagawa, Y., et al. Schnurri interacts with Mad in a Dpp-dependent manner
Journal Volume Year Pages Concerned
Genes Cells 5 2000 359-370

Author Title of Article
Beppu,, H., et al. BMP type II receptor is required for gastrulation and early development of mouse embryos
Journal Volume Year Pages Concerned
Dev. Biol. 221 2000 249-258

Author Title of Article
Aoki, H., et al. Synergistic effects of different bone morphogenetic protein type I receptors on alkaline phosphatase induction
Journal Volume Year Pages Concerned
J. Cell Sci. @ 2001 in press

Author Title of Article
Miyazono, K., et al. TGF- signaling by Smad proteins
Journal Volume Year Pages Concerned
Adv. Immunol. 75 2000 115-157

Author Title of Article
Miyazono, K. Positive and negative regulation of TGF- signaling
Journal Volume Year Pages Concerned
J. Cell Sci. 113 2000 1101-1109

Author Title of Article
Miyazono, K. TGF- signaling by Smad proteins
Journal Volume Year Pages Concerned
Cytokine Growth Factor Rev. 11 2000 15-22

Author Title of Article
Miyazono, K., et al. Divergence and convergence of TGF-/BMP signaling
Journal Volume Year Pages Concerned
J. Cell. Physiol. @ 2001 in press

Author Title of Article
Ebisawa, T., et al. Smurf1 interacts with transforming growth factor- type I receptor through Smad7 and induces receptor degradation
Journal Volume Year Pages Concerned
J. Biol. Chem. @ 2001 in press

Author Title of Article
Fukuchi, M., et al. Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins
Journal Volume Year Pages Concerned
Mol. Biol. Cell @ 2001 in press


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