Abrogation of cellular responses to Bone Morphogenetic Proteins (BMPs) and other members of TGF-( superfamily are associated with human bone diseases such as osteoporosis, pulmonary hypertension and heritable cancer. Our long-term objective is to understand the molecular basis of how BMP/TGF-( regulate cell growth and differentiation, and the underlying mechanisms through which alterations in BMP signaling leads to deregulation of growth and differentiation control in human bone diseases. BMPs induce the differentiation of mesenchymal cells towards the osteoblastic lineage to promote bone formation. One of the most critical events in activation of BMP signal transduction pathway is the phosphorylation of transcription factor Smad1/5/8 (collective term for Smad1, Smad5 and Smad8) by BMP receptors. While phosphorylated Smad1/5/8 directly activate the target genes in the nucleus, protein phosphatases are anticipated to dephosphorylate phospho-Smad1/5/8 and consequently inactivate BMP signaling. The identity of the long sought-after phosphatase has been one of the major unanswered questions in BMP/TGF-( biology until very recently. We have discovered that Smad1/5/8 can be dephosphorylated by several phosphatases. Our short-term strategy for this proposal is to characterize biochemical properties of the phosphatases and investigate their biological functions in the regulation of BMP signaling during osteoblast differentiation. Our preliminary studies (both published and unpublished) lead us to hypothesize that Smad phosphatases block or terminate BMP signaling during osteoblast differentiation. Thus, it is significantly important to investigate the physiological roles of Smad phosphatases in bone formation. In this application, we will focus our study on the functions and molecular mechanism of Smad dephosphorylation during osteoblast differentiation.
Three specific aims are proposed:
Aim 1 : Biochemical characterization of Smad phosphatases for dephosphorylation of BMP-specific Smad1/5/8.
Aim 2 : Elucidation of the functions of Smad phosphatases-mediated Smad dephosphorylation in BMP signaling.
Aim 3 : Investigation on the roles of Smad phosphatases in osteoblast differentiation from mesenchymal stem cells. The proposed experiments will open a new area of research on how Smad phosphatases modulate BMP signaling pathways through Smad dephosphorylation. Specifically, the elucidation of the physiological roles of Smad phosphatases-mediated dephosphorylation of Smad1/5/8, and perhaps other R-Smads as well, will provide insights into the important role of BMP/TGF-( signaling in bone growth and development.

Public Health Relevance

The major goal of this research proposal is to investigate the functions of protein phosphatases in bone formation. We have identified three phosphatases as negative regulators of bone morphogenetic proteins (BMP). Our results will be pertinent towards the development of novel therapeutic approaches for the prevention and treatment of human bone diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR053591-05
Application #
8308683
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Chen, Faye H
Project Start
2008-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$288,855
Indirect Cost
$100,676
Name
Baylor College of Medicine
Department
Surgery
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Zhao, Yulan; Xiao, Mu; Sun, Baoguo et al. (2014) C-terminal domain (CTD) small phosphatase-like 2 modulates the canonical bone morphogenetic protein (BMP) signaling and mesenchymal differentiation via Smad dephosphorylation. J Biol Chem 289:26441-50
Shen, Tao; Sun, Chuang; Zhang, Zhengmao et al. (2014) Specific control of BMP signaling and mesenchymal differentiation by cytoplasmic phosphatase PPM1H. Cell Res 24:727-41
Feng, Yili; Wu, Hongxing; Xu, Yongxian et al. (2014) Zinc finger protein 451 is a novel Smad corepressor in transforming growth factor-* signaling. J Biol Chem 289:2072-83
Dai, Fangyan; Shen, Tao; Li, Zhaoyong et al. (2011) PPM1A dephosphorylates RanBP3 to enable efficient nuclear export of Smad2 and Smad3. EMBO Rep 12:1175-81
Dai, Fangyan; Duan, Xueyan; Liang, Yao-Yun et al. (2010) Coupling of dephosphorylation and nuclear export of Smads in TGF-beta signaling. Methods Mol Biol 647:125-37
Liu, Ting; Feng, Xin-Hua (2010) Regulation of TGF-beta signalling by protein phosphatases. Biochem J 430:191-8
Martinez, Gustavo J; Zhang, Zhengmao; Reynolds, Joseph M et al. (2010) Smad2 positively regulates the generation of Th17 cells. J Biol Chem 285:29039-43
Wrighton, Katharine H; Lin, Xia; Yu, Paul B et al. (2009) Transforming Growth Factor {beta} Can Stimulate Smad1 Phosphorylation Independently of Bone Morphogenic Protein Receptors. J Biol Chem 284:9755-63
Martinez, Gustavo J; Zhang, Zhengmao; Chung, Yeonseok et al. (2009) Smad3 differentially regulates the induction of regulatory and inflammatory T cell differentiation. J Biol Chem 284:35283-6
Dai, Fangyan; Lin, Xia; Chang, Chenbei et al. (2009) Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-beta signaling. Dev Cell 16:345-57

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