Cell proliferation and differentiation are regulated by extracellular growth factors. Among these, transforming growth factor-beta (TGF-beta) plays a key role in growth control. Unlike growth factors that act through tyrosine kinase receptors and stimulate cell proliferation, TGF-beta inhibits cell growth and induces expression of various extracellular matrix proteins. TGF-beta is the prototype of many factors that play key roles in cell differentiation and development. The activities of TGF- beta-related proteins are mediated through a recently discovered class or receptors, the transmembrane serine-threonine kinases. Two types of receptors, the type II and type I receptors, form the functional heteromeric receptor complex. Following TGF-beta binding, the type II receptor transphosphorylates the type I receptor, leading to intracellular signaling that results in changes in gene expression. Smads have recently been identified as signaling effectors of TGF-beta receptors. Receptor activation by TGF-beta results in phosphorylation of Smad2 and/or 3, which then dissociate from the receptor and engage in a heteromeric complex with Smad4/DPC4. These Smads are then translocated into the nucleus where they activate transcription of defined genes. The TGF-beta type II receptor, Smad2 and Smad4/DPC4 all act as tumor suppressors, whose inactivation contributes to tumor development. To understand the mechanism of TGF-beta receptor signaling and the role of TGF-beta and related factors in normal and tumor development, it is essential that we understand the mechanisms of activation and action of the Smads. The goal of this research proposal is to characterize two key processes in Smad function, thereby using Smad2 and 3 and Smad4, i.e. the Smads that mediate TGF-beta receptor signaling, as models.
In Aim 1, we propose to characterize the mechanisms of nuclear translocation of Smads in response to receptor activation.
In Aim 2, we will characterize the mechanisms of transcriptional activation of genes by Smads in response to TGF- beta, thereby using two known TGF-beta-responsive promoters as model systems. Finally, in Aim 3, we will identify and functionally characterize proteins that associate with the TGF- beta responsive Smads. The latter studies will greatly complement and contribute to the characterization of the mechanisms of nuclear translocation of Smads and transcriptional activation by Smads. Taken together, our research program should result in the characterization of two essential key processes in Smad function and TGF-beta receptor signaling. Our findings should help us understand the role of TGF-beta receptor signaling in normal and tumor development, and in the regulation of cell growth and differentiation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA063101-08
Application #
6489287
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Program Officer
Freeman, Colette S
Project Start
1995-01-01
Project End
2003-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
8
Fiscal Year
2002
Total Cost
$401,850
Indirect Cost
Name
University of California San Francisco
Department
Dentistry
Type
Schools of Dentistry
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Du, Dan; Katsuno, Yoko; Meyer, Dominique et al. (2018) Smad3-mediated recruitment of the methyltransferase SETDB1/ESET controls Snail1 expression and epithelial-mesenchymal transition. EMBO Rep 19:135-155
Budi, Erine H; Xu, Jian; Derynck, Rik (2016) Regulation of TGF-? Receptors. Methods Mol Biol 1344:1-33
Muthusamy, Baby Periyanayaki; Budi, Erine H; Katsuno, Yoko et al. (2015) ShcA Protects against Epithelial-Mesenchymal Transition through Compartmentalized Inhibition of TGF-?-Induced Smad Activation. PLoS Biol 13:e1002325
Xu, Pinglong; Bailey-Bucktrout, Samantha; Xi, Ying et al. (2014) Innate antiviral host defense attenuates TGF-? function through IRF3-mediated suppression of Smad signaling. Mol Cell 56:723-37
Sakaki-Yumoto, Masayo; Katsuno, Yoko; Derynck, Rik (2013) TGF-? family signaling in stem cells. Biochim Biophys Acta 1830:2280-96
Katsuno, Yoko; Lamouille, Samy; Derynck, Rik (2013) TGF-ýý signaling and epithelial-mesenchymal transition in cancer progression. Curr Opin Oncol 25:76-84
Xu, Jian; Wang, A Hongjun; Oses-Prieto, Juan et al. (2013) Arginine Methylation Initiates BMP-Induced Smad Signaling. Mol Cell 51:5-19
Xu, Pinglong; Liu, Jianming; Derynck, Rik (2012) Post-translational regulation of TGF-* receptor and Smad signaling. FEBS Lett 586:1871-84
Xu, Pinglong; Liu, Jianming; Sakaki-Yumoto, Masayo et al. (2012) TACE activation by MAPK-mediated regulation of cell surface dimerization and TIMP3 association. Sci Signal 5:ra34

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