Members of the transforming growth factor-beta (TGF-beta) family of peptide growth factors, which include TGF-beta, bone morphogenetic proteins (BMPs) and activins, regulate a broad range of cellular processes from cell growth and differentiation to apoptosis. The signaling responses to TGF-beta and other family members are mediated by a heteromeric complex of two types of transmembrane serine/threonine kinase receptors at the cell surface, and their intracellular substrates, the Smad proteins. To date, genetic or epigenetic alterations of different components of the TGF-beta signaling pathway have been reported in a number of human developmental or hyper-proliferative disorders and in various forms of cancers. Our research has focused on three aspects of TGF-beta signaling in an attempt to gain further appreciation of its regulation, mechanisms of action and function in development and tumorigenesis. The first of these is to understand the role of the ubiquitin-proteasome system in modulating TGF-beta signaling. We, and others, have previously identified two Smad ubiquitin regulatory factors (Smurfs) of the HECT domain-containing ubiquitin ligase family and shown that Smurf1 and Smurf2 have the ability to interact directly with Smad1 and Smad5 of the BMP pathway and mediate their degradation. To address the physiological significance of Smurfs in TGF-beta signaling, we have generated mice lacking either Smurf1 or Smurf2, and reported that Smurf1-deficient mice are perinatally normal but exhibit an age-dependent increase of bone mass due to enhanced osteoblast activity and increased responsiveness to BMP. Surprisingly, this skeletal abnormality is not caused by alteration in Smad-mediated TGF-beta or BMP signaling. Instead, loss of Smurf1 results in accumulation of phosphorylated MEKK2 in osteoblasts and activation of its downstream JNK signaling cascade. Our results reveal a novel function of Smurf1 in the regulation of osteoblast physiology and bone homeostasis, and provide an interesting example for the importance of the mitogen-activated protein kinase (MAPK) signaling pathway in shaping specific biological response to the TGF-beta family of cytokines. Currently, we are characterizing the phenotypes of Smurf1 and Smurf2 double deficient mice to investigate how Smurf-mediated ubiquitination affects cell growth, tissue differentiation and other biological processes regulated by the TGF-beta family of ligands. Although Smads are involved in most actions of the TGF-beta superfamily, activated TGF-beta receptors also transduce signals through other intracellular signaling pathways, especially those mediated by MAP kinases. The second area of research of my group focuses on the specific mechanism by which TGF-beta receptors activate MAP kinases independent of Smads, and the biological significance of this non-Smad dependent pathway in TGF-beta signaling. Currently, we seek to determine the molecular mechanism of the Smad-independent activation MAP kinases by identifying proteins that are specifically associated with TGF-beta type I receptor and characterizing their functions. In addition, we are also interested in how TGF-beta signaling converges with other pathways in response to growth factors and consequent activation of mitogen-activated protein kinase(MAPK) pathways. We would like to understand the role of this cross-talk in controlling TGF-beta-regulated gene transcription, cell proliferation, differenciation, apoptosis and tumor progression. The third direction of my group focuses on the effect of aberrant Smad signaling in tumorigenesis. We have generated different lines of transgenic mice carrying either wild type, or dominant negative or Smad3 under the control of a tetracycline-repressible promoter (tet-off).

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Basic Sciences
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Millet, Caroline; Zhang, Ying E (2007) Roles of Smad3 in TGF-beta signaling during carcinogenesis. Crit Rev Eukaryot Gene Expr 17:281-93
Kaneki, Hiroyuki; Guo, Ruolin; Chen, Di et al. (2006) Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts. J Biol Chem 281:4326-33
Yang, Yu-An; Zhang, Gen-Mu; Feigenbaum, Lionel et al. (2006) Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2. Cancer Cell 9:445-57
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Yamashita, Motozo; Ying, Sai-Xia; Zhang, Gen-Mu et al. (2005) Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation. Cell 121:101-13
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Ying, Sai-Xia; Hussain, Zareena J; Zhang, Ying E (2003) Smurf1 facilitates myogenic differentiation and antagonizes the bone morphogenetic protein-2-induced osteoblast conversion by targeting Smad5 for degradation. J Biol Chem 278:39029-36
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