Through the action of its membrane bound type I receptor, TGF-beta elicits a wide range of cellular responses that regulate cell proliferation, differentiation and apoptosis. Many of these signaling responses are mediated by Smad proteins. As such, controlling Smad activity is crucial for proper signaling by TGF-beta and its related factors. The first area of our research focused on the regulation of TGF-beta signaling by post-translational modification that translate quantitative difference in ligand concentration into proportional transcriptional output, particularly the ubiquitin modification catalyzed by Smurf1 and Smurf2, which are HECT-domain E3 ligases. Resorting to mouse genetic approaches, we generated knockout alleles of both Smurf1 and Smurf2 genes to address their roles under physiological conditions. We found that Smurf1 and Smurf2 have both common and unique functions during embryogenesis and in maintaining adult physiological homeostasis. Our earlier work on characterizing Smurf1 knockout mice revealed a novel function of Smurf1 in the regulation of osteoblast function and bone homeostasis, suggesting that targeting Smurf1 may prove to be an effective strategy for treating age-related bone losses in osteoporosis. Our recent work on characterizing Smurf2 knockout mice clarified contradictory reports in the literature about Smurf regulation of TGF-beta signaling by showing that Smurf2 indeed has an inhibitory role, but it does so by attenuating Smad3 activity through mono-ubiquitination rather than promoting its degradation as previously reported. 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. Toward this goal, we found that TRAF6 is specifically required for the Smad-independent activation of JNK and p38 and its carboxyl TRAF homology domain physically interacts with TGF-beta receptors. TGF-beta induces K63-linked ubiquitination of TRAF6, and promotes association between TRAF6 and TAK1. Our results indicate that TGF-beta activates JNK and p38 through a mechanism similar to that operating in the interleukin-1beta/Toll-like receptor pathway. Currently, we are expanding this findings to characterize molecular mechanisms of the Smad-independent pathways by identifying proteins that are specifically associated with TGF-beta type I receptor using proteomics and characterizing their functions. In addition, we are also interested in how Smad signaling converges with other pathways and what kind of roles these cross-talks play in controlling TGF-beta-regulated gene transcription, cell proliferation, differenciation, apoptosis and tumor progression.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Cancer Institute Division of Basic Sciences
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Zhang, Ying E (2017) Non-Smad Signaling Pathways of the TGF-? Family. Cold Spring Harb Perspect Biol 9:
Tang, Liu-Ya; Heller, Mary; Meng, Zhaojing et al. (2017) Transforming Growth Factor-? (TGF-?) Directly Activates the JAK1-STAT3 Axis to Induce Hepatic Fibrosis in Coordination with the SMAD Pathway. J Biol Chem 292:4302-4312
Tripathi, Veenu; Zhang, Ying E (2017) Redirecting RNA splicing by SMAD3 turns TGF-? into a tumor promoter. Mol Cell Oncol 4:e1265699
Tripathi, Veenu; Sixt, Katherine M; Gao, Shaojian et al. (2016) Direct Regulation of Alternative Splicing by SMAD3 through PCBP1 Is Essential to the Tumor-Promoting Role of TGF-?. Mol Cell 64:549-564
Zhang, Ying E; Newfeld, Stuart J (2013) Meeting report - TGF-? superfamily: signaling in development and disease. J Cell Sci 126:4809-13
Tang, Liu-Ya; Zhang, Ying E (2011) Non-degradative ubiquitination in Smad-dependent TGF-? signaling. Cell Biosci 1:43
Zhang, Ying E (2011) A special issue on TGF-? signaling and biology. Cell Biosci 1:39
Zhang, Ying E (2011) Stopped in translation: EMT control meets eukaryotic elongation. Dev Cell 20:289-90
Tang, Liu-Ya; Yamashita, Motozo; Coussens, Nathan P et al. (2011) Ablation of Smurf2 reveals an inhibition in TGF-? signalling through multiple mono-ubiquitination of Smad3. EMBO J 30:4777-89
Zhang, Ming; Wang, Meina; Tan, Xiaohong et al. (2010) Smad3 prevents beta-catenin degradation and facilitates beta-catenin nuclear translocation in chondrocytes. J Biol Chem 285:8703-10

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