Smad ubiquitin regulatory factors (Smurfs) are members of the HECT family of E3 ubiquitin ligases. Two Smurfs, Smurf1 and Smurf2, were identified based on their activities to modulate TGF-beta/BMP signaling by promoting ubiquitin modification on Smads;however, subsequent studies have expanded the repertoire of Smurf substrates to include proteins such as RhoA, Runx2 and MEKK2 outside the TGF-beta/BMP pathway. To address the physiological function of Smurfs, we have generated mice lacking either Smurf1 or Smurf2. We found that these two paralogous E3 ubiquitin ligases 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 mechanism in regulating 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 more 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. Because loss of both Smurfs leads to embryonic lethality, we have created a conditional Smurf2 knockout allele, which enabled us to investigate physiological functions of Smurfs by completely removal of all Smurf activities in desired tissues using tissue-specific expression of cre recombinase and obtain conditional Smurf null cells from late stages embryos or adult tissues. Our study of Smurf2 knockout mice also led to an unexpected discovery of a previously unrecognized function of Smurf2 as a tumor suppressor that normally maintains genomic stability by controlling epigenetic landscape of histone modifications. We found that Smurf2 interacts with a group of proteins that regulate DNA replication, chromatin remodeling and histone modification. We are currently validating these findings using in vitro and in vivo approaches and to investigate the biological relevance of these interactions in genomic stability and tumorigenesis. Consistent with the tumor suppresser function of Smurf2, we found that Smurf2 expression is decreased in the nucleus but increased in the cytoplasm of breast cancer cells. Smurf1 expression is also upregulated in the cytoplasm of the breast cancer cells. Overexpression of Smurf1 and Smurf2 promotes metastasis in nude mouse models and induces epithelial-to-mesenmchymal transition, migration, and invasion of breast cancer cells, suggesting that Smurfs play important roles in breast cancer progression. We are currently studying the mechanism underpinning the role of Smurf1 and Smurf2 promoting breast cancer cell migration and invasion.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Tang, Yi; Tang, Liu-Ya; Xu, Xuan et al. (2018) Generation of Smurf2 Conditional Knockout Mice. Int J Biol Sci 14:542-548
Zhao, X; Parpart, S; Takai, A et al. (2015) Integrative genomics identifies YY1AP1 as an oncogenic driver in EpCAM(+) AFP(+) hepatocellular carcinoma. Oncogene 34:5095-104
Yue, Shen; Tang, Liu-Ya; Tang, Ying et al. (2014) Requirement of Smurf-mediated endocytosis of Patched1 in sonic hedgehog signal reception. Elife 3:
Wang, Xiangchun; Jin, Chaoyang; Tang, Yi et al. (2013) Ubiquitination of tumor necrosis factor receptor-associated factor 4 (TRAF4) by Smad ubiquitination regulatory factor 1 (Smurf1) regulates motility of breast epithelial and cancer cells. J Biol Chem 288:21784-92
Blank, Michael; Tang, Yi; Yamashita, Motozo et al. (2012) A tumor suppressor function of Smurf2 associated with controlling chromatin landscape and genome stability through RNF20. Nat Med 18:227-34
Orvedahl, Anthony; Sumpter Jr, Rhea; Xiao, Guanghua et al. (2011) Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 480:113-7
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
Tang, Liu-Ya; Zhang, Ying E (2011) Non-degradative ubiquitination in Smad-dependent TGF-? signaling. Cell Biosci 1:43
Cheng, Steven Y; Zhang, Ying E (2011) Smurfs have ""fused"" into the asymmetric division of stem cells. Protein Cell 2:2-4
Jin, Chaoyang; Yang, Yu-an; Anver, Miriam R et al. (2009) Smad ubiquitination regulatory factor 2 promotes metastasis of breast cancer cells by enhancing migration and invasiveness. Cancer Res 69:735-40

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