Controlled protein degradation mediated by E3 ubiquitin ligases plays a crucial role in modulating a broad range of cellular responses. Dysregulation of the ubiquitin-proteasome system often accompanies tumorigenesis and progression. We found that Smurf2 is up-regulated in certain breast cancer tissues and cells. We show that reduction of Smurf2 expression with specific short interfering RNA in metastatic breast cancer cells induces cell rounding and reorganization of the actin cytoskeleton that is associated with a less motile and invasive phenotype. Overexpression of Smurf2 promotes metastasis in the nude mouse model and induces epithelial-to-mesenmchymal transition, migration and invasion of breast cancer cells. Moreover, expression of an E3 ligase-defective mutant of Smurf2, Smurf2CG, suppressed the above metastatic behaviors. These results establish an important role for Smurf2 in breast cancer progression and indicate that Smurf2 is a novel regulator of breast cancer cell migration and invasion. 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 Smurf2 deficient mice and Smurf1/Smurf2 double deficient mice

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
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
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
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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