Physiological and pathological functions of E3 ubiquitin ligases Smurfs

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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