Physiological and pathological functions of E3 ubiquitin ligases Smurfs

由E3泛素连接酶介导的受控蛋白质降解在调节广泛的细胞反应中起着至关重要的作用。泛素-蛋白酶体系统的失调常常伴随着肿瘤的发生和发展。我们发现S-2在某些乳腺癌组织和细胞中表达上调。我们发现，在转移性乳腺癌细胞中，用特定的短干扰RNA降低SMurf2的表达可以诱导细胞圆化和肌动蛋白细胞骨架的重组，这与运动性和侵袭性较差的表型有关。SMurf2的过表达促进裸鼠模型的转移，并诱导乳腺癌细胞向上皮间充质转化、迁移和侵袭。此外，SMurf2的E3连接酶缺陷突变体SMurf2CG的表达抑制了上述转移行为。这些结果确立了SMurf2在乳腺癌进展中的重要作用，并表明SMurf2是一种新的乳腺癌细胞迁移和侵袭调节因子。为了探讨蓝精灵在转化生长因子-β信号转导中的生理意义，我们培育了缺乏SMurf1或SMurf2的小鼠，并报告了SMurf1缺陷小鼠出生时正常，但由于成骨细胞活性增强和对BMP的反应性增强，表现出随年龄增加的骨量增加。令人惊讶的是，这种骨骼异常并不是由Smad介导的转化生长因子-β或骨形态发生蛋白信号的改变引起的。相反，SMurf1的缺失会导致成骨细胞中磷酸化的MEKK2的积累，并激活其下游的JNK信号级联。我们的结果揭示了SMurf1在成骨细胞生理和骨稳态调节中的新功能，并为丝裂原活化蛋白激酶(MAPK)信号通路在形成对转化生长因子-β家族的特异性生物反应中的重要性提供了一个有趣的例子。目前，我们正在对SMurf2缺陷小鼠和SMurf1/SMurf2双缺陷小鼠的表型进行鉴定

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