去泛素化酶USP4与酪氨酸磷酸酶PRL-3的相互作用及其在结直肠癌中的作用

近期我们发现，酪氨酸磷酸酶PRL-3可能存在与泛素／蛋白酶体系统之间的功能联系（J Proteome Res，2010；Gut，2013）。免疫共沉淀结合蛋白质谱分析结果表明，去泛素化酶USP4可能是PRL-3新型相互作用蛋白；并且USP4可以通过将PRL-3去泛素化而稳定PRL-3的功能，这是USP4促进上皮间质转化和结直肠癌转移的重要分子基础；同时，PRL-3对USP4也存在一定的影响。基于此我们提出，去泛素化酶USP4与酪氨酸磷酸酶PRL-3之间的相互作用构成一种重要的调节机制，并参与结直肠癌发生或转移的过程。本研究拟应用肠粘膜上皮条件性USP4敲除小鼠、结直肠癌相关细胞系及结直肠癌临床组织标本从整体动物模型、细胞模型及临床标本等方面明确去泛素化酶USP4与酪氨酸磷酸酶PRL-3的相互作用及其调节机制，并探讨它们在结直肠癌发生及发展中的作用。

We recently suggested that these were some functional links between Phosphatase of regenerating liver-3 (PRL-3), a key metastasis associated protein, and ubiquitin proteasome system（J Proteome Res，2011；Gut，2013）. Interestingly, Ubiquitin Specific Protease 4 (USP4), a deubiquitylating enzyme, was identified as a candidate of PRL-3 interacting protein by co-immunoprecipitation and mass spectrometry. More importantly, abnormal expression of USP4 contributes to the development and progression of CRC and PRL-3is indispensable for USP4-mediated oncogenic activity in CRC. USP4 interacted with and stabilized PRL-3 via deubiquitination, which resulted in activation of Akt and reduction of E-cadherin, critical regulators of growth and metastasis of cancer cells. Based on these results, we proposed a key functional crosstalk between USP4 and PRL-3 in colorectal cancer.We will study the functional link between USP4 and PRL-3 and their roles in pathogenesis and progression of CRC in intestinal specific knockout of USP4 mouse model, cell models and clinical samples of CRC.