Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Semin Cancer Biol. 2020 Dec;67(Pt 2):117-130. doi: 10.1016/j.semcancer.2020.03.003. Epub 2020 Mar 10.
The ITCH/AIP4 ubiquitin E3 ligase was discovered independently by two groups searching for atrophin-1 interacting proteins and studying the genetics of mouse coat color alteration, respectively. ITCH is classified as a NEDD4 family E3 ligase featured with the C-terminal HECT domain for E3 ligase function and WW domains for substrate recruiting. ITCH deficiency in the mouse causes severe multi-organ autoimmune disease. Its roles in maintaining a balanced immune response have been extensively characterized over the past two and a half decades. A wealth of reports demonstrate a multifaceted role of ITCH in human cancers. Given the versatility of ITCH in catalyzing both proteolytic and non-proteolytic ubiquitination of its over fifty substrates, ITCH's role in malignancies is believed to be context-dependent. In this review, we summarize the downstream substrates of ITCH, the functions of ITCH in both tumor cells and the immune system, as well as the implications of such functions in human cancers. Moreover, we describe the upstream regulatory mechanisms of ITCH and the efforts have been made to target ITCH using small molecule inhibitors.
ITCH/AIP4 泛素 E3 连接酶分别被两组独立发现，一组在寻找萎缩蛋白-1 相互作用蛋白，另一组则在研究小鼠毛色改变的遗传学。ITCH 被归类为 NEDD4 家族 E3 连接酶，其特征是 C 端 HECT 结构域用于 E3 连接酶功能和 WW 结构域用于底物招募。在小鼠中，ITCH 的缺失会导致严重的多器官自身免疫性疾病。在过去的二十五年中，ITCH 在维持平衡的免疫反应中的作用得到了广泛的研究。大量的报告表明，ITCH 在人类癌症中具有多方面的作用。鉴于 ITCH 能够对其五十多个底物进行蛋白水解和非蛋白水解泛素化，ITCH 在恶性肿瘤中的作用被认为是依赖于上下文的。在这篇综述中，我们总结了 ITCH 的下游底物、ITCH 在肿瘤细胞和免疫系统中的功能，以及这些功能在人类癌症中的意义。此外，我们描述了 ITCH 的上游调控机制，并描述了使用小分子抑制剂靶向 ITCH 的努力。
