The Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Cancer Res. 2011 Mar 1;71(5):2010-20. doi: 10.1158/0008-5472.CAN-10-3516. Epub 2011 Jan 6.
The Hippo tumor suppressor pathway, originally defined in fruit flies, regulates cellular proliferation and survival and exerts profound effects on normal mammalian cell fate and tumorigenesis. The present understanding of Hippo pathway components and mechanisms remains incomplete in cancer. WW domain-containing proteins regulate diverse biological processes through interaction with proline-tyrosine (PPxY)-containing targets. In this study, we report that the E3 ubiquitin ligase ITCH regulates stability of LATS1, a serine/threonine kinase in the Hippo pathway, through protein-protein interaction of the PPxY motifs of LATS1 with the WW domains of ITCH. Ubiquitination of LATS1 catalyzed by ITCH stimulated the proteasomal degradation of LATS1. Furthermore, ITCH-mediated degradation of LATS1 was associated with enhanced cell growth, induction of epithelial-mesenchymal transition, and increased tumorigenicity. Conversely, ITCH depletion increased LATS1 levels, enhancing FAS-induced apoptosis and reducing proliferation, survival, and migration. These phenotypes were rescued when both ITCH and LATS1 were depleted. Together, our results reveal a novel functional link between ITCH and the Hippo pathway, deepening their critical roles in tumorigenesis.
Hippo 肿瘤抑制通路最初在果蝇中定义，调节细胞增殖和存活，并对正常哺乳动物细胞命运和肿瘤发生产生深远影响。目前对癌症中 Hippo 通路成分和机制的认识仍然不完整。WW 结构域蛋白通过与脯氨酸-酪氨酸（PPxY）含有目标的相互作用，调节多种生物学过程。在这项研究中，我们报告 E3 泛素连接酶 ITCH 通过 Hippo 通路中丝氨酸/苏氨酸激酶 LATS1 的 PPxY 基序与 ITCH 的 WW 结构域的蛋白-蛋白相互作用，调节 LATS1 的稳定性。由 ITCH 催化的 LATS1 的泛素化刺激了 LATS1 的蛋白酶体降解。此外，ITCH 介导的 LATS1 降解与增强的细胞生长、上皮-间充质转化的诱导和增加的肿瘤发生有关。相反，ITCH 的耗竭增加了 LATS1 的水平，增强了 FAS 诱导的细胞凋亡并减少了增殖、存活和迁移。当同时耗尽 ITCH 和 LATS1 时，这些表型得到挽救。总之，我们的结果揭示了 ITCH 和 Hippo 通路之间的新的功能联系，加深了它们在肿瘤发生中的关键作用。
