Itch E3 ubiquitin ligase regulates large tumor suppressor 1 tumor-suppressor stability
Itch E3 ubiquitin ligase regulates large tumor suppressor 1 tumor-suppressor stability
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DOI：
10.1073/pnas.1101273108
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发表时间：
2011-03-22
影响因子：
11.1
通讯作者：
Yang, Xiaolong
中科院分区：
文献类型：
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作者：
Ho, King Ching;Zhou, Zhonghua;Yang, Xiaolong
大肿瘤抑制因子1（LATS 1）是一种丝氨酸/苏氨酸激酶和肿瘤抑制因子，在广泛的人类癌症中被发现下调。LATS 1是新出现的Hippo-LATS抑制通路的核心参与者，其在细胞增殖、凋亡和干细胞分化中起重要作用。尽管有足够的数据支持LATS 1在肿瘤抑制中的作用，但LATS 1在分子水平上如何调节仍然是未知的。在这项研究中，我们已经确定了痒，HECT类E3泛素连接酶，作为一个独特的结合伴侣的LATS 1。瘙痒可以通过LATS 1的PPxY基序和瘙痒的WW结构域在体外和体内与LATS 1复合。值得注意的是，我们发现Itch的过度表达通过26 S蛋白酶体途径的多聚泛素化促进LATS 1降解。另一方面，通过shRNA敲低内源性瘙痒引起内源性LATS 1蛋白的稳定。最后，通过几种功能测定，我们还发现，Itch丰度的变化本身就足以改变LATS 1介导的下游信号传导，细胞增殖的负调控和凋亡的诱导。综合这些数据，我们的研究将E3泛素连接酶Itch鉴定为LATS 1的独特负调节因子，并提出了靶向LATS 1/Itch相互作用作为癌症治疗策略的可能性。
The large tumor suppressor 1 (LATS1) is a serine/threonine kinase and tumor suppressor found down-regulated in a broad spectrum of human cancers. LATS1 is a central player of the emerging Hippo-LATS suppressor pathway, which plays important roles in cell proliferation, apoptosis, and stem cell differentiation. Despite the ample data supporting a role for LATS1 in tumor suppression, how LATS1 is regulated at the molecular level remains largely unknown. In this study, we have identified Itch, a HECT class E3 ubiquitin ligase, as a unique binding partner of LATS1. Itch can complex with LATS1 both in vitro and in vivo through the PPxY motifs of LATS1 and the WW domains of Itch. Significantly, we found that overexpression of Itch promoted LATS1 degradation by polyubiquitination through the 26S proteasome pathway. On the other hand, knockdown of endogenous Itch by shRNAs provoked stabilization of endogenous LATS1 proteins. Finally, through several functional assays, we also revealed that change of Itch abundance alone is sufficient for altering LATS1-mediated downstream signaling, negative regulation of cell proliferation, and induction of apoptosis. Taking these data together, our study identifies E3 ubiquitin ligase Itch as a unique negative regulator of LATS1 and presents a possibility of targeting LATS1/Itch interaction as a therapeutic strategy in cancer.