Kindlin-2 Inhibits the Hippo Signaling Pathway by Promoting Degradation of MOB1
Kindlin-2 Inhibits the Hippo Signaling Pathway by Promoting Degradation of MOB1
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Kindlin-2 通过促进 MOB1 降解来抑制 Hippo 信号通路
DOI：
10.1016/j.celrep.2019.11.035
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发表时间：
2019-12-10
期刊：
影响因子：
8.8
通讯作者：
Zhang, Hongquan
中科院分区：
文献类型：
--
作者：
Song, Jiagui;Wang, Tianzhuo;Zhang, Hongquan
Hippo信号通路在发育和癌症进展中起着关键作用。然而，内在地抑制该途径的分子不太为人所知。在这里，我们报告说，黏着斑分子Kindlin-2抑制海马信号通过相互作用和降解MOB 1和促进MOB 1和E3连接酶praja 2之间的相互作用。因此，Kindlin-2抑制LATS 1和雅普的磷酸化，并促进雅普易位到细胞核中，在细胞核中激活下游Hippo靶基因转录。Kindlin-2缺失激活Hippo/雅普信号传导并加重单侧输尿管闭塞（UUO）的Kindlin-2敲除小鼠的肾纤维化。此外，肾纤维化患者样本中Kindlin-2水平与MOB 1和磷酸化（p）雅普呈负相关。总之，这些结果表明Kindlin-2通过降解MOB 1抑制Hippo信号传导。针对Kindlin-2的特异性长效siRNA可有效减轻UUO诱导的肾纤维化，可能成为肾纤维化的潜在治疗方法。
The Hippo signaling pathway plays a key role in development and cancer progression. However, molecules that intrinsically inhibit this pathway are less well known. Here, we report that the focal adhesion molecule Kindlin-2 inhibits Hippo signaling by interacting with and degrading MOB1 and promoting the interaction between MOB1 and the E3 ligase praja2. Kindlin-2 thus inhibits the phosphorylation of LATS1 and YAP and promotes YAP translocation into the nucleus, where it activates downstream Hippo target gene transcription. Kindlin-2 depletion activates Hippo/YAP signaling and alleviates renal fibrosis in Kindlin-2 knockout mice with unilateral ureteral occlusion (UUO). Moreover, Kindlin-2 levels are negatively correlated with MOB1 and phosphorylated (p) YAP in samples from patients with renal fibrosis. Altogether, these results demonstrate that Kindlin-2 inhibits Hippo signaling through degradation of MOB1. A specific long-lasting siRNA against Kindlin-2 effectively alleviated UUO-induced renal fibrosis and could be a potential therapy for renal fibrosis.