PTPN14 Forms a Complex with Kibra and LATS1 Proteins and Negatively Regulates the YAP Oncogenic Function
PTPN14 Forms a Complex with Kibra and LATS1 Proteins and Negatively Regulates the YAP Oncogenic Function
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DOI：
10.1074/jbc.m113.534701
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发表时间：
2014-08-22
影响因子：
4.8
通讯作者：
Zhang, Jianmin
中科院分区：
文献类型：
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作者：
Wilson, Kayla E.;Li, Ying-Wei;Zhang, Jianmin
背景：转录共激活因子YAP/TAZ是河马信号通路的关键效应者，其功能障碍促进了上皮向间充质转化(EMT)和恶性转化。结果：PTPN14与Kibra相互作用，激活YAP上游负调控因子LATS1。结论：PTPN14和Kibra激活LATS1，负性调节YAP的致癌功能。意义：研究YAP的调控机制对于了解其在生理和病理过程中的作用至关重要。Hippo信号通路调节细胞的增殖和存活，从而对正常细胞的命运和肿瘤的发生产生深远的影响。该途径的关键效应者是YAP/TAZ，这是一种转录共激活因子，其功能障碍有助于上皮向间充质转化和恶性转化。因此，破译YAP/TAZ在各个层面上的监管机制具有重要意义。在这里，我们报道了非受体酪氨酸磷酸酶14(PTPN14)与Kibra蛋白的相互作用。PTPN14与Kibra的相互作用是通过PTPN14的PPXY结构域和Kibra的WW结构域实现的。PTPN14和Kibra可独立或协同地诱导LATS1的激活。有趣的是，PTPN14对LATS1的激活依赖于PTPN14的C末端，而不依赖于哺乳动物STE20样蛋白(MST)的上游。此外，我们还证明了PTPN14提高了LAST1蛋白的稳定性。最后，Kibra的过表达挽救了PTPN14基因敲除引起的细胞迁移增加和异常的三维形态发生，这种挽救是通过激活上游LATS1激酶和随后的YAP胞浆隔离来实现的。综上所述，我们的结果表明PTPN14在河马途径中具有潜在的调节作用，并证明了YAP致癌功能的另一层调节。
Background: Transcriptional co-activators YAP/TAZ are pivotal effectors of the Hippo pathway and their dysfunction promote epithelial-to-mesenchymal transition (EMT) and malignant transformation. Results: PTPN14 interacts with Kibra and activates LATS1 (upstream negative regulator of YAP). Conclusion: PTPN14 and Kibra activate LATS1 and negatively regulate the YAP oncogenic function. Significance: Study of the YAP regulatory mechanism is crucial for understanding its role in the physiological and pathological processes.The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. Pivotal effectors of this pathway are YAP/TAZ, transcriptional co-activators whose dysfunction contributes to epithelial-to-mesenchymal transition and malignant transformation. Therefore, it is of great importance to decipher the mechanisms underlying the regulations of YAP/TAZ at various levels. Here we report that non-receptor tyrosine phosphatase 14 (PTPN14) interacts with the Kibra protein. The interaction between PTPN14 and Kibra is through the PPXY domain of PTPN14 and WW domain of Kibra. PTPN14 and Kibra can induce the LATS1 activation independently and cooperatively. Interestingly, activation of LATS1 by PTPN14 is dependent on the C terminus of PTPN14 and independent of the upstream mammalian STE20-like kinase (MST) proteins. Furthermore, we demonstrate that PTPN14 increases the LAST1 protein stability. Last, overexpression of Kibra rescues the increased cell migration and aberrant three-dimensional morphogenesis induced by knockdown of PTPN14, and this rescue is mediated through the activation of the upstream LATS1 kinase and subsequent cytoplasmic sequestration of YAP. In summary, our results indicate a potential regulatory role of PTPN14 in the Hippo pathway and demonstrate another layer of regulation in the YAP oncogenic function.