Yoo Geon, Kim Tackhoon, Chung Chaeuk, Hwang Deog-Su, Lim Dae-Sik
School of Biological Sciences, Seoul National University, Seoul 151-742, South Korea.
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea; National Creative Research Center for Cell Division and Differentiation, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea.
Biochem Biophys Res Commun. 2017 Aug 26;490(3):650-656. doi: 10.1016/j.bbrc.2017.06.092. Epub 2017 Jun 17.
YAP (Yes-associated protein) and TAZ (transcription activator with PDZ binding motif) are important in tissue regeneration and cancer development, highlighting the importance of discovering partners that regulate their oncogenicity. SGK1 (serum/glucocorticoid regulated kinase 1), initially identified as a homolog of Akt in phosphoinositide 3-kinase signaling, acts as a serine/threonine protein kinase in multiple oncogenic pathways. However, possible links between SGK1 and Hippo-YAP/TAZ signaling remain unexplored. Here, we reveal that SGK1 is a potential positive feedback regulator of YAP and TAZ, showing that the TEAD-YAP/TAZ complex directly activates SGK1 transcription by binding to the distal enhancer of SGK1, and SGK1, in turn, stabilizes YAP/TAZ. Moreover, we demonstrate that expression of YAP/TAZ target genes is positively regulated by SGK1. Mechanistically, SGK1 inhibits ubiquitin-mediated degradation of TAZ by inhibiting GSK3β activity. These findings expand our understanding of YAP/TAZ regulation to include the novel downstream target of YAP, SGK1.
Yes相关蛋白（YAP）和具有PDZ结合基序的转录激活因子（TAZ）在组织再生和癌症发展中起着重要作用，这凸显了发现调节其致癌性的伙伴的重要性。血清/糖皮质激素调节激酶1（SGK1）最初被鉴定为磷脂酰肌醇3激酶信号通路中Akt的同源物，在多个致癌途径中作为丝氨酸/苏氨酸蛋白激酶发挥作用。然而，SGK1与Hippo-YAP/TAZ信号通路之间的潜在联系仍未被探索。在这里，我们揭示SGK1是YAP和TAZ的潜在正反馈调节因子，表明TEAD-YAP/TAZ复合物通过结合SGK1的远端增强子直接激活SGK1转录，而SGK1反过来又稳定YAP/TAZ。此外，我们证明YAP/TAZ靶基因的表达受SGK1正向调节。从机制上讲，SGK1通过抑制糖原合酶激酶3β（GSK3β）的活性来抑制泛素介导的TAZ降解。这些发现扩展了我们对YAP/TAZ调节的理解，将YAP的新下游靶点SGK1纳入其中。
