Identification of SGK1 as a novel positive regulator of YAP and TAZ

Abstract

In recent years, an emerging role of YAP and TAZ in the increasingly sophisticated cancer biology field demands a more articulate understanding of protein networks surrounding YAP and TAZ. This also means elucidation of detailed regulatory mechanisms relevant to YAP/TAZ within the pre-established signaling pathway, is crucial to better understand the extent of YAP and TAZs activity during cancer development. With this in mind, I worked on candidate regulatory partners of YAP and TAZ. SGK1 is an oncoprotein of the PI3-K signaling pathway with recent therapeutic implication in AKT inhibitor-resistant cancers. I confirmed that SGK1 is a downstream target of YAP with rapid responsiveness to YAP activation. Moreover, SGK1 transcription was controlled by a critical YAP-interacting transcription factor, TEAD. In addition, I found that YAP directly binds to the distal enhancer of SGK1 to promote transcription. On the other hand, I discovered that SGK1 controls canonical YAP/TAZ targets, CTGF and CYR61 via its kinase domain and PPxY motif. Furthermore, SGK1 regulates YAP and TAZ protein levels to promote CTGF and CYR61 expression. Lastly, I found that SGK1 stabilizes TAZ via GSK3β phosphorylation. Alternatively, I discovered that TAZ is regulated by its paralog, YAP, in a negative way. I found that this regulation is rather unidirectional and conserved among numerous cell lines. TAZ regulation by YAP was controlled at the translational level, but not at the transcriptional or post-translational level. Finally, I found this regulatory mechanism was independent of the Hippo signaling pathway. In conclusion, I discovered two regulatory mechanisms controlling TAZ in both positive and negative manners.