â‘´Hippo signaling pathway
The Hippo pathway regulates tissue growth and cell fate and is considered a central regulator of tissue homeostasis and organ size[40-43]. The Hippo pathway can receive upstream stimuli, such as hypoxia, and can also interact with other pathways to convert signals into intracellular responses[37]. YAP/TAZ is a multifunctional transcriptional activator that is a downstream effector of the Hippo pathway, plays a negative regulatory role, participates in a variety of cellular responses and is closely related to cell proliferation and metabolism [44]. Under the regulation of the Hippo pathway, YAP/TAZ can enter the nucleus, combine with TEAD transcription factors to form a complex, and be recruited to specific target promoter sequences, thereby regulating gene expression during cell growth and other developmental processes and promoting tissue remodeling [43,45-47]. At the heart of the Hippo pathway is a kinase cascade in which Mst1/2 kinases and SAV1 form a complex that phosphorylates and activates LATS1/2[48]. LATS1/2 kinases in turn phosphorylate and inhibit the transcriptional coactivator YAP/TAZ[49]. YAP/TAZ phosphorylation prevents its nuclear localization and leads to cytoplasmic sequestration by binding to the 14-3-3 adaptor protein. Furthermore, YAP/TAZ can be targeted for degradation through subsequent phosphorylation of casein kinase 1[39,45]. Inactivation or loss of MST1/2 and LATS1/2 can lead to dephosphorylation and nuclear translocation of YAP/TAZ [31]. After dephosphorylation, YAP/TAZ is transported to the nucleus and interacts with other transcription factors to induce gene expression that promotes cell proliferation and inhibits apoptosis [31]. As one of the main effector proteins downstream of the Hippo pathway, YAP/TAZ is regulated by cell and tissue structure and is also affected by other signals, including mechanotransformation, Wnt signaling, and Notch metabolic signaling [50].