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].