Introduction
Introduction
The Hippo signaling pathway is a signaling pathway that has been found to play an important role in the regulation of multicellular biological organ size in recent years. Patient sample analysis and mouse model studies indicate that dysregulation of the Hippo signaling pathway plays a key role in the different stages of cancer development. The Hippo signaling pathway senses a variety of external stimuli such as the mechanical environment, G-protein coupled receptor signaling, and cellular energy levels, and is activated by protein kinase chains. then, the transcriptional coactivator YAP (Yes-associated protein) and its homologous protein TAZ (transcriptional coactivator with PDZ-binding motif) are directly phosphorylated, resulting in their cytoplasmic retention and degradation.
In general, this signaling pathway has three interrelated components: upstream regulatory signaling, the hippo core kinase cascade complex, and the downstream nuclear transcriptional regulatory complex. Among them, hippo upstream regulatory signals or abnormal activity of the core kinase cascade complex can lead to excessive organ growth and multiple tumors.
Figure 1 Regulation and functions of the Hippo pathway
Upstream signaling of Hippo
Activation of MST1/2
MST1/2 is a pro-apoptotic kinase that is activated by caspase-specific cysteine proteolytic enzymes under apoptotic signals. SAV1 directly binds to the SARAH domain of the MST1/2 protein via the SARAH domain, thereby activating MST1/2. In mammalian cells, MST1/2 can also be activated by binding to the RASSF (Ras-association domain family) protein, possibly due to altered MST1/2 subcellular localization.
In the protein kinase chain of the Hippo signaling pathway, MST1/2 activates LATS1/2 through a variety of mechanisms. Activation of LATS1/2 requires phosphorylation of a conserved serine or threonine residue within its activation loop and its C-terminal hydrophobic motif. MST1/2 phosphorylates the C-terminal hydrophobic motif of LATS1/2, which promotes autoactivation of the activation loop of LATS1/2. MST1/2 phosphorylates MOB1, which promotes the binding of MOB1 to the inhibitory region of LATS1/2, and activates the inhibition of LATS1/2 activity. In addition, crystal structure analysis indicated that MOB1 was phosphorylated by MST1/2 to form MST1/2-MOB1 complex, which was then combined with LATS1/2 to form MST1/2-MOB1-LATS1/2 ternary complex. When MST1/2 phosphorylates LATS1/2 and MOB1, phosphorylated MOB1 drives the ternary complex to dissociate. The activated LATS1/2 phosphorylation transcripts a specific amino acid residue of the auxiliary activator YAP/TAZ, resulting in its activity being inhibited. In addition to MST1/2, MAP4Ks (mitogen-activated protein kinase kinase kinase kinase) can also phosphorylate and activate LATS1/2.
The Hippo signaling pathway is a signaling pathway that has been found to play an important role in the regulation of multicellular biological organ size in recent years. Patient sample analysis and mouse model studies indicate that dysregulation of the Hippo signaling pathway plays a key role in the different stages of cancer development. The Hippo signaling pathway senses a variety of external stimuli such as the mechanical environment, G-protein coupled receptor signaling, and cellular energy levels, and is activated by protein kinase chains. then, the transcriptional coactivator YAP (Yes-associated protein) and its homologous protein TAZ (transcriptional coactivator with PDZ-binding motif) are directly phosphorylated, resulting in their cytoplasmic retention and degradation.
In general, this signaling pathway has three interrelated components: upstream regulatory signaling, the hippo core kinase cascade complex, and the downstream nuclear transcriptional regulatory complex. Among them, hippo upstream regulatory signals or abnormal activity of the core kinase cascade complex can lead to excessive organ growth and multiple tumors.
Figure 1 Regulation and functions of the Hippo pathway
Upstream signaling of Hippo
Activation of MST1/2
MST1/2 is a pro-apoptotic kinase that is activated by caspase-specific cysteine proteolytic enzymes under apoptotic signals. SAV1 directly binds to the SARAH domain of the MST1/2 protein via the SARAH domain, thereby activating MST1/2. In mammalian cells, MST1/2 can also be activated by binding to the RASSF (Ras-association domain family) protein, possibly due to altered MST1/2 subcellular localization.
In the protein kinase chain of the Hippo signaling pathway, MST1/2 activates LATS1/2 through a variety of mechanisms. Activation of LATS1/2 requires phosphorylation of a conserved serine or threonine residue within its activation loop and its C-terminal hydrophobic motif. MST1/2 phosphorylates the C-terminal hydrophobic motif of LATS1/2, which promotes autoactivation of the activation loop of LATS1/2. MST1/2 phosphorylates MOB1, which promotes the binding of MOB1 to the inhibitory region of LATS1/2, and activates the inhibition of LATS1/2 activity. In addition, crystal structure analysis indicated that MOB1 was phosphorylated by MST1/2 to form MST1/2-MOB1 complex, which was then combined with LATS1/2 to form MST1/2-MOB1-LATS1/2 ternary complex. When MST1/2 phosphorylates LATS1/2 and MOB1, phosphorylated MOB1 drives the ternary complex to dissociate. The activated LATS1/2 phosphorylation transcripts a specific amino acid residue of the auxiliary activator YAP/TAZ, resulting in its activity being inhibited. In addition to MST1/2, MAP4Ks (mitogen-activated protein kinase kinase kinase kinase) can also phosphorylate and activate LATS1/2.
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