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YAP1 and the Hippo signaling pathway: How does it determine cell life, death, and growth?
YAP1 (yes-associated protein 1) is a transcriptional coregulator that has attracted attention for its ability to promote cell growth and inhibit the transcription of apoptotic genes. As a core component of the Hippo signaling pathway, YAP1 plays an important role in regulating biological processes such as organ size, regeneration and tumor formation. This article will take a deep look at the structure and function of YAP1 and explore how it plays a key role in the cell life cycle.
Structure of YAP1
The cloning of the YAP1 gene allowed the scientists to identify a modular protein domain called the WW domain. Initially, two splicing isoforms of the YAP1 gene product were identified and named YAP1-1 and YAP1-2. The difference between the two is that YAP1-2 has 38 more amino acids, which encode the WW domain.
Function of YAP1In addition, the modular structure of YAP1 also contains a proline-rich region followed by a TID region that interacts with TEAD transcription factors. This is followed by a single WW domain (characteristic of YAP1-1) or two WW domains (characteristic of YAP1-2), followed by the SH3-BM and TAD.
As a transcriptional coactivator, the proliferative and oncogenic activities of YAP1 are primarily driven by binding to TEAD family transcription factors. These transcription factors upregulate genes that promote cell growth and inhibit apoptosis. YAP1 also works with multiple functional partners, including RUNX, SMADs, TP53BP2, and others.
Regulation of YAP1In the Hippo tumor suppressor signaling pathway, YAP1 and its close relative TAZ are major effectors. When the signaling pathway is activated, YAP1 and TAZ are phosphorylated on a tyrosine residue and are sequestered in the cytoplasm by 14-3-3 proteins. In contrast, when Hippo signaling is inactivated, YAP1 and TAZ enter the nucleus and regulate gene expression.
Biochemical Regulation
At the biochemical level, YAP1, as a component of the Hippo signaling pathway, is regulated by a kinase cascade. This reaction triggers a series of phosphorylation events, ultimately leading to the inhibition of YAP1 and TAZ and their exclusion from the nucleus.
Mechanical Control
YAP1 localization is also affected by mechanical cues, including the stiffness of the extracellular matrix and the cell surface area, which are closely related to the integrity of the cytoskeleton. These mechanical factors are involved in the behavior of cancer cells and may contribute to the high expression and proliferation of YAP1 in tumor cells.
Clinical significance CancerDysregulated transcriptional activity of YAP1 is closely associated with abnormal cell growth and cancer development. Because YAP1 is overexpressed in a variety of cancers, it has emerged as a potential therapeutic target. However, depending on the cellular context, YAP1 can also act as a tumor suppressor.
As drug targets
YAP1 is a target for large-scale drug development, and researchers have found that some small molecules can interfere with the binding of YAP1 to TEAD or inhibit the function of the WW domain. These small molecules provide clues for potential therapeutic approaches to treat patients with cancers that carry high expression or amplification of YAP1.
Neuroprotection
The Hippo/YAP signaling pathway may also play a neuroprotective role by reducing the breakdown of the blood-brain barrier during ischemia/reperfusion injury.
Mutation
Hemizygous loss-of-function mutations in the YAP1 gene have been found in some families, and these family members have major eye malformations and may be accompanied by other features such as deafness, cleft lip and palate, intellectual disability, and kidney disease.
With the advancement of science, YAP1 and its role in the Hippo signaling pathway have become increasingly hot topics of research. In the future, there may be more therapeutic innovations targeting YAP1. Will this lead to new ways to fight cancer?
