Introduction About YAP: A Drug Target and Biomarker (G10413)

NCBI ID: G10413

YAP1

Introduction About YAP: A Drug Target and Biomarker

YAP (Yes-associated protein) is a key component of the Hippo signaling pathway that regulates cell proliferation and organ growth. When unphosphorylated, YAP translocates to the nucleus and acts as a co-transcriptional activator.

One proposed mechanism involving YAP is its interaction with the Wnt/beta-catenin pathway. YAP/TAZ and beta-catenin need to bind with specific proteins in the nucleus to carry out their functions.

CPZ (chlorpromazine) inhibits YAP signaling by promoting YAP degradation, inhibiting REST signaling, and blocking DNA synthesis, leading to inhibition of cell proliferation and tumorigenesis.

Another study suggests that lncARSR overexpression disrupts the interaction between LATS (upstream kinase) and YAP, resulting in the nuclear translocation of YAP and the activation of lncARSR expression. This establishes a feed-forward loop that promotes the expansion of renal T-ICs (tumor-initiating cells).

Overall, YAP plays a crucial role in various signaling pathways and cellular processes, including cell proliferation, transcriptional activation, and tumorigenesis. Its regulation and interaction with other proteins are essential for maintaining cellular homeostasis and organ development .
Based on the provided context information, YAP1, also known as Yes-associated protein, is a key regulator in various signaling pathways, including the Wnt/beta-catenin pathway and the Notch pathway. It plays a crucial role in stem cell preservation, differentiation, and intercellular communication.

In the Wnt/beta-catenin signaling pathway, YAP1 is involved in regulating the transcription of Wnt/beta-catenin target genes. It acts by interacting with phosphorylated beta-catenin, promoting its degradation via interaction with TAZ. This pathway is important for gene expression and cellular processes such as cell proliferation and development.

Furthermore, YAP1 is involved in mechanotransduction and tissue regeneration. It is activated by stiffening of the limbus, leading to YAP1's increased nuclear translocation and subsequent cell differentiation, which can result in the loss of limbal epithelial stem cell (LESC) phenotype. Conversely, by softening the burned limbus with collagenase, YAP1 activation is prevented, contributing to LESC maintenance and epithelial recovery.

YAP1 is regulated by the Hippo pathway, which includes core components such as Mst1/2, Lats1/2, Sav1, and Mob. The Hippo pathway phosphorylates YAP1, leading to its cytoplasmic retention and degradation. When the kinase cascade is inactivated, YAP1 translocates into the nucleus and promotes gene expression through interaction with TEAD.

The Hippo signaling pathway can be targeted using various methods. Elevating the cellular level of cAMP through forskolin and PDE inhibitors enhances LATS1/2 kinase activity, resulting in YAP1 phosphorylation, cytoplasmic accumulation, and degradation. Other substances such as dobutamine and statins also induce YAP1/TAZ phosphorylation. Inhibitors like verteporfin and Super-TDU block the physical interaction between YAP1/TAZ and TEADs, thereby inhibiting their function. Additionally, CDK9 inhibitors and BET inhibitors impede the transcription of YAP1/TAZ target genes.

In summary, YAP1 plays a crucial role in regulating multiple signaling pathways, including the Wnt/beta-catenin pathway and the Notch pathway. It is involved in stem cell preservation, differentiation, mechanotransduction, and tissue regeneration. The Hippo pathway regulates YAP1 activity, and various molecules and inhibitors can target this pathway to modulate YAP1 function .

Protein Name: Yes1 Associated Transcriptional Regulator

Functions: Transcriptional regulator which can act both as a coactivator and a corepressor and is the critical downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis (PubMed:17974916, PubMed:18280240, PubMed:18579750, PubMed:21364637, PubMed:30447097). The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ (PubMed:18158288). Plays a key role in tissue tension and 3D tissue shape by regulating cortical actomyosin network formation. Acts via ARHGAP18, a Rho GTPase activating protein that suppresses F-actin polymerization (PubMed:25778702). Plays a key role in controlling cell proliferation in response to cell contact. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration (PubMed:18158288). The presence of TEAD transcription factors are required for it to stimulate gene expression, cell growth, anchorage-independent growth, and epithelial mesenchymal transition (EMT) induction (PubMed:18579750). Suppresses ciliogenesis via acting as a transcriptional corepressor of the TEAD4 target genes AURKA and PLK1 (PubMed:25849865). In conjunction with WWTR1, involved in the regulation of TGFB1-dependent SMAD2 and SMAD3 nuclear accumulation (By similarity)

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