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Exploring the magical structure of YAP1: What is the unique module design of this transcriptional co-regulator?
YAP1 (Yes-associated protein 1), also known as YAP or YAP65, is a transcriptional coregulator that promotes the transcription of genes involved in cell proliferation and inhibits the expression of apoptosis genes. YAP1 is a component of the Hippo signaling pathway, which regulates organ size, regeneration and tumor formation. It was originally identified by interacting with the SH3 binding domain of Yes and Src protein tyrosine kinases.
YAP1 is considered a potent oncogene and has increased expression in a variety of human cancers.
Structure
The cloning of the YAP1 gene facilitated the identification of modular protein structures, specifically a region called the WW domain. Two splice isoforms of the YAP1 gene product were initially identified, named YAP1-1 and YAP1-2 respectively. The difference between the two is that YAP1-2 has an extra WW domain encoding 38 amino acids. In addition to the WW domain, the modular structure of YAP1 also contains a proline-rich region located at the amino terminus, followed by a TEAD transcription factor interaction domain (TID). There is a single WW domain in the YAP1-1 isoform, whereas the YAP1-2 isoform possesses two WW domains followed by a SH3 binding motif (SH3-BM). After SH3-BM, there are transactivation domain (TAD) and PDZ domain binding motif (PDZ-BM).
Function
YAP1 is a transcriptional coactivator. Its proliferation and oncogene activities mainly come from interactions with TEAD family transcription factors. These factors can upregulate genes that promote cell growth and inhibit apoptosis. Several functional partners of YAP1 were identified, including RUNX, SMADs, p73, ErbB4, TP53BP2, LATS1/2, PTPN14, AMOTs, and ZO1/2. YAP1 and its close homologous protein TAZ (WWTR1) are major effectors of the Hippo tumor suppressor pathway.
When the Hippo pathway is activated, YAP1 and TAZ are phosphorylated on a serine residue and then sealed in the cytoplasm by 14-3-3 proteins.
When the Hippo pathway is not activated, YAP1/TAZ enters the nucleus and regulates gene expression. It has been reported that genes regulated by YAP1 include Birc2, Birc5, connective tissue growth factor (CTGF), amino acid regulatory hormone (AREG), Cyr61, Hoxa1 and Hoxc13. YAP/TAZ has also been shown to act as stiffness sensors, regulating mechanotransduction independently of the Hippo signaling pathway.
Regulation
Biochemical regulation
From a biochemical perspective, YAP participates in and is regulated by the Hippo signaling pathway. This signaling pathway consists of an enzyme kinase cascade that leads to the "inactivation" of YAP and TAZ. In this signaling cascade, TAO kinase phosphorylates the activation loop of the Ste20-like kinase MST1/2 (Thr183 for MST1 and Thr180 for MST2). Active MST1/2 then phosphorylates SAV1 and MOB1A/B, scaffolding proteins that assist in the recruitment and phosphorylation of LATS1/2. LATS1/2 can also be phosphorylated by two sets of MAP4K. LATS1/2 rephosphorylates YAP and TAZ, binding them to 14-3-3, resulting in the blocking of YAP and TAZ in the cytoplasm.
Mechanotransduction
Furthermore, YAP is regulated by mechanical cues, such as extracellular matrix (ECM) stiffness, strain, shear stress, or adhesion area, and these processes rely on the integrity of the cytoskeleton. These mechanically induced localization phenomena are thought to be caused by various factors such as changes in pore size caused by nuclear flattening, mechanosensitive nuclear membrane ion channels, and mechanical protein stability. These mechanical factors have also been linked to certain cancer cells, affecting their behavior through nuclear softening and higher ECM stiffness.
The nuclear softening phenotype of cancer cells promotes nuclear flattening, leading to the localization of YAP, which may explain its overexpression in cancer cells and its role in promoting proliferation.
Clinical significance
Cancer
Deregulation of YAP/TAZ-mediated transcriptional activity is associated with the development of abnormal cell growth, and hyperactivation of YAP and TAZ is observed in many cancers. Therefore, YAP1 is considered a potential target for anticancer therapy. YAP is identified as a proto-oncogene but may also act as a tumor suppressor in different cellular contexts.
As a drug target
YAP1 oncogene becomes target for new cancer drug development. Certain small compounds are known to disrupt the YAP1-TEAD complex or block the binding function of the WW domain. These small molecules represent potential parent compounds for the development of therapies to treat cancer patients with enhanced or overexpressed YAP oncogenes.
Neuroprotection
Hippo/YAP signaling pathway may play a neuroprotective role by reducing blood-brain barrier damage after cerebral ischemia/reperfusion injury.
Mutation
Heterogeneous loss-of-function mutations in the YAP1 gene have been identified in two families with major ocular malformations, with or without additional external eye characteristics such as hearing loss, cleft lip and palate, and intellectual disability and kidney disease.
In the modular design of YAP1, how do these unique structural features affect its key biological functions and potential clinical applications?
