YAP1

Official Full Name

Yes1 associated transcriptional regulator

Organism

Homo sapiens

GeneID

10413

Background

This gene encodes a downstream nuclear effector of the Hippo signaling pathway which is involved in development, growth, repair, and homeostasis. This gene is known to play a role in the development and progression of multiple cancers as a transcriptional regulator of this signaling pathway and may function as a potential target for cancer treatment. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2013]

Synonyms

YAP; YKI; COB1; YAP2; YAP-1; YAP65;

Protein Sequence

MDPGQQPPPQPAPQGQGQPPSQPPQGQGPPSGPGQPAPAATQAAPQAPPAGHQIVHVRGDSETDLEALFNAVMNPKTANVPQTVPMRLRKLPDSFFKPPEPKSHSRQASTDAGTAGALTPQHVRAHSSPASLQLGAVSPGTLTPTGVVSGPAATPTAQHLRQSSFEIPDDVPLPAGWEMAKTSSGQRYFLNHIDQTTTWQDPRKAMLSQMNVTAPTSPPVQQNMMNSASGPLPDGWEQAMTQDGEIYYINHKNKTTSWLDPRLDPRFAMNQRISQSAPVKQPPPLAPQSPQGGVMGGSNSNQQQQMRLQQLQMEKERLRLKQQELLRQAMRNINPSTANSPKCQELALRSQLPTLEQDGGTQNPVSSPGMSQELRTMTTNSSDPFLNSGTYHSRDESTDSGLSMSSYSVPRTPDDFLNSVDEMDTGDTINQSTLPSQQNRFPDYLEAIPGTNVDLGTLEGDGMNIEGEELMPSLQEALSSDILNDMESVLAATKLDKESFLTWL

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Detailed Information

YAP1 (Yes-Associated Protein 1) is a central transcriptional coactivator in the Hippo signaling pathway. It lacks a DNA-binding domain and requires association with TEAD family transcription factors (TEAD1-4) to regulate downstream gene expression. YAP1 activity is tightly controlled through phosphorylation-dephosphorylation cycles. When the Hippo pathway is active, the kinases MST1/2 phosphorylate LATS1/2, which in turn phosphorylate YAP1 at Ser127. This phosphorylation promotes binding to 14-3-3 proteins, retaining YAP1 in the cytoplasm.

Figure 1. Overview YAP1 protein domains and interaction partners. (Szulzewsky F, et al., 2021)

In the inactive state, dephosphorylated YAP1 translocates to the nucleus, associates with TEAD, and initiates the transcription of target genes, including CTGF, CYR61, and AMOTL2, thereby driving cell proliferation, migration, and the expression of stem cell characteristics. Beyond classical Hippo signaling, YAP1 is also regulated by mechanical cues, including extracellular matrix stiffness and cell-cell contact, as well as metabolic signals such as glucose availability. For example, under contact inhibition, YAP1 is recruited to the Crumbs complex, where monoubiquitination of AMOTL2 by WWP1 activates LATS2, establishing a negative feedback loop.

Figure 2. Overview of the Hippo/YAP signaling pathway. (Molina L, et al., 2022)

Physiological and Pathological Functions

The spatial and temporal expression of YAP1 determines its dual roles in organ development and disease. In the reproductive system, YAP1 localization in postnatal mouse ovarian granulosa cells changes dynamically: nuclear at postnatal day 3, shifting to the cytoplasm by days 7–10, and returning to the nucleus after day 14. This nucleocytoplasmic shuttling coincides with lymphangiogenesis and the transition of follicles from primary to antral stages, suggesting coordination of follicle maturation and lymphatic remodeling. In spermatogonial stem cells (SSCs), YAP1 interacts with the adhesion protein subunit RAD21, activating transcription of the E3 ubiquitin ligase NEDD4 to promote SSC self-renewal. Mutations in YAP1, such as S227L, can reduce protein stability and are associated with impaired DNA synthesis and increased apoptosis in male infertility.

In cancer, YAP1 exhibits context-dependent roles. It is frequently amplified in liver and lung cancers, where nuclear accumulation correlates with poor outcomes. Conversely, in colorectal and hematologic malignancies, YAP1 can induce apoptosis via PUMA activation, functioning as a tumor suppressor. These contrasting effects reflect tissue-specific interactions: in basal cell carcinoma, YAP1 binds ΔNp63 to promote proliferation, whereas in intestinal epithelial cells, it competes with AP-1 to suppress oncogenic transcription. YAP1 also influences metabolism and the immune microenvironment by upregulating GLUT3 to enhance glycolysis and inducing PD-L1 and cytokines like IL-6 to inhibit CD8+ T cell infiltration, fostering an immunosuppressive niche.

Targeted Intervention Strategies

Direct targeting of YAP1 is challenging due to its lack of kinase activity, so current approaches focus on upstream regulators or downstream cofactors. Hippo pathway activators, such as verteporfin, disrupt the YAP1-TEAD interaction to inhibit transcriptional activity. TEAD palmitoylation inhibitors, like IAG933, prevent TEAD autopalmitoylation and block YAP1/TEAD complex formation. Combination strategies are also under exploration. In ovarian cancer, YAP1 inhibition reduces VEGF-C-mediated lymphangiogenesis, while in preclinical models, verteporfin combined with anti-PD-1 therapy significantly suppresses tumor growth and enhances T cell infiltration.

Future research aims to elucidate YAP1 conformational dynamics and epigenetic regulatory networks across tissues, enabling the development of precise and context-specific therapeutic interventions.

Reference

Mui CW, Chan WN, Chen B, et al. Targeting YAP1/TAZ in nonsmall-cell lung carcinoma: From molecular mechanisms to precision medicine. Int J Cancer. 2023 Feb 15;152(4):558-571.
Szulzewsky F, Holland EC, Vasioukhin V. YAP1 and its fusion proteins in cancer initiation, progression, and therapeutic resistance. Dev Biol. 2021 Jul;475:205-221.
Molina L, Nejak-Bowen K, Monga SP. Role of YAP1 Signaling in Biliary Development, Repair, and Disease. Semin Liver Dis. 2022 Feb;42(1):17-33.

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