High-risk human papillomavirus (HPV) oncoproteins inactivate cellular tumor suppressors to reprogram host cell signaling pathways. HPV E7 proteins bind and degrade the tumor suppressor PTPN14, thereby promoting the nuclear localization of the YAP1 oncoprotein and inhibiting keratinocyte differentiation. YAP1 is a transcriptional coactivator that drives epithelial cell stemness and self-renewal. YAP1 activity is inhibited by the highly conserved Hippo pathway, which is frequently inactivated in human cancers. MST1/2 and LATS1/2 kinases form the core of the Hippo kinase cascade. Active LATS1 kinase is phosphorylated on threonine 1079 and inhibits YAP1 by phosphorylating it on amino acids including serine 127. Here, we tested the effect of high-risk (carcinogenic) HPV18 E7 on Hippo pathway activity. We found that either PTPN14 knockout or PTPN14 degradation by HPV18 E7 decreased the phosphorylation of LATS1 T1079 and YAP1 S127 in human keratinocytes and inhibited keratinocyte differentiation. Conversely, PTPN14-dependent differentiation required LATS kinases and certain PPxY motifs in PTPN14. Neither MST1/2 kinases nor the putative PTPN14 phosphatase active sites were required for PTPN14 to promote differentiation. Together, these data support that PTPN14 inactivation or degradation of PTPN14 by HPV18 E7 reduce LATS1 activity, promoting active YAP1 and inhibiting keratinocyte differentiation.IMPORTANCEThe Hippo kinase cascade inhibits YAP1, an oncoprotein and driver of cell stemness and self-renewal. There is mounting evidence that the Hippo pathway is targeted by tumor viruses including human papillomavirus. The high-risk HPV E7 oncoprotein promotes YAP1 nuclear localization and the carcinogenic activity of high-risk HPV E7 requires YAP1 activity. Blocking HPV E7-dependent YAP1 activation could inhibit HPV-mediated carcinogenesis, but the mechanism by which HPV E7 activates YAP1 has not been elucidated. Here we report that by degrading the tumor suppressor PTPN14, HPV18 E7 inhibits LATS1 kinase, reducing inhibitory phosphorylation on YAP1. These data support that an HPV oncoprotein can inhibit Hippo signaling to activate YAP1 and strengthen the link between PTPN14 and Hippo signaling in human epithelial cells.

Background: ATP11A, a P-type ATPase, functions as flippases at the plasma membrane to maintain cellular function and vitality in several cancers. However, the role of ATP11A in gastric cancer remains unknown. This study aimed to identify ATP11A related to the biological behavior of gastric cancer, and elucidate the underlying mechanism. Methods: The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were used to analyze the expression and prognosis of ATP11A. The biofunctions of ATP11A were explored through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA). The expression of ATP11A were validated by immunohistochemistry (IHC), qRT-PCR and Western blotting. Transwell, wound healing, CCK8 and colony-formation were to detected the migration, invasion and proliferation of gastric cancer cells. The epithelial-mesenchymal transition (EMT) and Hippo pathway markers were examined by Western blotting. Results: The expression of ATP11A was higher in gastric cancer tissues than in normal tissues, and high ATP11A levels were related to worse prognosis of gastric cancer patients. Additionally, we proved that ATP11A promoted the migration, invasion and proliferation in gastric cancer cells. Furthermore, ATP11A was found to promote EMT by devitalizing the Hippo pathway. Conclusion: ATP11A promoted migration, invasion, proliferation and EMT via Hippo signaling devitalization in gastric cancer cells.

UNASSIGNED: Prostate cancer (PCa), one of the most prevalent malignant tumors in the genitourinary system, is characterized by distant metastasis and the development of castration-resistant prostate cancer (CRPC), which are major determinants of poor prognosis. Current treatment approaches for PCa primarily involve surgery and endocrine therapy, but effective strategies for managing distant metastasis and CRPC remain limited.
UNASSIGNED: We utilized qPCR, WB, and other methods to measure the expression levels of respective proteins, concurrently assessing lipid metabolism to validate the role of FATP5 in lipid metabolism. Additionally, we employed bioinformatics analysis and WB techniques to explore the corresponding mechanisms.
UNASSIGNED: In this study, we conducted an analysis of clinical samples and public databases to identify differential expression of FATP5 and further investigated its association with clinical outcomes. Through biochemical and functional experiments, we elucidated the potential underlying mechanisms by which FATP5 facilitates the progression of PCa. Our findings demonstrate that specific upregulation of FATP5 significantly enhances proliferation, migration, and invasion of PCa cell lines, while also modulating lipid metabolism in PCa. Mechanistically, the expression of FATP5 is closely associated with the Hippo signaling pathway, as it promotes the nuclear accumulation of YAP1 by inhibiting AMPK and facilitating the activation of β-catenin and RHOA. Furthermore, the transcription of FATP5 is mediated by TEAD4, and this transcriptional activation requires the involvement of YAP1.
UNASSIGNED: FATP5 is highly expressed in prostate cancer and can enhance the biological activity and lipid metabolism of prostate cancer. We have also elucidated that FATP5 is regulated by the Hippo signaling pathway. This provides a new potential target for the treatment of prostate cancer.

Yes-associated protein (YAP) and its homolog, transcriptional coactivator with PDZ-binding motif (TAZ), are the main transcriptional downstream effectors of the Hippo pathway. Decreased Hippo pathway activity leads to nuclear translocation of YAP/TAZ where they interact with TEAD transcription factors to induce target gene expression. Unrestrained YAP/TAZ activity can lead to excessive growth and tumor formation in a short time, underscoring the evolutionary need for tight control of these two transcriptional coactivators. Here, we report that the AP-1 component JUN acts as specific repressor of YAP/TAZ at joint target sites to decrease YAP/TAZ activity. This function of JUN is independent of its heterodimeric AP-1 partner FOS and the canonical AP-1 function. Since expression of JUN is itself induced by YAP/TAZ, our work identifies a JUN-dependent negative feedback loop that buffers YAP/TAZ activity at joint genomic sites. This negative feedback loop gets disrupted in liver cancer to unlock the full oncogenic potential of YAP/TAZ. Our results thus demonstrate an additional layer of control for the interplay of YAP/TAZ and AP-1.

This focused review highlights the importance of yes-associated protein (YAP)/transcriptional coactivator with PDZ binding motif (TAZ) mechanosignaling in human trabecular meshwork and Schlemm\'s canal cells in response to glaucoma-associated extracellular matrix stiffening and cyclic mechanical stretch, as well as biochemical pathway modulators (with signaling crosstalk) including transforming growth factor beta 2, glucocorticoids, Wnt, lysophosphatidic acid, vascular endothelial growth factor, and oxidative stress. We provide a comprehensive overview of relevant literature from the last decade, highlight intriguing research avenues with translational potential, and close with an outlook on future directions.

The Hippo pathway transducers yes-associated protein (YAP) and WW-domain containing transcription regulator 1 (WWTR1/TAZ) are key regulators of liver tumorigenesis, promoting tumor formation and progression. Although the first inhibitors are in clinical trials, targeting the relevant upstream regulators of YAP/TAZ activity could prove equally beneficial. To identify regulators of YAP/TAZ activity in hepatocarcinoma (HCC) cells, we carried out a proximity labelling approach (BioID) coupled with mass spectrometry. We verified CRK-like proto-oncogene adaptor protein (CRKL) as a new YAP-exclusive interaction partner. CRKL is highly expressed in HCC patients, and its expression is associated with YAP activity as well as poor survival prognosis. In vitro experiments demonstrated CRKL-dependent cell survival and the loss of YAP binding induced through actin disruption. Moreover, we delineated the activation of the JNK/JUN pathway by CRKL, which promoted YAP transcription. Our data illustrate that CRKL not only promoted YAP activity through its binding but also through the induction of YAP transcription by JNK/JUN activation. This emphasizes the potential use of targeting the JNK/JUN pathway to suppress YAP expression in HCC patients.

BACKGROUND: Cilia loss and impaired motile ciliary functions are among the typical pathological features of chronic rhinosinusitis with nasal polyps (CRSwNP). IL17A and IL22 are the canonical cytokines of type 3 inflammation, exhibiting similar functional effects on epithelial cells. In this study, we sought to examine the effects of IL17A and IL22 on ciliated cells and investigate the potential involvement of Hippo-YAP signaling in their influence on ciliogenesis.
METHODS: We assessed both the mRNA and protein expression levels of IL17A and IL22 in nasal tissues obtained from patients with CRSwNP and compared them to those from healthy controls. To further explore the impact of IL17A and IL22, we established a primary human nasal epithelial cell model using different concentrations (2 ng/mL, 10 ng/mL, 50 ng/mL) for a duration of 28 days in an air-liquid interface culture. Additionally, we employed the inhibitor verteporfin to investigate whether IL17A and IL22 exert their effects on ciliated cells via the Hippo-YAP pathway.
RESULTS: The mRNA and protein levels of IL17A and IL22 in CRSwNP were significantly higher than those in healthy controls, revealing a robust correlation between IL17A and IL22. YAP was highly expressed in the nucleus of ciliated cells in CRSwNP and displayed a positive correlation with clinical symptoms. Both IL17A and IL22 were found to reduce the number of ciliated cells. IL17A, but not IL22, suppressed ciliogenesis by disrupting the proper development and docking of the basal body of ciliated cells, resulting in motile ciliary dysfunctions. Furthermore, the expression of YAP within the nucleus of ciliated cells gradually declined as these cells reached the final stage of differentiation. However, this process was obstructed by IL17A only. YAP inhibitors, such as verteporfin, markedly reversed the effects of IL17A by increasing the proportion of ciliated cells, suppressing nuclear YAP expression in these cells, and enhancing ciliary beating frequency.
CONCLUSIONS: Both IL17A and IL22 are overexpressed in nasal epithelium of CRSwNP, which is associated with the impairment of epithelial cell differentiation. Furthermore, IL17A has been shown to exert a disruptive effect on morphogenesis of motile cilia via activation of YAP.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with poor prognosis and inadequate response to treatment, such as gemcitabine (Gem), the first-line chemotherapeutic drug. Understanding the molecular determinants that control drug resistance to Gem is critical to predict potentially responsive patients and improve the benefits of Gem therapy. Emerging evidence suggests that certain developmental pathways, such as Hippo signaling, are aberrated and play important roles in Gem resistance in cancers. Although Hippo signaling has been reported to play a role in chemoresistance in cancers, it has not been clarified which specific target gene(s) functionally mediates the effect. In the present study, we found that YAP serves as a potent barrier for the cellular sensitivity of PDAC cells to Gem. We then identified and characterized laminin subunit beta 3 (LAMB3) as a bona fide target of YAP-TEAD4 to amplify YAP signaling via a feedback loop. Such a YAP-LAMB3 axis is critical to induce epithelial-mesenchymal transition and mediate Gem resistance. Taken together, we uncovered that YAP-LAMB3 axis is an important regulator of Gem, thus providing potential therapeutic targets for overcoming Gem resistance in PDAC.

Hippo pathway functions as a tumor suppressor pathway by inhibiting the oncogenic potential of pathway effectors YAP/TAZ. However, YAP can also function as a context-dependent tumor suppressor in several types of cancer including clear cell renal cell carcinomas (ccRCC). Here we show that YAP blocks NF-κB signaling in ccRCC to inhibit cancer cell growth. Mechanistically, YAP inhibits the expression of ZHX2, a critical p65 co-factor in ccRCC. Furthermore, YAP competes with ZHX2 for binding to p65. Consequently, elevated nuclear YAP blocks the cooperativity between ZHX2 and p65, leading to diminished NF-κB target gene expression. Pharmacological inhibition of Hippo/MST1/2 blocked NF-κB transcriptional program and suppressed ccRCC cancer cell growth, which can be rescued by ZHX2/p65 overexpression. Our study uncovers a novel crosstalk between the Hippo and NF-κB pathways and its involvement in ccRCC growth inhibition, suggesting that targeting the Hippo pathway may provide a therapeutical opportunity for ccRCC treatment.

Tissue regeneration after damage is generally thought to involve the mobilization of adult stem cells that divide and differentiate into progressively specialized progeny. However, recent studies indicate that tissue regeneration can be accompanied by reversion to a fetal-like state. During this process, cells at the injury site reactivate programs that operate during fetal development but are typically absent in adult homeostasis. Here, we summarize our current understanding of the molecular signals and epigenetic mediators that orchestrate \"fetal-like reversion\" during intestinal regeneration. We also explore evidence for this phenomenon in other organs and species and highlight open questions that merit future examination.