WWC Proteins: Important Regulators of Hippo Signaling in Cancer

Höffken, Verena; Hermann, Anke; Pavenstädt, Hermann; Kremerskothen, Joachim

doi:10.3390/cancers13020306

Cited by 30 publications

(28 citation statements)

References 72 publications

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“…Complete abrogation of NF2 activity results in an inability to suppress the activity of YAP/TAZ [26,27]. WWC1, WWC2, and WWC3 are another family that positively regulates the Hippo pathway via the activation of LATS1/2 [28,29]. Importantly, loss of WWC activity results in the nuclear translocation of YAP/TAZ, enabling their activation as transcription factors [28,29].…”

Section: Aripiprazole and Clozapinementioning

confidence: 99%

Transcriptional Modulation of the Hippo Signaling Pathway by Drugs Used to Treat Bipolar Disorder and Schizophrenia

Panizzutti

Bortolasci

Spolding

et al. 2021

IJMS

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Recent reports suggest a link between positive regulation of the Hippo pathway with bipolar disorder (BD), and the Hippo pathway is known to interact with multiple other signaling pathways previously associated with BD and other psychiatric disorders. In this study, neuronal-like NT2 cells were treated with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM), or vehicle control for 24 h. Genome-wide mRNA expression was quantified and analyzed using gene set enrichment analysis (GSEA), with genes belonging to Hippo, Wnt, Notch, TGF- β, and Hedgehog retrieved from the KEGG database. Five of the eight drugs downregulated the genes of the Hippo pathway and modulated several genes involved in the interacting pathways. We speculate that the regulation of these genes, especially by aripiprazole, clozapine, and quetiapine, results in a reduction of MAPK and NFκB pro-inflammatory signaling through modulation of Hippo, Wnt, and TGF-β pathways. We also employed connectivity map analysis to identify compounds that act on these pathways in a similar manner to the known psychiatric drugs. Thirty-six compounds were identified. The presence of antidepressants and antipsychotics validates our approach and reveals possible new targets for drug repurposing.

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Section: Aripiprazole and Clozapinementioning

confidence: 99%

Transcriptional Modulation of the Hippo Signaling Pathway by Drugs Used to Treat Bipolar Disorder and Schizophrenia

Panizzutti

Bortolasci

Spolding

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…In turn, the proteins of the angiomotin family (e.g., AMOT, AMOTL1 and AMOTL2) stimulate LATS1/2 activation and serve as scaffolds connecting LATS1/2 to both SAV1-MST1 and YAP [109]. Similarly, the WWC proteins function as scaffolds that stimulate LATS1/2 [110]. Clearly, these studies illustrate that Hippo is not a linear pathway but a complex network that regulates YAP/TAZ localization and stability.…”

Section: Yap Regulation: Succinct Descriptionmentioning

confidence: 95%

“…Activated LATS1/2, in complex with its regulatory protein MOB1, phosphorylates YAP and TAZ, the major downstream effectors of the Hippo pathway and novel sensors of the mevalonate and glycolytic pathways [97,104,105]. Recent studies identified other kinases and scaffolds in the Hippo pathway [106][107][108][109][110], including MAP4K1/2/3 and MAP4K4/6/7, which activate LATS1/2 and thereby lead to YAP/TAZ phosphorylation [106][107][108]. In turn, the proteins of the angiomotin family (e.g., AMOT, AMOTL1 and AMOTL2) stimulate LATS1/2 activation and serve as scaffolds connecting LATS1/2 to both SAV1-MST1 and YAP [109].…”

Section: Yap Regulation: Succinct Descriptionmentioning

confidence: 99%

“…These interactions further support the notion that YAP/TAZ play a central role in driving PDAC. For example, p63 interacts with Actin Like 6A (ACTL6A), a subunit of SWI/SNF, to decrease the expression of WWC1 [110] which stimulates LATS1/2 and thereby prevents YAP nuclear translocation [151]. Reciprocally, the absence of deubiquitinating enzyme BAP1 reduces the level of LATS1/2 leading to YAP activation and increased PDAC development in KC mice [152].…”

Section: Role Of Yap In Panin and Pdac Development And Maintenancementioning

confidence: 99%

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Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance

Eibl

2021

Cancers

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Pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer, remains a devastating disease. The purpose of this review is to highlight recent literature on mechanistic and translational developments that advance our understanding of a complex crosstalk between KRAS, YAP and Src tyrosine kinase family (SFK) in PDAC development and maintenance. We discuss recent studies indicating the importance of RAS dimerization in signal transduction and new findings showing that the potent pro-oncogenic members of the SFK phosphorylate and inhibit RAS function. These surprising findings imply that RAS may not play a crucial role in maintaining certain subtypes of PDAC. In support of this interpretation, current evidence indicates that the survival of the basal-like subtype of PDAC is less dependent on RAS but relies, at least in part, on the activity of YAP/TAZ. Based on current evidence, we propose that SFK propels PDAC cells to a state of high metastasis, epithelial-mesenchymal transition (EMT) and reduced dependence on KRAS signaling, salient features of the aggressive basal-like/squamous subtype of PDAC. Strategies for PDAC treatment should consider the opposite effects of tyrosine phosphorylation on KRAS and SFK/YAP in the design of drug combinations that target these novel crosstalk mechanisms and overcome drug resistance.

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“…Then, the phosphorylation of downstream effector YAP (Yes-associated protein) /TAZ (Tafazzin) could be increased. Phosphorylated YAP/TAZ could be in the cytoplasm through binding 14-3-3 proteins 8 , 9 and it could promote proteasome degradation, eventually inhibiting cell proliferation 7 , 10 , 11 . However, when the cells become cancerous, Hippo pathways are suppressed.…”

Section: Introductionmentioning

confidence: 99%

The regulatory networks of the Hippo signaling pathway in cancer development

et al. 2021

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The Hippo signaling pathway is a relatively young tumor-related signaling pathway. Although it was discovered lately, research on it developed rapidly. The Hippo signaling pathway is closely relevant to the occurrence and development of tumors and the maintenance of organ size and other biological processes. This manuscript focuses on YAP, the core molecule of the Hippo signaling pathway, and discussion the upstream and downstream regulatory networks of the Hippo signaling pathway during tumorigenesis and development. It also summarizes the relevant drugs involved in this signaling pathway, which may be helpful to the development of targeted drugs for cancer therapy.

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WWC Proteins: Important Regulators of Hippo Signaling in Cancer

Cited by 30 publications

References 72 publications

Transcriptional Modulation of the Hippo Signaling Pathway by Drugs Used to Treat Bipolar Disorder and Schizophrenia

Transcriptional Modulation of the Hippo Signaling Pathway by Drugs Used to Treat Bipolar Disorder and Schizophrenia

Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance

The regulatory networks of the Hippo signaling pathway in cancer development

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