Hippo Signaling Pathway as a Central Mediator of Receptors Tyrosine Kinases (RTKs) in Tumorigenesis

Azad, Taha; Rezaei, Reza; Surendran, Abera; Singaravelu, Ragunath; Boulton, Stephen; Dave, Jaahnavi; Bell, John C.; Ilkow, Carolina S.

doi:10.3390/cancers12082042

Cited by 20 publications

(13 citation statements)

References 133 publications

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“…In addition to the FAK pathway, internal signals are capable of modulating the YAP1 pathway. One of the key initiators of internal signaling networks in cell proliferation and growth is the family of receptor tyrosine kinases (RTKs), which carries out the Hippo/YAP1 pathway by two main RTKs—the RTK/RAS/PI3K and the RTK-RAS-MAPK pathways [ 32 ]. On the other hand, several RTKs, including GFR, RET, and MERTK, have been shown to directly interact with and phosphorylate YAP/TAZ at multiple tyrosine residues independent of upstream Hippo signaling, thereby activating their functions in tumorigenesis [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Gene Regulation Network of Prognostic Biomarker YAP1 in Human Cancers: An Integrated Bioinformatics Study

Tang

et al. 2021

Pathol. Oncol. Res.

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Background: Yes-associated protein 1 (YAP1) is the main downstream effector of the Hippo signaling pathway, which is involved in tumorigenesis. This study aimed to comprehensively understand the prognostic performances of YAP1 expression and its potential mechanism in pan-cancers by mining databases.Methods: The YAP1 expression was evaluated by the Oncomine database and GEPIA tool. The clinical significance of YAP1 expression was analyzed by the UALCAN, GEPIA, and DriverDBv3 database. Then, the co-expressed genes with YAP1 were screened by the LinkedOmics, and annotated by the Metascape and DAVID database. Additionally, by the MitoMiner 4.0 v tool, the YAP1 co-expressed genes were screened to obtain the YAP1-associated mitochondrial genes that were further enriched by DAVID and analyzed by MCODE for the hub genes.Results: YAP1 was differentially expressed in human cancers. Higher YAP1 expression was significantly associated with poorer overall survival and disease-free survival in adrenocortical carcinoma (ACC), brain Lower Grade Glioma (LGG), and pancreatic adenocarcinoma (PAAD). The LinkedOmics analysis revealed 923 co-expressed genes with YAP1 in adrenocortical carcinoma, LGG and PAAD. The 923 genes mainly participated in mitochondrial functions including mitochondrial gene expression and mitochondrial respiratory chain complex I assembly. Of the 923 genes, 112 mitochondrial genes were identified by MitoMiner 4.0 v and significantly enriched in oxidative phosphorylation. The MCODE analysis identified three hub genes including CHCHD1, IDH3G and NDUFAF5.Conclusion: Our findings showed that the YAP1 overexpression could be a biomarker for poor prognosis in ACC, LGG and PAAD. Specifically, the YAP1 co-expression genes were mainly involved in the regulation of mitochondrial function especially in oxidative phosphorylation. Thus, our findings provided evidence of the carcinogenesis of YAP1 in human cancers and new insights into the mechanisms underlying the role of YAP1 in mitochondrial dysregulation.

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Section: Discussionmentioning

confidence: 99%

Gene Regulation Network of Prognostic Biomarker YAP1 in Human Cancers: An Integrated Bioinformatics Study

Tang

et al. 2021

Pathol. Oncol. Res.

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“…Once phosphorylated, the YAP/TAZ complex is inactivated through cytoplasm sequestration via binding to 14-3-3 or by its increased ubiquitination and degradation. Conversely, inhibition of the Hippo pathway leads to dephosphorylation of the YAP/TAZ complex, its increased nuclear abundance and transcriptional enhancer activation domain (TEAD) transcriptional activity, which promotes cell proliferation [ 56 , 57 ]. Beside the TEAD family of transcription factors, YAP/TAZ also interacts with other transcription factors, including Smad, p63 and PAX [ 56 , 58 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

Evidence of Cooperation between Hippo Pathway and RAS Mutation in Thyroid Carcinomas

Carneiro

Bim

Buzatto

et al. 2021

Cancers

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Thyroid cancer incidences have been steadily increasing worldwide and are projected to become the fourth leading cancer diagnosis by 2030. Improved diagnosis and prognosis predictions for this type of cancer depend on understanding its genetic bases and disease biology. RAS mutations have been found in a wide range of thyroid tumors, from benign to aggressive thyroid carcinomas. Based on that and in vivo studies, it has been suggested that RAS cooperates with other driver mutations to induce tumorigenesis. This study aims to identify genetic alterations or pathways that cooperate with the RAS mutation in the pathogenesis of thyroid cancer. From a cohort of 120 thyroid carcinomas, 11 RAS-mutated samples were identified. The samples were subjected to RNA-Sequencing analyses. The mutation analysis in our eleven RAS-positive cases uncovered that four genes that belong to the Hippo pathway were mutated. The gene expression analysis revealed that this pathway was dysregulated in the RAS-positive samples. We additionally explored the mutational status and expression profiling of 60 RAS-positive papillary thyroid carcinomas (PTC) from The Cancer Genome Atlas (TCGA) cohort. Altogether, the mutational landscape and pathway enrichment analysis (gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genome (KEGG)) detected the Hippo pathway as dysregulated in RAS-positive thyroid carcinomas. Finally, we suggest a crosstalk between the Hippo and other signaling pathways, such as Wnt and BMP.

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“…PDK1 phosphorylates at threonine-308 residue while PDK2 and PDK3 phosphorylate Serine-473 to make it completely functional. In addition, activated RAS induced by growth factor binding to RTK is another upstream regulator of AKT [20].…”

Section: Rtk (Receptor Tyrosine Kinase) and Akt Regulationmentioning

confidence: 99%

Upstreaming and Downstreaming Regulators and Associated Signaling Transduction Pathways of AKT/PKB: A Molecular Gateway to Progressive Carcinoma

Sayed

Hossain

Islam

et al. 2023

AJOB

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AKT or Protein Kinase B, the serine/threonine-specific protein kinase, is found in three analogous isoforms in cells of human and animal bodies. AKT is regulated and activated via various upstream regulators including GPCR (G protein-coupled receptor), RTK (Receptor tyrosine kinase), SYK (spleen tyrosine kinase), JAK (Janus kinase), and RAS lead to the further activation of multiple coordinated downstream cascades. The dysregulation of these pathways affects the cell cycle and cell proliferation, resulting in the development of carcinoma. Therefore, the study aimed with the objectives to explore all the major upstreaming and downstreaming regulators and associated signaling transduction pathways of AKT as an approach for further detailed studies or clinical management of tumors or cancers via targeted protein-based drug developments.

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Hippo Signaling Pathway as a Central Mediator of Receptors Tyrosine Kinases (RTKs) in Tumorigenesis

Cited by 20 publications

References 133 publications

Gene Regulation Network of Prognostic Biomarker YAP1 in Human Cancers: An Integrated Bioinformatics Study

Gene Regulation Network of Prognostic Biomarker YAP1 in Human Cancers: An Integrated Bioinformatics Study

Evidence of Cooperation between Hippo Pathway and RAS Mutation in Thyroid Carcinomas

Upstreaming and Downstreaming Regulators and Associated Signaling Transduction Pathways of AKT/PKB: A Molecular Gateway to Progressive Carcinoma

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