A gain-of-functional screen identifies the Hippo pathway as a central mediator of receptor tyrosine kinases during tumorigenesis

Azad, Taha; Nouri, Kazem; Rensburg, Helena J. Janse van; Maritan, Sarah M.; Wu, Liqing; Hao, Yawei; Montminy, Tess; Yu, Jihang; Khanal, Prem; Mulligan, Lois M.; Yang, Xiaolong

doi:10.1038/s41388-019-0988-y

Cited by 59 publications

(48 citation statements)

References 57 publications

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“…22,23 Recent studies also observed that AXL stimulated YAP activity. 29,30 We found that YAP was indirectly dephosphorylated at Ser127 by AXL activation, which was different from YAP directly phosphorylation at tyrosine residues in Saab's study. 29 However, the complex regulatory mechanism mediating AXL effect remained obscure.…”

Section: Discussionmentioning

confidence: 69%

The crosstalk between AXL and YAP promotes tumor progression through STAT3 activation in head and neck squamous cell carcinoma

Shi

Zhou

et al. 2020

Cancer Science

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Receptor tyrosine kinases (RTKs) and Yes‐associated protein (YAP) are critical driving factors in tumors. Currently, the regulation of RTKs in the Hippo‐YAP pathway has been recognized as an important issue. However, the relationship between AXL, one of the RTKs, and YAP in head and neck squamous cell carcinoma (HNSCC) remains unknown. In this study, the crosstalk between AXL and YAP was thoroughly investigated in vitro and in vivo. We determined that there was a positive correlation between AXL and YAP in the HNSCC tissue samples and the Cancer Genome Atlas (TCGA) dataset, and high co‐expression was associated with poor prognosis. Inhibiting YAP decreased AXL expression in HNSCC cells, while YAP overexpression increased AXL. Moreover, ectopic expression of AXL reversed tumor suppressor phenotypes mediated by YAP silencing. This reversal effect was also confirmed in vivo. In addition, AXL overexpression and Gas6, a ligand of AXL, stimulated YAP dephosphorylation, nuclear translocation, and target gene transcription. AXL inhibition decreased YAP dephosphorylation and nuclear translocation. Mechanistically, Gas6 induced a competitive binding to phosphorylated signal transducers and activators of transcription 3 (STAT3) with large tumor suppressor kinase 1 (LATS1) and inhibited the Hippo pathway. This study revealed a novel non‐transcriptional effect of STAT3 in Gas6/AXL‐induced YAP activity, suggesting that STAT3 acted as a critical “molecular switch” during the mutual promotion between AXL and YAP, which might be a promising therapeutic target in HNSCC.

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Section: Discussionmentioning

confidence: 69%

The crosstalk between AXL and YAP promotes tumor progression through STAT3 activation in head and neck squamous cell carcinoma

Shi

Zhou

et al. 2020

Cancer Science

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“…For example, tissue mechanics and nutritional cues are integrated via IGF1R and PI3K/AKT activation, which is required for YAP/TAZ nuclear localization [72,123,124]. Moreover, in a comprehensive gain-of-function screen for directly YAP/TAZ-activating RTKs, FGFR, RET and MER proto-oncogene tyrosine kinase (MERTK) were found to phosphorylate YAP and activate TEAD-driven transcription [125]. In response to TGFβ signaling, phosphorylated complexes of SMAD2/3-4 directly interact with TAZ, which is required for their nuclear retention and transcriptional activity [126], while high YAP was reported to suppress BMP-induced phosphorylation and activity of SMAD1, 5 and 8 [127].…”

Section: Yap/taz In Epithelial-mesenchymal Transition (Emt)mentioning

confidence: 99%

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Kovar

Bierbaumer

Radic-Sarikas

2020

Cells

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YAP and TAZ are intracellular messengers communicating multiple interacting extracellular biophysical and biochemical cues to the transcription apparatus in the nucleus and back to the cell/tissue microenvironment interface through the regulation of cytoskeletal and extracellular matrix components. Their activity is negatively and positively controlled by multiple phosphorylation events. Phenotypically, they serve an important role in cellular plasticity and lineage determination during development. As they regulate self-renewal, proliferation, migration, invasion and differentiation of stem cells, perturbed expression of YAP/TAZ signaling components play important roles in tumorigenesis and metastasis. Despite their high structural similarity, YAP and TAZ are functionally not identical and may play distinct cell type and differentiation stage-specific roles mediated by a diversity of downstream effectors and upstream regulatory molecules. However, YAP and TAZ are frequently looked at as functionally redundant and are not sufficiently discriminated in the scientific literature. As the extracellular matrix composition and mechanosignaling are of particular relevance in bone formation during embryogenesis, post-natal bone elongation and bone regeneration, YAP/TAZ are believed to have critical functions in these processes. Depending on the differentiation stage of mesenchymal stem cells during endochondral bone development, YAP and TAZ serve distinct roles, which are also reflected in bone tumors arising from the mesenchymal lineage at different developmental stages. Efforts to clinically translate the wealth of available knowledge of the pathway for cancer diagnostic and therapeutic purposes focus mainly on YAP and TAZ expression and their role as transcriptional co-activators of TEAD transcription factors but rarely consider the expression and activity of pathway modulatory components and other transcriptional partners of YAP and TAZ. As there is a growing body of evidence for YAP and TAZ as potential therapeutic targets in several cancers, we here interrogate the applicability of this concept to bone tumors. To this end, this review aims to summarize our current knowledge of YAP and TAZ in cell plasticity, normal bone development and bone cancer.Cells 2020, 9, 972 2 of 34 co-activators Yes-associated protein 1 (YAP-1, YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ, WWTR1), which are typically controlled on the post-translational level by upstream regulatory signaling pathways in organ development and tissue homeostasis [2,3]. YAP and TAZ were reported to affect self-renewal and lineage commitment of stem cells [4][5][6][7], while hyperactivation of YAP and TAZ have been linked to cancer growth and metastasis in various tumors [8][9][10]. TAZ levels are elevated in approximately 20% of cancers and drive invasion and metastasis [11,12], while YAP is frequently overexpressed or amplified in cancer and was shown to promote resistance to chemotherapy in oncogene-addicted tumors up...

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“…7). We show that Met YAP activity has been shown to be regulated by several upstream mechanisms 10,14,71,70 .…”

Section: Discussionmentioning

confidence: 82%

YAP and β-catenin co-operate to drive oncogenesis in basal breast cancer

Quinn

Koren

Vogel

et al. 2020

Preprint

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Targeting cancer stem cells (CSCs) can serve as an effective approach toward limiting resistance to therapies and the development of metastases in many forms of cancer. While basal breast cancers encompass cells with CSC features, rational therapies remain poorly established. Here, we show that receptor tyrosine kinase Met signalling promotes the activity of the Hippo component YAP in basal breast cancer. Further analysis revealed enhanced YAP activity within the CSC population. Using both genetic and pharmaceutical approaches, we show that interfering with YAP activity delays basal cancer formation, prevents luminal to basal trans-differentiation and reduces CSC survival. Gene expression analysis of YAP knock-out mammary glands revealed a strong decrease in β -catenin target genes in basal breast cancer, suggesting that YAP is required for nuclear β -catenin activity. Mechanistically, we find that nuclear YAP interacts and overlaps with β -catenin and TEAD4 at common gene regulatory elements. Analysis of proteomic data from primary breast cancer patients identified a significant upregulation of the YAP activity signature in basal compared to other breast cancers, suggesting that YAP activity is limited to basal types. Our findings demonstrate that in basal breast cancers, β -catenin activity is dependent on YAP signalling and controls the CSC program. These findings suggest that targeting the YAP/TEAD4/βcatenin complex offers a potential therapeutic strategy for eradicating CSCs in basal (triplenegative) breast cancers.

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A gain-of-functional screen identifies the Hippo pathway as a central mediator of receptor tyrosine kinases during tumorigenesis

Cited by 59 publications

References 57 publications

The crosstalk between AXL and YAP promotes tumor progression through STAT3 activation in head and neck squamous cell carcinoma

The crosstalk between AXL and YAP promotes tumor progression through STAT3 activation in head and neck squamous cell carcinoma

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

YAP and β-catenin co-operate to drive oncogenesis in basal breast cancer

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