YAP and TAZ are distinct effectors of corneal myofibroblast transformation

Muppala, Santoshi; Raghunathan, Vijay Krishna; Jalilian, Iman; Thomasy, Sara M; Murphy, Christopher J.

doi:10.1016/j.exer.2018.12.009

Cited by 34 publications

(29 citation statements)

References 42 publications

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“…First, increased cytoplasmic TAZ may bind to β-catenin and/or disheveled in the cytoplasm to hinder β-catenin's nuclear translocation consistent with previous studies. 38 , 39 Alternatively, increased cytoplasmic TAZ may negatively regulate expression/activity of YAP in the nucleus in agreement with a previous study from our group in corneal stromal cells, 86 and that of Tang and colleagues, 87 who demonstrated that the transcriptional co-activator functions of YAP and TAZ are inversely regulated by tyrosine phosphorylation status of parafibromin. It is also likely that 10% XCDM-induced cell stiffening may be independent of the conventional mechanotransduction signaling axis of YAP/TAZ, which typically involves ROCK or actomyosin activity.…”

Section: Discussionsupporting

confidence: 88%

Crosslinked Extracellular Matrix Stiffens Human Trabecular Meshwork Cells Via Dysregulating β-catenin and YAP/TAZ Signaling Pathways

Yemanyi

Vranka

Raghunathan

2020

Invest. Ophthalmol. Vis. Sci.

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Purpose The purpose of this study was to determine whether genipin-induced crosslinked cell-derived matrix (XCDM) precipitates fibrotic phenotypes in human trabecular meshwork (hTM) cells by dysregulating β-catenin and Yes-associated protein (YAP)/ transcriptional coactivator with PDZ-binding motif (TAZ) signaling pathways. Methods Cell-derived matrices were treated with control or genipin for 5 hours to obtain respective uncrosslinked (CDM) and XCDMs and characterized. hTM cells were seeded on these matrices with/without Wnt pathway modulators in serum-free media for 24 hours. Elastic modulus, gene, and protein (whole cell and subcellular fractions) expressions of signaling mediators and targets of Wnt/β-catenin and YAP/TAZ pathways were determined. Results At the highest genipin concentration (10% XCDM), XCDM had increased immunostaining of N-ε(γ-glutamyl)-lysine crosslinks, appeared morphologically fused, and was stiffer (5.3-fold, P < 0.001). On 10% XCDM, hTM cells were 7.8-fold ( P < 0.001) stiffer, total β-catenin was unchanged, pβ-catenin was elevated, and pGSK3β was suppressed. Although 10% XCDM had no effect on cytoplasmic β-catenin levels, it reduced nuclear β-catenin, cadherin 11, and key Wnt target genes/proteins. The 10% XCDM increased total TAZ, decreased pTAZ, and increased cytoplasmic TAZ levels in hTM cells. The 10% XCDM increased total YAP, reduced nuclear YAP levels, and critical YAP/TAZ target genes/proteins. Wnt activation rescued hTM cells from 10% XCDM-induced stiffening associated with increased nuclear β-catenin. Conclusions Increased cytoplasmic TAZ may inhibit β-catenin from its nuclear shuttling or regulating cadherin 11 important for aqueous homeostasis. Elevated cytoplasmic TAZ may inhibit YAP's probable homeostatic function in the nucleus. Together, TAZ's cytoplasmic localization may be an important downstream event of how increased TM extracellular matrix (ECM) crosslinking may cause increased stiffness and ocular hypertension in vivo. However, Wnt pathway activation may ameliorate ocular hypertensive phenotypes induced by crosslinked ECM.

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Section: Discussionsupporting

confidence: 88%

Crosslinked Extracellular Matrix Stiffens Human Trabecular Meshwork Cells Via Dysregulating β-catenin and YAP/TAZ Signaling Pathways

Yemanyi

Vranka

Raghunathan

2020

Invest. Ophthalmol. Vis. Sci.

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“…No (Lu et al), Yes (Cai et al) [113,116] Mutual regulation TAZ does not affect YAP expression or stability (Finch-Edmondson et al), knockdown of TAZ upregulates YAP (Muppala et al) YAP promotes TAZ degradation via GSK3 and HSP90 [109,110] Mouse embryonic null phenotype Viable, but kidney disease present by E15.5 as well as lung defects, and post-natal survival is poor Embryonic lethal between E9.5 and E10.5 with a shortened body axis, yolk sac vascular defect, caudal dysgenesis, and more [26][27][28][29] Mouse EpiSC and human ESC self-renewal Sustains primed pluripotency by sequestering and stabilizing β-catenin in the cytoplasm; in hESCs, partners with OCT4 to repress mesendoderm genes In hESCs, partners with OCT4 to repress mesendoderm genes;…”

Section: Yesmentioning

confidence: 99%

“…Activates CTGF and Smad2/3/4 [110] T-cell differentiation Prevents differentiation of T cells toward Treg cells and encourages TH17 helper T-cell differentiation Inhibits differentiation of CD4 + T cells to TH1, TH17, TH2, and Treg fates and reduce tumor infiltration [136,137] Myoblasts and mouse skeletal muscle tissues Promotes myoblast proliferation, muscle growth, and myogenic differentiation, but not regeneration Promotes myoblast proliferation and muscle regeneration, but not differentiation [135] Promoting apoptosis in cancer Represses MYC and its targets in multiple myeloma Binds to p73 and upregulates BAX in various cancer tissues [142,164,165,185,197,198] Ferroptosis in cancer Pro-ferroptotic via regulation of EMP1 in renal cell carcinoma or ANGPTL4 in ovarian cancer Pro-ferroptotic via ACSL4 in colon cancer [131,186,187] apoptosis as well as whether other TFs can switch YAP to a pro-apoptotic transcriptional program.…”

Section: Yesmentioning

confidence: 99%

Context-dependent roles of YAP/TAZ in stem cell fates and cancer

LeBlanc

Ramirez

Kim

2021

Cell. Mol. Life Sci.

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Hippo effectors YAP and TAZ control cell fate and survival through various mechanisms, including transcriptional regulation of key genes. However, much of this research has been marked by conflicting results, as well as controversy over whether YAP and TAZ are redundant. A substantial portion of the discordance stems from their contradictory roles in stem cell self-renewal vs. differentiation and cancer cell survival vs. apoptosis. In this review, we present an overview of the multiple context-dependent functions of YAP and TAZ in regulating cell fate decisions in stem cells and organoids, as well as their mechanisms of controlling programmed cell death pathways in cancer.

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“…YAP and TAZ have also been reported to play distinct roles in wound healing. Upon transforming growth factor beta 1 (TGFβ1)-induced myofibroblast transformation of keratinocytes after injury, YAP and TAZ were reported to inversely regulate alpha-smooth muscle actin and CTGF expression through distinct interactions with SMADs and TEADs [116]. In myoblasts, both Yap and Taz promote proliferation, but only Taz enhances myogenic differentiation later on [117].…”

Section: Yap and Taz-functionally Redundant?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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YAP and TAZ are distinct effectors of corneal myofibroblast transformation

Cited by 34 publications

References 42 publications

Crosslinked Extracellular Matrix Stiffens Human Trabecular Meshwork Cells Via Dysregulating β-catenin and YAP/TAZ Signaling Pathways

Crosslinked Extracellular Matrix Stiffens Human Trabecular Meshwork Cells Via Dysregulating β-catenin and YAP/TAZ Signaling Pathways

Context-dependent roles of YAP/TAZ in stem cell fates and cancer

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

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