Crosstalk between Hippo and TGFβ: Subcellular Localization of YAP/TAZ/Smad Complexes

Grannas, Karin; Arngården, Linda; Lönn, Peter; Mazurkiewicz, Magdalena; Blokzijl, Andries; Zięba, Agata; Söderberg, Ola

doi:10.1016/j.jmb.2015.04.015

Cited by 130 publications

(91 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, direct interaction of YAP/TAZ with Smad3 of the TGFβ signaling pathway has been shown in keratinocytes [219] and LLC-PK1 cells [220]. As such, YAP/TAZ activation may comprise a mechanism for the established necessity of mechanical stress for TGFβ-induced myofibroblast differentiation [221].…”

Section: Mechanotransduction By the Cytoskeleton: Actin’ On Nucleamentioning

confidence: 99%

The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart

Herum

Lunde

McCulloch

et al. 2017

JCM

136

123

View full text Add to dashboard Cite

Cardiac fibrosis, the excessive accumulation of extracellular matrix (ECM), remains an unresolved problem in most forms of heart disease. In order to be successful in preventing, attenuating or reversing cardiac fibrosis, it is essential to understand the processes leading to ECM production and accumulation. Cardiac fibroblasts are the main producers of cardiac ECM, and harbor great phenotypic plasticity. They are activated by the disease-associated changes in mechanical properties of the heart, including stretch and increased tissue stiffness. Despite much remaining unknown, an interesting body of evidence exists on how mechanical forces are translated into transcriptional responses important for determination of fibroblast phenotype and production of ECM constituents. Such mechanotransduction can occur at multiple cellular locations including the plasma membrane, cytoskeleton and nucleus. Moreover, the ECM functions as a reservoir of pro-fibrotic signaling molecules that can be released upon mechanical stress. We here review the current status of knowledge of mechanotransduction signaling pathways in cardiac fibroblasts that culminate in pro-fibrotic gene expression.

show abstract

Section: Mechanotransduction By the Cytoskeleton: Actin’ On Nucleamentioning

confidence: 99%

The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart

Herum

Lunde

McCulloch

et al. 2017

JCM

136

123

View full text Add to dashboard Cite

show abstract

“…YAP/TAZ are located in close proximity to Smad2/3. 42 We performed an in situ PLA, which specifically visualizes the interactions of proteins located in close proximity, to examine the spatial distribution of YAP/TAZ and Smad. In unstimulated cells, a weak but clear fluorescence signal was detected in the cytosol.…”

Section: Yap Knockdown Suppresses Tgf-b2-smad Signalingmentioning

confidence: 99%

YAP/TAZ Are Essential for TGF-β2–Mediated Conjunctival Fibrosis

Futakuchi

Inoue

Wei

et al. 2018

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

PURPOSE. To investigate the roles of Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ), the major effector molecules of the Hippo pathway, in TGFb2-mediated conjunctival fibrosis.METHODS. Primary human conjunctival fibroblasts were treated with TGF-b2. The expression of YAP/TAZ was examined by Western blot analyses and immunocytochemistry. The expression of fibrotic proteins and genes were evaluated by Western blot analyses and quantitative real-time PCR, respectively. The effects of YAP/TAZ on fibrotic changes were examined by knockdown experiments and the YAP/TAZ inhibitor, verteporfin.RESULTS. TGF-b2 stabilized YAP/TAZ and subsequently activated Smad2/3, which led to the transcription of fibrotic genes in human primary conjunctival fibroblasts. These fibrotic genes were differently regulated by YAP/TAZ. Notably, a-smooth muscle actin, fibronectin, collagen I, and collagen IV were primarily regulated by YAP. In contrast, CCN family proteins (CTGF and CYR61) depended on both YAP and TAZ. Mechanistically, YAP/TAZ were located in close proximity to Smad2/3, and in particular, YAP was required for TGF-b2-mediated phosphorylation and the nuclear translocation of Smad2/3. Furthermore, a YAP/TAZ inhibitor markedly suppressed TGF-b2-mediated fibrotic changes in conjunctival fibroblasts.CONCLUSIONS. YAP/TAZ acted as a molecular hub of TGF-b2 signaling in a cellular model of conjunctival fibrosis. Moreover, verteporfin, a YAP/TAZ inhibitor exerted potent antifibrosis effects by suppressing TGF-b2-YAP/TAZ-Smad signaling. Our study highlights YAP/TAZ as essential regulators of conjunctival fibrosis and shows that inhibition of YAP/TAZ might potentially improve the outcomes of glaucoma filtration surgery.

show abstract

“…When phosphorylated, Smad1 affinity to Yap is enhanced, which in turns activates proliferation and renewal of embryonic stem cells (Grannas et al, 2015). Similarly, Taz, and Smad2/3 binding induces their nuclear localization, transcription of TGF-β targets genes, and renewal of embryonic stem cells.…”

Section: Interplay With Other Signaling Pathwaysmentioning

confidence: 99%

Hippo Pathway and Skeletal Muscle Mass Regulation in Mammals: A Controversial Relationship

2017

View full text Add to dashboard Cite

Skeletal muscle mass reflects a dynamic turnover between net protein synthesis and degradation. In addition, satellite cell inclusion may contribute to increase muscle mass while fiber loss results in a reduction of muscle mass. Since 2010, a few studies looked at the involvement of the newly discovered Hippo pathway in the regulation of muscle mass. In line with its roles in other organs, it has been hypothesized that the Hippo pathway could play a role in different regulatory mechanisms in skeletal muscle as well, namely proliferation and renewal of satellite cells, differentiation, death, and growth of myogenic cells. While the Hippo components have been identified in skeletal muscle, their role in muscle mass regulation has been less investigated and conflicting results have been reported. Indeed, the first studies described both atrophic and hypertrophic roles of the Hippo pathway and its effectors Yap/Taz using different biochemical approaches. Further, investigation is therefore warranted to determine the role of the Hippo pathway in the regulation of skeletal muscle mass. New components of the pathway will probably emerge and unsuspected roles will likely be discovered due to its numerous interactions with different cellular processes. This mini-review aims to summarize the current literature concerning the roles of the Hippo pathway in the regulation of muscle mass and to develop the hypothesis that this pathway could contribute to muscle mass adaptation after exercise.

show abstract

Crosstalk between Hippo and TGFβ: Subcellular Localization of YAP/TAZ/Smad Complexes

Cited by 130 publications

References 16 publications

The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart

The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart

YAP/TAZ Are Essential for TGF-β2–Mediated Conjunctival Fibrosis

Hippo Pathway and Skeletal Muscle Mass Regulation in Mammals: A Controversial Relationship

Contact Info

Product

Resources

About