The Hippo signaling pathway regulates organ size, tissue regeneration, and stem cell self-renewal. The two key downstream transcription coactivators in this pathway, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), mediate the major gene regulation and biological functions of the Hippo pathway. The biological functions of YAP and TAZ in many tissues are known; however, their roles in skin wound healing remain unclear. To analyze whether YAP and/or TAZ are required for cutaneous wound healing, we performed small interfering RNA (siRNA)-mediated knockdown of YAP/TAZ in full-thickness skin wounds. YAP is strongly expressed in the nucleus and cytoplasm in the epidermis and hair follicle. Interestingly, YAP is expressed in the nucleus in the dermis at 2 and 7 days after wounding. TAZ normally localizes to the cytoplasm in the dermis but is distributed in both the nucleus and cytoplasm at 1 day after wounding. The knockdown of YAP and TAZ markedly delayed the rate of wound closure and reduced the transforming growth factor-β1 (TGF-β1) expression in the wound. YAP and TAZ also modulate the expression of TGF-β1 signaling pathway components such as Smad-2, p21, and Smad-7. These results suggest that YAP and TAZ localization to the nucleus is required for skin wound healing.

Myoblast differentiation is indispensable for skeletal muscle formation and is governed by the precisely coordinated regulation of a series of transcription factors, including MyoD and myogenin, and transcriptional coregulators. TAZ (transcriptional coactivator with PDZ-binding motif) has been characterized as a modulator of mesenchymal stem cell differentiation into osteoblasts and adipocytes through its regulation of lineage-specific master transcription factors. In this study, we investigated whether TAZ affects myoblast differentiation, which is one of the differentiated lineages of mesenchymal stem cells. Ectopic overexpression of TAZ in myoblasts increases myogenic gene expression in a MyoD-dependent manner and hastens myofiber formation, whereas TAZ knockdown delays myogenic differentiation. In addition, enforced coexpression of TAZ and MyoD in fibroblasts accelerates MyoD-induced myogenic differentiation. TAZ physically interacts with MyoD through the WW domain and activates MyoD-dependent gene transcription. TAZ additionally enhances the interaction of MyoD with the myogenin gene promoter. These results strongly suggest that TAZ functions as a novel transcriptional modulator of myogenic differentiation by promoting MyoD-mediated myogenic gene expression.

TAZ, a transcriptional modulator, has a key role in cell proliferation, differentiation and stem cell self-renewal. TAZ activity is regulated by several signalling pathways, including Hippo, GPCR and Wnt signalling, but the regulatory mechanisms of TAZ activation are not yet clearly understood. In this report, we show that TAZ is regulated by canonical Wnt signalling during osteogenic differentiation. Wnt3a increases TAZ expression and an inhibitor of GSK3b, a downstream effector of Wnt signalling, induces TAZ. Wnt3a facilitates the dephosphorylation of TAZ, which stabilises TAZ and prevents it from binding 14-3-3 proteins, thus inducing the nuclear localisation of TAZ. Dephosphorylation of TAZ occurs via PP1A, and depletion of PP1A blocks Wnt3a-induced TAZ stabilisation. Wnt3a-induced TAZ activates osteoblastic differentiation and siRNA-induced TAZ depletion decreases Wnt3a-induced osteoblast differentiation. Taken together, these results show that TAZ mediates Wnt3a-stimulated osteogenic differentiation through PP1A, suggesting that the Wnt signal regulates the Hippo pathway. Transcriptional co-activator with PDZ-binding motif (TAZ, also known as WWTR1) is a transcriptional modulator that has a key role in cell proliferation, differentiation and stem cell selfrenewal. TAZ interacts with several transcription factors including Runx2, PPARg, TEADS, TTF-1/Nkx2.1, Tbx5, Pax3, Smad2/3-4 complexes, MyoD and NFAT5. [1][2][3][4][5][6][7][8][9][10][11] This interaction regulates the transcription of target genes with diverse biological functions. For example, TAZ and its paralogue YAP interact with TEADs and stimulate their target genes, including CTGF and Cyr61, to promote cell proliferation and migration. This stimulation is inhibited by Hippo signalling, which regulates organ size, cell proliferation, differentiation and stem cell self-renewal.12-15 Several components are involved in the transduction of the signal. In Drosophila, Hippo and its regulatory protein Salvador stimulate Warts, which inactivates Yorkie. These components are highly evolutionarily conserved and their mammalian orthologues have been characterised. MST1/2 and its regulatory protein WW45 stimulate the downstream kinase Lats1/2, which inhibits nuclear localisation of TAZ/YAP and induces their proteolytic degradation.In cellular differentiation, TAZ modulates the cellular fate of mesenchymal stem cells (MSCs) via the activation of osteoblast and myoblast differentiation, and the inhibition of adipocytes differentiation. 2,10 The interaction between TAZ and Runx2 stimulates Runx2-mediated gene transcription. Wnts are a family of secreted glycoproteins that are involved in the regulation of cell proliferation, differentiation, axis formation, organ development and tissue homeostasis. 16-18b-Catenin is a transcriptional regulator in the canonical Wnt pathway, and, in the absence of Wnts, cytoplasmic b-catenin is phosphorylated by casein kinase I (CKI) and glycogen synthase kinase 3b (GSK3b). This phosphorylation facilitates its ubiquitination and pr...

Mesenchymal stem cell (MSC) differentiation is regulated by the extracellular matrix (ECM) through activation of intracellular signaling mediators. The stiffness of the ECM was shown to be an important regulatory factor for MSC differentiation, and transcriptional coactivator with PDZ-binding motif (TAZ) was identified as an effector protein for MSC differentiation. However, the detailed underlying mechanism regarding the role of ECM stiffness and TAZ in MSC differentiation is not yet fully understood. In this report, we showed that ECM stiffness regulates MSC fate through ERK or JNK activation. Specifically, a stiff hydrogel matrix stimulates osteogenic differentiation concomitant with increased nuclear localization of TAZ, but inhibits adipogenic differentiation. ERK and JNK activity was significantly increased in cells cultured on a stiff hydrogel. TAZ activation was induced by ERK or JNK activation on a stiff hydrogel because exposure to an ERK or JNK inhibitor significantly decreased the nuclear localization of TAZ, indicating that ECM stiffness-induced ERK or JNK activation is important for TAZ-driven osteogenic differentiation. Taken together, these results suggest that ECM stiffness regulates MSC differentiation through ERK or JNK activation.

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