VSports最新版本 - Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site. VSports app下载.

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. V体育官网.

Review
. 2015 Sep;25(9):499-513.
doi: 10.1016/j.tcb.2015.05.002. Epub 2015 Jun 2.

YAP and TAZ: a nexus for Hippo signaling and beyond (V体育平台登录)

Carsten Gram Hansen #  1   2 , Toshiro Moroishi #  1   2 , Kun-Liang Guan  1   2
Affiliations
Review

YAP and TAZ: a nexus for Hippo signaling and beyond

"V体育ios版" Carsten Gram Hansen et al. Trends Cell Biol. 2015 Sep.

Abstract

The Hippo pathway is a potent regulator of cellular proliferation, differentiation, and tissue homeostasis. Here we review the regulatory mechanisms of the Hippo pathway and discuss the function of Yes-associated protein (YAP)/transcriptional coactivator with a PDZ-binding domain (TAZ), the prime mediators of the Hippo pathway, in stem cell biology and tissue regeneration VSports手机版. We highlight their activities in both the nucleus and the cytoplasm and discuss their role as a signaling nexus and integrator of several other prominent signaling pathways such as the Wnt, G protein-coupled receptor (GPCR), epidermal growth factor (EGF), bone morphogenetic protein (BMP)/transforming growth factor beta (TGFβ), and Notch pathways. .

Keywords: Notch; Wnt; extracellular matrix; primary cilia; regeneration; stem cells. V体育安卓版.

PubMed Disclaimer

Figures

Figure 1
Figure 1
The core of the Hippo pathway. The core components of the Hippo pathway comprise a regulatory serine–threonine kinase module and a transcriptional module. In mammals, this kinase module comprises two groups of kinases: mammalian STE20-like protein kinase 1 (MST1) (also known as STK4) and MST2 (also known as STK3) and large tumor suppressor 1 (LATS1) and LATS2 in combination with their activating adaptor proteins Salvador family WW domain-containing protein 1 (SAV1) and MOB kinase activator 1A/B (MOB1A/B), respectively. MAP4K4 has recently been identified as an alternative activator of LATS independent of MST. The transcriptional module comprises the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with a PDZ-binding domain (TAZ) and several transcription factors, of which the most prominently studied are TEA domain family members 1–4 (TEAD1–4). In a classical view, when the upstream kinase module is activated, MST1/2 phosphorylates SAV1, MOB1A/B, and LATS1/2 to activate the LATS1/2 kinases, which in turn directly phosphorylate YAP and TAZ on multiple serine residues leading to cytoplasmic retention of YAP/TAZ via a 14-3-3 interaction. Furthermore, the phosphorylation of YAP/TAZ by LATS1/2 primes YAP/TAZ for proteasomal degradation. The requirement for MST1/2 to phosphorylate LATS1/2 is cell-type dependent, suggesting the existence of additional kinases (drawn as a question mark) that regulate the activating phosphorylation of LATS1/2. By contrast, when the kinase module is inactivated, hypophosphorylated YAP/TAZ translocate into the nucleus and induce target gene expression.
Figure 2
Figure 2
Regulators of Yes-associated protein (YAP)/transcriptional coactivator with a PDZ-binding domain (TAZ) activities. (A) Spatial organization and regulation of the kinase module. Neurofibromatosis 2 (NF2) (also known as Merlin) activates large tumor suppressor (LATS) kinases at multiple levels. NF2 recruits LATS at the plasma membrane to coordinate the activating phosphorylation by the mammalian STE20-like protein kinase (MST)–Salvador family WW domain-containing protein 1 (SAV1) kinase complex. NF2 directly interacts with α-catenin and Angiomotin (AMOT) to recruit LATS kinases at the adherens junction, which in turn activate LATS. NF2 inhibits the E3 ubiquitin ligase CRL4DCAF1-mediated ubiquitylation of LATS1/2 in the nucleus to inhibit proteasomal degradation of LATS1 and ubiquitylation-induced conformational change of LATS2. Scribble (SCRIB) recruits the core kinases MST and LATS to facilitate LATS activation at the basolateral junction. LATS recruitment by AJUBA at adherens junctions inhibits LATS kinase activity. (B) Physical regulation of the transcription module. AMOT, protein tyrosine phosphatase 14 (PTPN14), and α-catenin inhibit the activity of the transcription module by complexing YAP and TAZ, thus sequestering and preventing their nuclear access. AMOT interacts with and thereby causes cytoplasmic sequestration of YAP and TAZ by recruiting them to tight junctions. PTPN14 also causes cytoplasmic localization of YAP and decreased nuclear YAP activity. The adherens junctions protein α-catenin also regulates YAP by sequestering YAP–14-3-3 protein complexes in the cytoplasm. WW domain-binding protein 2 (WBP2) and multiple ankyrin repeats single KH domain-containing protein (MASK) interact with nuclear YAP and TAZ, which enhances YAP and TAZ transcriptional coactivator properties, but the precise mechanism remains unknown. Vestigial-like family member 4 (VGLL4) represses target gene expression by competing with YAP–TEA domain family (TEAD) interactions.
Figure 3
Figure 3
Function of nuclear and cytoplasmic Yes-associated protein (YAP) and transcriptional coactivator with a PDZ-binding domain (TAZ). (A) Transcriptional coactivation. Nuclear YAP and TAZ bind to transcription factors (TFs) and recruit the NCOA6 methyltransferase complex as well as the BRM-containing SWI/SNF chromatin-remodeling complex, which mediates TF target-specific gene transcription. (B) miRNA processing. Nuclear YAP inhibits DDX17, a regulatory component of the microprocessor complex. This nuclear inhibition decreases global miRNA on YAP stimulation. Of note, some specific miRNAs are upregulated on YAP nuclear activation. (C) Wnt signaling. Cytoplasmic YAP and TAZ sequester β-catenin and in some instances recruit β-TrCP to the destruction complex. This leads to nuclear β-catenin downregulation and therefore dampens Wnt signaling. Cytoplasmic YAP and TAZ also negatively regulate Wnt signaling by sequestering β-catenin and disheveled (DVL). YAP and TAZ dictate nuclear and cytoplasmic localization of SHP2 and therefore its function. This feeds into the Wnt signaling pathway because nuclear SHP2 dephosphorylates parafibromin (CDC73), which leads to increased β-catenin transcriptional activity. (D) Transforming growth factor beta (TGFβ)/BMP–SMAD signal. Cytoplasmic YAP and TAZ sequester SMAD2/3 in the cytoplasm and therefore inhibit SMAD2/3-mediated signaling, although these mechanisms seem not to be universal and somewhat controversial. Nuclear YAP activates SMAD1-mediated transcription.
Figure 4
Figure 4
Signal crosstalk with Yes-associated protein (YAP) and transcriptional coactivator with a PDZ-binding domain (TAZ). Wnt signaling activates YAP and TAZ by inhibiting the formation of the β-catenin destruction complex that in some instances functions as a cytoplasmic sink and causes degradation of YAP and TAZ. Nuclear YAP can form a complex with β-catenin and the transcription factor TBX5 to promote antiapoptotic gene expression, including BCL2L1 and BIRC5. G protein-coupled receptor (GPCR) signaling is relayed via small G proteins. Activation of Gα12/13 and Gαq/11 induces YAP and TAZ nuclear translocation and activity, whereas active Gαs represses YAP and TAZ nuclear activity, which causes either activation or inhibition of large tumor suppressor (LATS) kinase activity. The family of epidermal growth factor (EGF) ligands activates YAP and TAZ in both a LATS-dependent and -independent manner. EGF receptor (EGFR) stimulation inhibits the kinase module by dissociating phosphoinositide-dependent kinase-1 (PDK1) from the Hippo pathway components [LATS, mammalian STE20-like protein kinase 1 (MST), and Salvador family WW domain-containing protein 1 (SAV1)], preventing activation of LATS by MST. EGFR–Ras–MAPK signaling also enhances the AJUBA family protein Wilms’ tumor protein 1-interacting protein (WTIP) binding to LATS, which inhibits LATS activity toward YAP. In addition, a cytoplasmic intracellular domain of the ERRB4 receptor (ICD-ERBB4) is cleaved and released on neuregulin 1 (NRG1) stimulation, which in turn binds to YAP and promotes target gene expression. On transforming growth factor beta (TGFβ) signal activation, nuclear YAP and TAZ form a complex with SMAD2, SMAD3, and TEA domain family (TEAD) transcription factors, coordinating a protumorigenic transcriptional program. YAP and TAZ also directly promote transcription of several receptors and ligands to mediate endocrine and paracrine signal crosstalk and potential feedback loops. Notable examples are the Wnt signal inhibitor DKK1, ligands of the BMP/TGFβ family BMP4, the EGF-like growth factor AREG, NOTCH2, the Notch ligand Jagged1 (JAG1), integrin/extracellular matrix (ECM) signaling components such as β2-integrin (ITGB2) and the α5 subunit of laminin 511 (LAMA5), and the focal adhesion component zyxin (ZYX).
See this image and copyright information in PMC

"V体育平台登录" References

    1. Pan D. The hippo signaling pathway in development and cancer. Dev. Cell. 2010;19:491–505. - "V体育ios版" PMC - PubMed
    1. Oh H, Irvine KD. Yorkie: the final destination of Hippo signaling. Trends Cell Biol. 2010;20:410–417. - PMC - PubMed
    1. Varelas X. The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease. Development. 2014;141:1614–1626. - PubMed
    1. Moroishi T, et al. The emerging roles of YAP and TAZ in cancer. Nat. Rev. Cancer. 2015;15:73–79. - PMC - PubMed
    1. Harvey KF, et al. The Hippo pathway and human cancer. Nat. Rev. Cancer. 2013;13:246–257. - PubMed (V体育官网入口)

Publication types