Movatterモバイル変換

[0]ホーム
URL:

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.

Https

The site is secure.
Thehttps:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

Nature Publishing Group full text link Nature Publishing Group Free PMC article
Full text links

Actions

Share

Review
.2015 Feb;15(2):73-79.
doi: 10.1038/nrc3876. Epub 2015 Jan 16.

The emerging roles of YAP and TAZ in cancer

Affiliations
Review

The emerging roles of YAP and TAZ in cancer

Toshiro Moroishi et al. Nat Rev Cancer.2015 Feb.

Abstract

Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are the major downstream effectors of the Hippo pathway, which regulates tissue homeostasis, organ size, regeneration and tumorigenesis. In this Progress article, we summarize the current understanding of the biological functions of YAP and TAZ, and how the regulation of these two proteins can be disrupted in cancer. We also highlight recent findings on their expanding role in cancer progression and describe the potential of these targets for therapeutic intervention.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Regulation of YAP and TAZ
The core inhibitory kinase module is composed of two groups of kinases, the mammalian STE20-like protein kinase 1 (MST1) and MST2, and the large tumour suppressor 1 (LATS1) and LATS2, in combination with their activating adaptor proteins, salvador family WW domain-containing protein 1 (SAV1), MOB kinase activator 1A (MOB1A) and MOB1B. The transcriptional module is composed of the transcriptional co-activators yes-associated protein (YAP) and its paralogue, transcriptional co-activator with PDZ-binding motif (TAZ), and the TEA domain family members (TEAD1–TEAD4). When the upstream kinase module is activated, LATS1 and LATS2 phosphorylate YAP and TAZ, which leads to inhibition of the transcriptional activity through 14-3-3-mediated cytoplasmic retention of YAP and TAZ priming them for ubiquitin-mediated proteasomal degradation,. Neurofibromin 2 (NF2) is an additional and potent activator of LATS1 and LATS2 (indicated by the dashed arrow) but is devoid of kinase activity. A yet unidentified kinase (or several of them) may directly phosphorylate LATS1 and LATS2 on the key activation site(s) in a MST1- and MST2-independent manner (indicated by the dashed arrow); when this site is not phosphorylated, the Hippo–LATS pathway is ‘off’. When YAP and TAZ are not phosphorylated by LATS kinases, they translocate to the nucleus and bind to sequence specific transcription factors TEAD1–TEAD4 (and other transcription factors, such as SMAD, RUNX, TP73, TBX5 and PAX), which enables the transcription of target genes encoding proteins that are involved in cell proliferation and survival,. AMOTL2, angiomotin-like protein 2; AREG, amphiregulin; BIRC5, baculoviral IAP repeat-containing protein 5; CTGF, connective tissue growth factor; CYR61, cysteine-rich angiogenic inducer 61; TF, transcription factor.
Figure 2
Figure 2. Pathway crosstalks regulate YAP and TAZ
Regulation of yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) activity goes well beyond the core kinases in the Hippo pathway.a | The liver kinase B1 (LKB1)–microtubule affinity-regulating kinase (MARK) pathway inhibits YAP and TAZ through scribble homologue (SCRIB)-mediated activation of mammalian STE20-like protein kinase 1 (MST1), MST2, large tumour suppressor 1 (LATS1) and LATS2. LKB1 tumour suppressor directly phosphorylates and activates substrates of the MARK family kinases to induce membrane localization of the basolateral polarity complex containing SCRIB. This relocalization of SCRIB activates the MST–LATS canonical Hippo kinase cascade to induce phosphorylation-dependent inhibition of YAP and TAZ. LKB1 also regulates the AMP-activated protein kinase (AMPK)–mammalian target of rapamycin (mTOR) pathway to confer its tumour suppressor function. In addition, YAP and TAZ inhibition mediated by the LKB1–MARK pathway can suppress mTOR complex 1 (mTORC1) function by restricting the transcription of micro-RNA 29 (miR-29), which inhibits the translation of phosphatase and tensin homologue (PTEN), an upstream negative regulator of mTOR.b | Gαq- and Gα11-coupled receptor signals activate YAP and TAZ through RHO and/or RAC-regulated signalling circuitry. Cancer-associated Gαq and Gα11 mutants activate RHO to inhibit LATS through actin cytoskeleton reorganization, resulting in dephosphorylation and activation of YAP. Gαq also stimulates triple functional domain protein (TRIO)–RHO and TRIO–RAC signalling to promote actin polymerization, which causes the dissociation of angiomotin (AMOT)–YAP complexes through AMOT binding to filamentous actin (F-actin), thereby contributing to YAP nuclear translocation. Phosphorylation of AMOT by LATS prevents AMOT binding to F-actin, which potentiates its inhibitory effects on YAP and TAZ activity.c | YAP and TAZ are transcriptionally inactivated by the tumour suppressor adenomatous polyposis coli (APC). WNT stimulation or loss of APC causes YAP and TAZ nuclear localization and activation of YAP–TEA domain family member (TEAD)-dependent and TAZ–TEAD-dependent transcription.d | Inhibitors that suppress YAP and TAZ function. Verteporfin abrogates the interaction between YAP and TEAD, thus inhibiting YAP-induced transcription. Vestigial-like family member 4 (VGLL4) directly competes with YAP in binding to TEAD, and a peptide mimicking this function of VGLL4 is capable of functioning as a YAP antagonist. The mevalonate cholesterol biosynthesis pathway provides a source of geranylgeranyl pyrophosphate, which is required for membrane localization and activation of RHO GTPases. Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) by statins reduces the geranylgeranylation and membrane localization of RHO GTPases, restricting YAP and TAZ nuclear accumulation and thus activity. DDX17, DEAD box helicase 17; GPCR, G protein-coupled receptor.
Figure 3
Figure 3. Tumour suppressor role of YAP
Yes-associated protein (YAP) can, in a context-dependent manner, function as a tumour suppressor by either inhibiting WNT signalling or triggering apoptosis.a | Cytoplasmic YAP dampens WNT signalling by multiple mechanisms. YAP recruits β-transducin repeat-containing protein (βTRCP) to the destruction complex for β-catenin degradation, which leads to β-catenin downregulation in the absence of WNT. Cytoplasmic YAP also restricts the nuclear translocation of β-catenin and Dishevelled (DVL),, which facilitates the WNT transcriptional response when forming a complex with β-catenin–T cell factor (TCF). Expression of YAP abrogates the DVL-mediated upregulation of the WNT target genes, such asLGR5 (which encodes leucine-rich repeat-containing G-protein coupled receptor 5) andAXIN2 (REFS 23,24).b | Oncogene-induced DNA damage promotes the activation of the ataxia telangiectasia mutated (ATM)–JUN N-terminal kinase (JNK) axis to phosphorylate the adaptor protein 14-3-3 at the binding site of ABL1, releasing the ABL1 tyrosine kinase from the cytoplasm into the nucleus where it phosphorylates YAP on a tyrosine residue. Tyrosine-phosphorylated YAP then forms a complex with the tumour suppressor TP73 to support the transcription of pro-apoptotic genes, such asBAX (which encodes BCL-2-associated X gene) andPUMA (which encodes p53-upregulated modulator of apoptosis; also known asBBC3). Mammalian STE20-like protein kinase 1 (MST1)-induced activation of the Hippo pathway suppresses this pro-apoptotic response by phosphorylating YAP at specific serine residues and thereby inhibiting its activity. APC, adenomatous polyposis coli; GSK3, glycogen synthase kinase 3; LATS, large tumour suppressor.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Pan D. The Hippo signaling pathway in development and cancer. Dev. Cell. 2010;19:491–505. - PMC - PubMed
    1. Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nature Rev. Cancer. 2013;13:246–257. - PubMed
    1. Mo JS, Park HW, Guan KL. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15:642–656. - PMC - PubMed
    1. Johnson R, Halder G. The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nature Rev. Drug Discov. 2014;13:63–79. - PMC - PubMed
    1. Nishioka N, et al. The Hippo signaling pathway components LATS and YAP pattern TEAD4 activity to distinguish mouse trophectoderm from inner cell mass. Dev. Cell. 2009;16:398–410. - PubMed

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full text links
Nature Publishing Group full text link Nature Publishing Group Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp