The emerging roles of YAP and TAZ in cancer

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.

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. 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 | Gα_q- and Gα₁₁-coupled receptor signals activate YAP and TAZ through RHO and/or RAC-regulated signalling circuitry. Cancer-associated Gα_q and Gα₁₁ mutants activate RHO to inhibit LATS through actin cytoskeleton reorganization, resulting in dephosphorylation and activation of YAP. Gα_q 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. 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 as LGR5 (which encodes leucine-rich repeat-containing G-protein coupled receptor 5) and AXIN2 (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 as BAX (which encodes BCL-2-associated X gene) and PUMA (which encodes p53-upregulated modulator of apoptosis; also known as BBC3). 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.