Published OnlineFirst September 17, 2015; DOI: 10.1158/1078-0432.CCR-15-0411 Molecular Pathways Clinical Cancer Research Molecular Pathways: Hippo Signaling, a Critical Tumor Suppressor Ana Sebio1,2 and Heinz-Josef Lenz2,3,4 Abstract The Salvador–Warts–Hippo pathway controls cell fate and linked to some of the most important signaling pathways tissue growth. The main function of the Hippo pathway is to involved in cancer development and progression. A better prevent YAP and TAZ translocation to the nucleus where they understanding of the Hippo pathway is thus essential to untan- induce the transcription of genes involved in cell proliferation, gle tumor biology and to develop novel anticancer therapies. survival, and stem cell maintenance. Hippo signaling is, thus, a Here, we comment on the progress made in understanding complex tumor suppressor, and its deregulation is a key feature in Hipposignalinganditsconnections,andalsoonhownew many cancers. Recent mounting evidence suggests that the over- drugs modulating this pathway, such as VerteporfinandC19, expression of Hippo components can be useful prognostic bio- are highly promising cancer therapeutics. Clin Cancer Res; 21(22); markers. Moreover, Hippo signaling appears to be intimately 5002–7. Ó2015 AACR. Background way is inactive or suppressed, YAP and TAZ translocate to the nucleus. In the nucleus, they regulate the activity of various The Salvador–Warts–Hippo pathway (known as Hippo path- transcription factors involved in cell proliferation, survival, way) was first discovered to be involved in controlling tissue microRNA processing, metastases development, and stem cell growth in Drosophila melanogaster in 2002, and it has recently maintenance such as SMADs, TEADs, TBX5, and RUNT1,2 and emerged as a critical tumor-suppressor network (1). The Hippo p73 (2–4). On the basis of this action mechanism, Hippo pathway is a highly evolutionarily conserved pathway that effectors YAP and TAZ can act either as tumor suppressors controls multiple functions that are crucial to several carcino- when located in the cytoplasm or as oncogenes by facilitating genesis processes such as proliferation, apoptosis, and stem cell transcriptional activationinthenucleus(Fig.1). maintenance. Hippo controls cell proliferation and survival mainly by The core of the mammalian Hippo pathway consists of a sensing the physical state of cells within a tissue through several protein complex that includes kinases MST1 and MST2 (also mechanisms. Unlike other pathways, Hippo does not have known as STK4 and STK3), large tumor suppressors 1 and 2 dedicated extracellular ligand–receptor complexes. Instead, the (LATS1 and LATS2) and adaptor proteins SAV1 (Salvador upstream signaling of Hippo involves many mechanisms and homolog 1) and MOB kinase activator 1A and 1B (MOB1A other signaling pathways. These upstream inputs can be divid- and MOB1B). MST1 and MST2 facilitate LATS1 and LATS2 ed into those controlling the pathway by retaining YAP/TAZ in phosphorylation, which in turn facilitates LATS-dependent the cytoplasm by physical interaction, and those that activate phosphorylation of the homologous oncoproteins YAP (Yes- the core kinase complex MST/LATS leading to YAP/TAZ phos- associated protein; encoded by YAP1) and TAZ (PDZ-binding phorylation. Some of the most relevant upstream regulators of motif, also known as WWTR1). When the Hippo pathway is Hippo include the following: (i) FERM domain–containing active, its main effectors, YAP and TAZ, are phosphorylated by proteins NF2 and KIBRA and WILLIN (5), (ii) polarization the Hippo core complex and retained in the cytoplasm where and adhesion proteins, including those controlling basolateral they undergo proteasomal degradation. When the Hippo path- polarity like the SCRIBBLE complex (6), apical polarity like the CRUMBS complex (7), and planar cell polarity like the FAT and 1 Dachsous family of cadherins (8). Cell adhesion proteins, such Medical Oncology Department, Santa Creu I Sant Pau Hospital, Uni- a versitat Autonoma de Barcelona, Barcelona, Spain. 2Sharon A. Car- as -catenin and E-cadherin (9), (iii) extracellular factors, G penter Laboratory, Norris Comprehensive Cancer Center, Keck School protein–coupled receptors (GPCR) and tyrosine kinase inhib- of Medicine, University of Southern California, Los Angeles, California. itor (TKI) receptors, and (iv) changes in mechanical forces 3Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los regulated by Rho and F-actin polymerization that can also Angeles, California. 4Department of Preventive Medicine, Norris Com- regulate YAP/TAZ nuclear localization (10). prehensive Cancer Center, Keck School of Medicine, University of Other proteins can also directly affect TAZ and YAP. These Southern California, Los Angeles, California. include WBP2, MASK proteins, HIPK2 and 14-3-3 proteins. Corresponding Author: Heinz-Josef Lenz, Norris Comprehensive Cancer Cen- Moreover, other proteins can interact with the upstream kinase ter, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA complex. Of particular interest is Rassf1, a tumor-suppressor 90033. Phone: 323-865-3967; Fax: 323-865-0061; E-mail: [email protected] frequently methylated in several tumors, which can act as a Hippo doi: 10.1158/1078-0432.CCR-15-0411 regulator. Rassf1a can bind MST regulating LATS1/2 phosphor- Ó2015 American Association for Cancer Research. ylation and promoting proapoptotic signals through p73. 5002 Clin Cancer Res; 21(22) November 15, 2015 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst September 17, 2015; DOI: 10.1158/1078-0432.CCR-15-0411 Hippo as a Tumor Suppressor FAT Cytoplasm G-protein coupled WILLIN KIBRA NF2 receptors Gα Junctions other Adrenaline, Rassf1a YAP MST1/2 TAZ glucagon, Gαs P E-cadherin dihydrexidine SAV1 α-catenin C19 MOB1 P Dobutamin β-adrenergic LATS1/2 YAP P CRUMBS complex TAZ P P YAP YAP YAP YAP 14-3-3 TAZ TAZ TAZ SCRIBBLE complex YAP/TAZ TAZ Botulinum proteosomal toxin C3, degradation Y27632, Nucleus simvastatin YAP YAP F-actin TAZ TAZ Verteporfin, VGLL4- mimicking peptide Rho SMAD 1–4 TEAD mRNA processing YAP AREG, Axin2, TAZ TCF p73 Hippo target genes Sox2, CTGF, Cyr61, Cytochalasin β-catenin Birc5, Id1, Id2, Mechanical D, latrunculin Pai-1, SMAD7, Myc stress A and B, Blebbistain Dasatinib © 2015 American Association for Cancer Research Figure 1. The Hippo signaling pathway and main regulators. The core of Hippo signaling consists of a group of kinases (MST1/2 and LATS1/2) and adaptor proteins SAV1 and MOB1, which by phosphorylating the Hippo pathway effectors YAP and TAZ, retain them in the cytoplasm. In the cytoplasm, YAP/TAZ undergo proteosomal degradation. YAP and TAZ, if not retained in the cytoplasm, can translocate to the nucleus where they regulate the activity of several transcription factors that induce the expression of Hippo target genes involved in cancer development and progression. Upstream regulation of Hippo includes: (i) FERM domain– containing proteins (NF2 KIBRA and WILLIN) that activate the core kinase complex, (ii) polarization and adhesion proteins like a-catenin, E-cadherin, CRUMBS, and SCRIBBLE complexes that can sequester YAP/TAZ in the cytoplasm, (iii) GPCRs that can be divided in those signaling through GaS leading to activation of Hippo cascade or those signaling through other Ga subunits that favor YAP/TAZ nuclear translocation, and (iv) Mechanical stress regulated by F-actin can also increase YAP/TAZ cytoplasmic location. In addition, independent proteins like Rassf1a and several pathways regulate Hippo signaling. New molecules and drugs under development to modulate Hippo signaling are represented in yellow. For more detailed information on Hippo upstream regulators schwanomas (13). In addition, mutations and deletions in LATS2 and downstream effectors, we refer the reader to some of the can be frequently found in malignant mesothelioma (14). In excellent reviews previously published (8, 11). mice, mutations in Hippo components lead to developmental deficiencies within the intestinal epithelium, liver, or skin kera- – – – tinocytes (15 17). Although YAP/TAZ activating mutations have Clinical Translational Advances not been described, high YAP/TAZ nuclear levels are present in Disruptions in the correct function of this pathway have been several cancer types (18). High YAP/TAZ nuclear levels favor cell found to take part in several tumorigenesis mechanisms. How- proliferation and survival as well as the acquisition of a cancer- ever, in human cancer, mutations in the Hippo components are promoting phenotype. Stem cell maintenance is intimately linked infrequent (12). The most established mutation is located in the to Hippo signaling in tumor cells. In breast tumors, in vitro studies tumor-suppressor NF2, an upstream Hippo regulator, causing the show how TAZ acts as a stem cell promoter, providing stem cells autosomal dominant syndrome type 2 neurofibromatosis that with self-renewal and tumor-initiating capacity. This property is entails, among others the development of meningiomas and acquired in part by forming a complex with the polarity complex www.aacrjournals.org Clin Cancer Res; 21(22) November 15, 2015 5003 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst September 17, 2015; DOI: 10.1158/1078-0432.CCR-15-0411