BMB Rep. 2014; 47(10): 540-545 BMB www.bmbreports.org Reports Invited Mini Review Cross-talk between Wnt/β-catenin and Hippo signaling pathways: a brief review Minseong Kim & Eek-hoon Jho* Department of Life Science, The University of Seoul, Seoul 130-743, Korea Balanced cell growth is crucial in animal development as well negatively regulates cell proliferation (5). Uncontrolled cell as tissue homeostasis. Concerted cross-regulation of multiple proliferation due to dysregulation of Hippo signaling is respon- signaling pathways is essential for those purposes, and the dys- sible for tumor formation (1, 4, 6). Therefore, Hippo signaling regulation of signaling may lead to a variety of human diseases is under intense scrutiny because of its significant roles in both such as cancer. The time-honored Wnt/β-catenin and recently developmental and cancer biology. identified Hippo signaling pathways are evolutionarily con- Cell growth and proliferation are also controlled by other served in both Drosophila and mammals, and are generally well-known signaling pathways, such as Wnt/β-catenin and considered as having positive and negative roles in cell pro- TGFβ signaling (7-9). Recent studies have proven that multiple liferation, respectively. While most mainstream regulators of signaling pathways cross-regulate each other to attain fine regu- the Wnt/β-catenin signaling pathway have been fairly well lation of certain biological phenomenon. Specifically, it has re- identified, the regulators of the Hippo pathway need to be cently been suggested that diverse signaling pathways such as more defined. The Hippo pathway controls organ size primarily Wnt/β-catenin (10-12), Shh (13), BMP/TGFβ (14-16), and GPCR by regulating cell contact inhibition. Recently, several cross- signaling (17) cooperate with the Hippo signaling pathway to regulations occurring between the Wnt/β-catenin and Hippo control cell growth and proliferation. signaling pathways were determined through biochemical and In this mini-review, we mainly describe recent advances in genetic approaches. In the present mini-review, we mainly dis- the Hippo signaling pathway, along with a brief explanation of cuss the signal transduction mechanism of the Hippo signaling the Wnt/β-catenin signaling pathway. Several examples of the pathway, along with cross-talk between the regulators of the merging of the two signaling pathways by unexpected cross-talk Wnt/β-catenin and Hippo signaling pathways. [BMB Reports between components of the Wnt/β-catenin and Hippo signaling 2014; 47(10): 540-545] pathways, which may provide novel therapeutic targets for can- cer treatment, are also discussed. INTRODUCTION Wnt/β-CATENIN SIGNALING PATHWAY Understanding the mechanisms for controlling the size of ani- Wnt signaling plays critical roles during embryonic develop- mals and their organs has been a challenging issue in biology, ment as well as in homeostatic mechanisms in adult tissues (7, 8). and the molecular mechanisms remain poorly understood Complexity inferred by the temporal and spatial expression of (1-3). It is obvious that cell growth, proliferation, differentiation, 19 different Wnts and 10 types of Frizzled receptors, in mice and death should be tightly controlled to attain organs of the and human, enables the Wnt signaling pathway to be involved proper size during development, and that tissue homeostasis in the control of diverse biological processes such as cell pro- should be maintained in adults. Relatively recent studies sug- liferation, differentiation, fate determination, adipogenesis, ag- gested that the Hippo signaling pathway is a key mechanism ing, etc (18, 19). Therefore, dysregulation of Wnt signaling can for the control of organ size (1-5). The upstream regulators and lead to diverse human diseases including cancers, osteopo- the list of genes regulated by the Hippo pathway suggest that it rosis, and neurodegeneration. Wnt signaling can be divided into canonical (β-catenin de- *Corresponding author. Tel: +82-2-6490-2671; Fax: +82-2-6490- pendent) and non-canonical (β-catenin independent) pathways 2664; E-mail: [email protected] based on whether increase of and nuclear localization of β-cat- enin occur in the presence of Wnt ligands (19, 20). Combina- http://dx.doi.org/10.5483/BMBRep.2014.47.10.177 tions of certain types of Wnt and Wnt receptors leads to the stabi- lization of β-catenin, while other combinations transduce sig- Received 7 August 2014 nals via small G-proteins such as Rho/Rac or through regulation Keywords: β-catenin, Crosstalk, Hippo signaling, Wnt signaling, of the intracellular calcium level. Since most of the known YAP/TAZ cross-talk occurring between Hippo and Wnt signaling, the main ISSN: 1976-670X (electronic edition) Copyright ⓒ 2014 by the The Korean Society for Biochemistry and Molecular Biology This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/li- censes/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Cross-talk between Wnt/β-catenin and Hippo signaling pathways: a brief review Minseong Kim and Eek-hoon Jho theme of this review, are restricted to Wnt/β-catenin signaling, dependent manner, though it is still controversial whether Axin the canonical Wnt signaling pathway will be described in the translocates to the phosphorylated LRP5/6 apart from the com- present review. Outstanding reviews on non-canonical Wnt sig- ponents of the β-catenin destruction complex or as a whole com- naling are available elsewhere (21-23). plex (26, 27). The accumulated cytoplasmic β-catenin then en- Wnts are highly conserved secreted proteins with glyco- ters into the nucleus and interacts with TCF (T-cell factor)/LEF sylation and lipid-modification, and act as ligands (24, 25). β-cat- (lymphoid enhancer factor) to activate the expression of Wnt tar- enin is a transcriptional co-activator, and regulation of the level get genes, which control cell proliferation (for example, c-myc of and nuclear localization of β-catenin is a pivotal regulatory and cyclin D1) and developmental processes (for example, twin, step in the Wnt/β-catenin signaling pathway. In the absence of brachyuryetc.). Due to space limitations the basic frame of signal Wnt, cytoplasmic β-catenin is consistently phosphorylated by transduction of the Wnt/β-catenin pathway was explained only GSK3β (glycogen synthase kinase 3β) in a destruction complex briefly; however, much more elaborated regulatory mechanisms containing Axin and APC (adenomatous polyposis coli) (Fig. 1). can be found in recent reviews, including ours (7, 8, 19). The phosphorylated β-catenin is then ubiquitinated by the E3 li- gase β-TrCP (β-transducin repeat-containing protein), and sub- HIPPO SIGNALING PATHWAY sequently degraded in a proteasome-dependent manner to result in low cytoplasmic levels of β-catenin. The expression of genes Recent studies have shown that the Hippo signaling pathway regulated by Wnt/β-catenin signaling is thereby repressed due to is a conserved regulator of organ size. The Hippo signaling the low levels of the transcriptional co-activator, β-catenin (Fig. pathway is composed of a core kinase cascade initiating from 1A). However, in the presence of Wnt, binding of Wnt to its re- Hippo (Mst1 and Mst2 in mammals) to the phosphorylation of ceptor Fz (Frizzled) and co-receptor LRP5/6 leads to phosphor- a Yki (YAP and TAZ in mammals), which leads to change of ylation of the intracellular region of LRP5/6 by GSK3β and CK1γ. the subcellular localization of Yki from the nucleus, where it Axin interacts with the phosphorylated LRP5/6 resulting in elevation acts as a transcriptional activator, to the cytoplasm (4, 28, 29). in the levels of cytoplasmic β-catenin in a Dvl (Dishevelled)- The Hippo signaling pathway does not have specifically allo- Fig. 1. Wnt/β-catenin signaling pathway. Schematic diagram for the core components and signal transduction of Wnt/β-catenin pathway. (A) In the absence of Wnt, GSK3β and CK1 phosphorylate β-catenin degradation complex which includes APC and Axin. The phosphorylated β-catenin is recognized by β-TrCP and subsequently degraded by proteasomal pathway. As a result, TCF/LEF1 suppresses the expression of target genes. (B) In the presence of Wnt, binding of Wnt to Fz and its co-receptor LRP5/6 leads to phosphorylation of LRP6. Axin, itself alone or whole β-catenin degradation complex including Axin, translocates to the phosphorylated LRP5/6, which leads to stabilization of cytoplasmic β-catenin. The stabilized β-catenin translocates into the nucleus and interacts with TCF/LEF1, which in turn enhances the ex- pression of target genes. http://bmbreports.org BMB Reports 541 Cross-talk between Wnt/β-catenin and Hippo signaling pathways: a brief review Minseong Kim and Eek-hoon Jho cated extracellular ligands or receptors, but instead appears to mals), which interacts with Salvador (SAV1 or also known as be regulated by a network of upstream components which are WW45 in mammals); and (2) Warts (LATS1 and LATS2 in mainly involved in the regulation of cell adhesion and cell po- mammals), which interacts with Mats (MOB1A and MOB1B in larity (1, 30-33). It is evident that the core kinase cascade is mammals) (1, 5). The transcriptional co-activator Yorkie (YAP strictly conserved, while the upstream signals influencing the and TAZ in mammals) forms a complex with the transcription kinase activity are much more diverse, for which the bio- factor Scalloped (TEAD 1-4 in mammals) to finally control the chemical mechanisms of regulation are still obscure. The expression of genes regulated by the Hippo signaling pathway Hippo signaling pathway was also found to cross-talk with (Fig. 2). multiple signaling pathways in a tissue or context-dependent Hippo signaling is regulated in a cell-density-dependent manner. manner; therefore, it may be reasonable to consider Hippo sig- When the MST1/2 and LATS1/2 kinases are activated at high cell naling as a complex network rather than a single linear pathway.