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New Insights Into Posttranslational Modifications of Hippo Pathway in Carcinogenesis and Therapeutics Mingjing He1,2, Zhuan Zhou1, Anil A

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New Insights Into Posttranslational Modifications of Hippo Pathway in Carcinogenesis and Therapeutics Mingjing He1,2, Zhuan Zhou1, Anil A He et al. Cell Div (2016) 11:4 DOI 10.1186/s13008-016-0013-6 Cell Division REVIEW Open Access New insights into posttranslational modifications of Hippo pathway in carcinogenesis and therapeutics Mingjing He1,2, Zhuan Zhou1, Anil A. Shah1, Yang Hong1, Qianming Chen2 and Yong Wan1* Abstract PTMs (posttranslational modifications) such as ubiquitylation, sumoylation, acetylation and protein methylation are pivotal modifiers that determine the activation, deactivation or subcellular localization of signaling proteins, facili- tating the initiation, amplification and transduction of signaling. Accumulating evidence suggest that several key signaling molecules in Hippo signaling pathway are tightly regulated by various types of PTMs. Malfunction of these critical signaling modules such as YAP/TAZ, MAT1/2 and LATS1/2 due to deregulated PTMs has been linked to a variety of human diseases such as cancer. In this review article, we summarized the current understanding of the impact of PTMs in regulating Hippo signaling pathway and further discussed the potential therapeutic intervention from the view of PTMs and Hippo pathway. Keywords: Hippo pathway, Posttranslational modifications, Phosphorylation, Ubiquitylation, Sumoylation, Acetylation, Methylation, Cancer and anti-cancer treatment Background yes-associated protein (YAP)/TAZ, a critical signaling The impact of Hippo signaling pathway has been linked node in Hippo pathway, could directly drive tumor ini- to a variety of critical biological processes and human tiation and invasion. This review aims to summarize the diseases, including organ growth control, stem cell func- recently expanded understanding of PTMs in regulating tion, tissue regeneration and tumor suppression. Signal- Hippo signaling pathway. We will discuss how dysfunc- ing modules in the Hippo pathway are tightly regulated tion of Hippo cascade due to the deregulated PTMs in order to orchestrate the organ size and cellular prolif- contributes to tumorigenesis and the current strategies eration during the development as well as homeostasis. of anti-cancer therapeutics through targeting the Hippo While regulation of Hippo cascade can be achieved at signaling pathway. various levels such as gene replication, transcription and protein translation, increasing emerging evidence has Overview of the Hippo pathway drawn our attention to posttranslational modifications Kinases cascade of Hippo pathway in mammals (PTMs). PTMs converts the properties of functional The classic Hippo pathway reveals the pivotal roles of protein through a series manners, including proteolytic PTMs in biological processes, especially phosphorylation cleavage, the addition of a modifying group to one or and ubiquitination. The core of the Hippo pathway com- more amino acid, which result in alteration of protein prises a highly conserved signaling module that functions activity, subcellular localization, turnover, and interac- similarly in mammals and in Drosophila melanogaster. tions with partner proteins. Malfunction of PTMs in Since the discovery of the serine/threonine kinases Mam- malian Ste20-like kinases (MST1/2) and Large tumor *Correspondence: [email protected] suppressor (LATS1/2) in humans (known as the Hpo and 1 Department of Cell Biology, University of Pittsburgh School of Medicine Warts kinases in fruit flies respectively), many additional and University of Pittsburgh Cancer Institute, Hillman Cancer Center, 5117 Centre Avenue, HCC2.6c, Pittsburgh, PA 15213, USA components of the Hippo pathway have been identified, Full list of author information is available at the end of the article and a complex signaling cascade has emerged which © 2016 He et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/ zero/1.0/) applies to the data made available in this article, unless otherwise stated. He et al. Cell Div (2016) 11:4 Page 2 of 10 integrates multiple upstream inputs from the plasma RASSF isoforms in mammals showed different roles on membrane into the nucleus, including the scaffolding the Hippo pathway, suggesting a divergent role through protein Salvador homolog 1 (SAV1; Salvador in fruit flies, evolution. RASSF6 inhibited MST2 and antagonized which interacts with MST1 and MST2) and the scaffold- Hippo signaling in a manner similar to that of dRASSF ing proteins MOB kinase activator 1A (MOB1A) and [11]. RASSF1 and RASSF5 stimulate Hippo signaling and MOB1B (Mats in fruit fly, which interact with LATS1 and play a distinct role from dRASSF. They bind the MST LATS2, respectively) [1]. and counteract dephosphorylation, then activate NDR1, When the Hippo pathway is on, MST1/2 phosphoryl- NDR2, and LATS1 to induce apoptosis [12, 13]. ates LATS1/2 through their SARAH coiled-coil domains. KIBRA was identified as a regulator of the Hippo path- It also phosphorylates MOB1, which enhances MOB1’s way recently. In Drosophila, Kibra functions together ability to bind and activate LATS1/2. The LATS1/2 phos- with Mer (homolog merlin in mammals) and Ex in a phorylation of YAP/TAZ (Yki in fruit flies) is a key event protein complex and regulates the Hippo kinase cascade in the canonical Hippo pathway [2]. LATS1/2 phospho- via direct binding to Hpo and Sav [14]. In addition to the rylates YAP at S127 and TAZ at S89 to enhance cytoplas- regulation of MST1/2, KIBRA directly regulates LATS1/2 mic retention of YAP/TAZ by increasing the interaction kinase activity by modulating the phosphorylation and between YAP/TAZ and 14-3-3 protein. When the Hippo stabilizes LATS2 by inhibiting its ubiquitination [15]. pathway is off, the final effectors of Hippo pathway—tran- In this Review, we largely refer to Hippo signaling com- scriptional co-activators YAP and TAZ—are translocated ponents using the mammalian nomenclature, and the D. into nucleus and bind to DNA via forming complexes melanogaster components are listed in Table 1. with transcriptional enhancer factor TEFs (TEAD1- TEAD4; scalloped in fruit flies). They also bind to other Post‑translational modification of Hippo pathway transcription factors such as SMADs, T-box transcrip- The Hippo pathway is considered to be in the active tion factor 5 (TBX5), RUNT-related transcription factor state when the MST and LATS kinases are active [16]. 1 (RUNX1) and RUNX2 as well as Tumor protein p73 The MST1/2, aided by their regulatory protein SAV1, to regulate gene expression. As the major downstream phosphorylates and activates the LATS kinases and effector of the tumor suppressing Hippo pathway, YAP/ MOB1A/B. The activated LATS1/2 in turn phosphoryl- TAZ were at first recognized as oncogenes. Elevated ates their downstream targets YAP and TAZ, leading to YAP/TAZ expression and nuclear localization have been these two transcriptional co-activators in their nuclear observed in multiple types of human cancers, including export, cytoplasmic retention and/or proteasomal deg- which located in breast, lung, liver, colon, cervix, ovary, radation. TEADs, without YAP and TAZ interaction, and esophagus [3–5]. However, recent data suggest an form complexes with the transcription cofactor vestigial- interesting hypothesis that YAP also has tumor suppres- like protein 4 (VGL4), repressing target gene expression sor function in certain contexts [6, 7]. involved in cell proliferation. Thus, when the Hippo path- way is activated, YAP/TAZ activity is inhibited, and YAP/ Upstream regulators of Hippo pathway TAZ-driven gene expression is suppressed. Inversely, The Hippo pathway bears many upstream regulators YAP and TAZ accumulate in the nucleus when the activ- that feed into the serine/threonine kinases MST1/2 ity of upstream of Hippo pathway is inhibited, forming and LATS1/2. PTMs regulation network is described complexes with TEADs or other transcription factors. In in Fig. 1. Most well-known ones are Merlin, RAS asso- this regard, the Hippo pathway acts primarily by inhibit- ciation domain-containing family proteins (RASSFs) and ing the nuclear functions of YAP and TAZ. Main PTMs protein kidney and brain expressed protein (KIBRA). of core components are described in Fig. 2; Table 1. Merlin is a cytoskeletal protein and was identified as a tumor suppressor underlying Neurofibromatosis type Phosphorylation II. Merlin contains a conserved FERM domain and was The fate of YAP/TAZ mainly decided by the phosphoryl- reported to be an upstream regulator of Hippo path- ation status, determining their protein stability, activity way [8]. Recently, Merlin was found to directly bind and and subcellular location. recruit LATS to the plasma membrane and promote LATS1/2 phosphorylate YAP at five serine residues LATS phosphorylation via the MST-SAV kinase complex, (S61, S109, S127, S164 and S397) and TAZ has four of suggesting an important role of Merlin in activating the these sites (S66, S89, S117 and S311) [17]. Among these Hippo-pathway [9]. residues, S127 (S89 in TAZ) and S397 (S311 in TAZ) In Drosophila, dRASSF competes with Sav for Hpo are key phosphorylation sites in suppressing YAP/TAZ and recruits a PP2A complex (dSTRIPAK) to dephos- oncogenic activity. The former is responsible for the phorylate and inactivate
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