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Hippo Signaling Pathway in Liver and Pancreas: the Potential Drug Target for Tumor Therapy

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Hippo Signaling Pathway in Liver and Pancreas: the Potential Drug Target for Tumor Therapy http://informahealthcare.com/drt ISSN: 1061-186X (print), 1029-2330 (electronic) J Drug Target, Early Online: 1–9 ! 2014 Informa UK Ltd. DOI: 10.3109/1061186X.2014.983522 REVIEW ARTICLE Hippo signaling pathway in liver and pancreas: the potential drug target for tumor therapy Delin Kong*, Yicheng Zhao*, Tong Men, and Chun-Bo Teng College of life science, Northeast Forestry University, Harbin, China Abstract Keywords Cell behaviors, including proliferation, differentiation and apoptosis, are intricately controlled Cancer gene therapy, hepatic targeting, during organ development and tissue regeneration. In the past 9 years, the Hippo signaling in vitro model, tumor targeting pathway has been delineated to play critical roles in organ size control, tissue regeneration and tumorigenesis through regulating cell behaviors. In mammals, the core modules of the Hippo History signaling pathway include the MST1/2-LATS1/2 kinase cascade and the transcriptional co-activators YAP/TAZ. The activity of YAP/TAZ is suppressed by cytoplasmic retention due Received 5 September 2014 to phosphorylation in the canonical MST1/2-LATS1/2 kinase cascade-dependent manner or the Revised 21 October 2014 non-canonical MST1/2- and/or LATS1/2-independent manner. Hippo signaling pathway, which Accepted 29 October 2014 can be activated or inactivated by cell polarity, contact inhibition, mechanical stretch and Published online 3 December 2014 extracellular factors, has been demonstrated to be involved in development and tumorigenesis of liver and pancreas. In addition, we have summarized several small molecules currently available that can target Hippo-YAP pathway for potential treatment of hepatic and pancreatic cancers, providing clues for other YAP initiated cancers therapy as well. Introduction buds, the progenitor cells give rise, through a stepwise For personal use only. process, to endocrine, acinar and duct cells. Both liver and pancreas are important internal glands in The processes of hepatic and pancreatic regeneration in mammals, and each plays an obligatory role in orchestrating adult are well known and acknowledged [3]. In response to the balance between lipid and glucose metabolism [1]. The drug treatment or mechanical injury, mature hepatic and liver is responsible for storage of glycogen, production of bile pancreatic cells can rescue the damage via self-proliferation. In for lipid emulsification and secretion of a variety of serum the extensive necrosis, progenitors in organs will be induced to proteins for homeostasis maintenance, whereas the pancreas proliferate and differentiate to achieve tissue regeneration. is a mixed gland with both exocrine and endocrine functions: However, regulatory disorders in the processes will lead to acinar is able to secrete enzymes including protease and abnormal phenotypes including cancers. lipase to digest food, while islet is able to secrete hormones The Hippo signaling pathway was first defined by genetic including glucagon and insulin to control glucose levels. mosaic screens in Drosophila, the core components of which Journal of Drug Targeting Downloaded from informahealthcare.com by 61.180.240.144 on 12/03/14 Liver and pancreas are both derived from the endoderm. included two kinases, the Ste-like kinase HIPPO and the NDR During gastrulation, the endoderm germ layer is established family kinase Warts (WTS), and a transcription factor Yorkie and forms a primitive gut tube that is subdivided into foregut, (Yki). In the year of 2005, Huang et al. [4] revealed the midgut and hindgut regions [2]. Fate mapping studies indicate signaling cascade: Hippo phosphorylates and activates WTS, that the embryonic liver originates from the ventral foregut and then p-WTS phosphorylates but inhibits Yki via blocking endoderm. The anterior portion of the hepatic diverticulum its translocation into nucleus, which leads to sequestration of gives rise to the liver and intrahepatic biliary tree, while the its target genes including CycE and Diap1. Two years later, posterior portion forms the gall bladder and extrahepatic bile Dong et al. [5] found that Hippo pathway was highly ducts. Like the liver, the pancreas develops as outgrowths of conserved from invertebrate to vertebrate and identified the the endoderm from the foregut–midgut junction at both dorsal core mammalian counterparts: MST1/2, LATS1/2 and YAP. and ventral directions. Finally, the ventral and dorsal pancre- Inactivation of the Hippo pathway induces YAP-mediated atic buds are fused to a whole pancreas. Within the pancreatic activation of various target genes that functionally result in cellular proliferation and outgrowth of organ size. Moreover, YAP has been implicated as an oncogene in solid tumors, * These authors contributed equally to this work. but its exact molecular mechanism in carcinogenesis still Address for correspondence: Chun-Bo Teng, E-mail: chunboteng@ remains unclear. It has been reported that several signaling nefu.edu.cn components of the Hippo pathway are implicated as tumor 2 D. Kong et al. J Drug Target, Early Online: 1–9 suppressors, while the downstream effector YAP, which is Regulation of the Hippo pathway negatively regulated by this signaling cascade, is proved to Activated by cell polarities functionally work as an oncogene in hepatic and pancreatic cancers. Ten years of researches demonstrate that the Hippo Both the liver and pancreas originate from the endodermal signaling is an intriguing pathway involved in organ size epithelia, in which cell proliferation, differentiation and control, tissue regeneration and tumorigenesis through apoptosis are closely related to the apical–basal polarity and modulating cell proliferation, differentiation and apoptosis. contact inhibition [16]. During embryogenesis, epithelial In this review, we will discuss the latest important findings on cells also exhibit planar cell polarity. The specialized the Hippo signaling pathway as well as possible means by structures are orientated within the plane of the epithelial which it can be targeted in the hepatic and pancreatic sheets [17]. In establishing planar cell polarity, the ligand development and tumorigenesis. and receptor, DS and FAT [18], but not the subsequent pathway of Hippo signaling [8,19], are involved. Probably, the DS-FAT downstream complex formed by FRMD6, NF2 The Hippo signaling pathway components and KIBRA is relevant to the apical polarity, given that it is Nowadays, two kinds of Hippo signaling, canonical and non- located on the inner side of the apical cytoplasmic membrane. canonical, have been acknowledged. The canonical Hippo It is noteworthy that the apical–basal polarity is mainly signaling pathway consists of three parts: the upstream co-regulated by the apical polarity complexes PAR3/PAR6/ signaling components (ligands, receptors and cytoplasmic aPKC (PAR) and Crumbs/PALS1/PATJ (CRB), together with regulatory factors), the core kinases and their adaptors, and the basolateral polarity complex Scribble/DLG/LGL (SCRIB) the downstream transcriptional activators. Although the non- [20–22], all of which can activate Hippo signaling to regulate canonical Hippo signaling has not been fully elucidated yet, it cell proliferation (Figure 2). is clear that the two ways are distinct in the manner of YAP CRB controls the apical polarity of the epithelium regulation: in the canonical pathway, YAP phosphorylation is and couples Hippo signaling to sense cell density. When dependent on the MST1/2-LATS1/2 kinase cascade, whereas the breast epithelium-derived cell line Eh4 is cultured at in the non-canonical one, YAP inactivation does not require a high density, CRB can interact with the angiostatin MST1/2 and/or LATS1/2 [6]. binding protein Agiomotin (AMOT) in the presence of In Drosophila, surface ligand Dachsous (transmembrane PATJ. AMOT has been proved to bind to not only YAP/ cadherin, DS) and its receptor FAT have been identified as a TAZ on cytomembrane [9], but also to MST2 and LATS2 in common trigger of the Hippo signaling. DS1/2 and FAT4 are cytoplasm to activate the latter, thereby promoting phosphor- the homologous mammalian proteins; however, whether they ylation of YAP [23]. Further, p-YAP/TAZ can retain SMADs can be employed by the Hippo pathway still remains unclear in cytoplasm so as to block the TGF-b signaling and repress [7,8]. In mammals, plasma membrane linked protein FRMD6 the epithelial-mesenchymal transition (EMT) [24]. Another Drosophila Drosophila For personal use only. (Expanded in ), NF2 (MERLIN in ) apical complex PAR can be recruited by CRB from cytoplasm and KIBRA form a complex to activate MST1/2 (Mammalian to the apical membrane. It is also found to be localized at tight sterile 20-like kinase 1/2, HIPPO in Drosophila). With the junctions (TJ). KIBRA, one of the Hippo regulator compo- help of adaptor proteins SAV1 (Salvador 1, SAV in nents, is able to bind to PAR and TJ [25]. Otherwise, the Drosophila), MOBKL1A and MOBKL1B (Mps One Binder atypical protein kinase aPKC in the PAR complex can kinase activator-like 1, MATS in Drosophila), MST1/2 can phosphorylate MST1/2, thereby regulating the activity of phosphorylate and activate LATS1/2 (Large tumor suppressor YAP indirectly [26]. 1/2, WTS in Drosophila) [9]. The requirement for MST1/2 to The basolateral complex SCRIB, composed of Scribble activate LATS1/2 might be cell type dependent. For instance, (SCRIB), Lethal giant larvae (LGL) and Discs large (DLG), MST1/2 knockout in mouse livers does not significantly has antagonistic effect against the PAR complex,
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