DOCSLIB.ORG

Cross-Talk Between Wnt/Β-Catenin and Hippo Signaling Pathways: a Brief Review

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Cross-Talk Between Wnt/Β-Catenin and Hippo Signaling Pathways: a Brief Review 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.
Load more

Recommended publications
  • Dysfunctional Mechanotransduction Through the YAP/TAZ/Hippo Pathway As a Feature of Chronic Disease
    cells Review Dysfunctional Mechanotransduction through the YAP/TAZ/Hippo Pathway as a Feature of Chronic Disease 1, 2, 2,3, 4 Mathias Cobbaut y, Simge Karagil y, Lucrezia Bruno y, Maria Del Carmen Diaz de la Loza , Francesca E Mackenzie 3, Michael Stolinski 2 and Ahmed Elbediwy 2,* 1 Protein Phosphorylation Lab, Francis Crick Institute, London NW1 1AT, UK; [email protected] 2 Department of Biomolecular Sciences, Kingston University, Kingston-upon-Thames KT1 2EE, UK; [email protected] (S.K.); [email protected] (L.B.); [email protected] (M.S.) 3 Department of Chemical and Pharmaceutical Sciences, Kingston University, Kingston-upon-Thames KT1 2EE, UK; [email protected] 4 Epithelial Biology Lab, Francis Crick Institute, London NW1 1AT, UK; [email protected] * Correspondence: [email protected] These authors contribute equally to this work. y Received: 30 November 2019; Accepted: 4 January 2020; Published: 8 January 2020 Abstract: In order to ascertain their external environment, cells and tissues have the capability to sense and process a variety of stresses, including stretching and compression forces. These mechanical forces, as experienced by cells and tissues, are then converted into biochemical signals within the cell, leading to a number of cellular mechanisms being activated, including proliferation, differentiation and migration. If the conversion of mechanical cues into biochemical signals is perturbed in any way, then this can be potentially implicated in chronic disease development and processes such as neurological disorders, cancer and obesity. This review will focus on how the interplay between mechanotransduction, cellular structure, metabolism and signalling cascades led by the Hippo-YAP/TAZ axis can lead to a number of chronic diseases and suggest how we can target various pathways in order to design therapeutic targets for these debilitating diseases and conditions.
    [Show full text]
  • The Hippo Pathway Component Wwc2 Is a Key Regulator of Embryonic Development and Angiogenesis in Mice Anke Hermann1,Guangmingwu2, Pavel I
    Hermann et al. Cell Death and Disease (2021) 12:117 https://doi.org/10.1038/s41419-021-03409-0 Cell Death & Disease ARTICLE Open Access The Hippo pathway component Wwc2 is a key regulator of embryonic development and angiogenesis in mice Anke Hermann1,GuangmingWu2, Pavel I. Nedvetsky1,ViktoriaC.Brücher3, Charlotte Egbring3, Jakob Bonse1, Verena Höffken1, Dirk Oliver Wennmann1, Matthias Marks4,MichaelP.Krahn 1,HansSchöler5,PeterHeiduschka3, Hermann Pavenstädt1 and Joachim Kremerskothen1 Abstract The WW-and-C2-domain-containing (WWC) protein family is involved in the regulation of cell differentiation, cell proliferation, and organ growth control. As upstream components of the Hippo signaling pathway, WWC proteins activate the Large tumor suppressor (LATS) kinase that in turn phosphorylates Yes-associated protein (YAP) and its paralog Transcriptional coactivator-with-PDZ-binding motif (TAZ) preventing their nuclear import and transcriptional activity. Inhibition of WWC expression leads to downregulation of the Hippo pathway, increased expression of YAP/ TAZ target genes and enhanced organ growth. In mice, a ubiquitous Wwc1 knockout (KO) induces a mild neurological phenotype with no impact on embryogenesis or organ growth. In contrast, we could show here that ubiquitous deletion of Wwc2 in mice leads to early embryonic lethality. Wwc2 KO embryos display growth retardation, a disturbed placenta development, impaired vascularization, and finally embryonic death. A whole-transcriptome analysis of embryos lacking Wwc2 revealed a massive deregulation of gene expression with impact on cell fate determination, 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; cell metabolism, and angiogenesis. Consequently, a perinatal, endothelial-specific Wwc2 KO in mice led to disturbed vessel formation and vascular hypersprouting in the retina.
    [Show full text]
  • Hippo Signaling Regulates Drosophila Intestine Stem Cell Proliferation Through Multiple Pathways
    Hippo signaling regulates Drosophila intestine stem cell proliferation through multiple pathways Fangfang Rena, Bing Wanga, Tao Yuea, Eun-Young Yunb,1, Y. Tony Ipb, and Jin Jianga,c,2 aDepartment of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; bProgram in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and cDepartment of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390 Edited* by Michael Levine, University of California, Berkeley, CA, and approved October 6, 2010 (received for review August 27, 2010) Intestinal stem cells (ISCs) in the Drosophila adult midgut are essen- investigated. In this study, we demonstrate that the Hpo pathway tial for maintaining tissue homeostasis and replenishing lost cells in restricts ISC proliferation in the adult midgut. We uncover response to tissue damage. Here we demonstrate that the Hippo a non–cell-autonomous mechanism by which the Hpo pathway (Hpo) signaling pathway, an evolutionarily conserved pathway im- negatively regulates stem cell proliferation by restricting the plicated in organ size control and tumorigenesis, plays an essential production of cytokines and mitogens that activate the JAK- role in regulating ISC proliferation. Loss of Hpo signaling in either STAT and EGFR pathways. In addition, we demonstrate that midgut precursor cells or epithelial cells stimulates ISC proliferation. Yki is required in the precursor cells for dextran sulfate sodium We provide evidence that loss of Hpo signaling in epithelial cells (DSS)-induced ISC proliferation. increases the production of cytokines of the Upd family and multiple EGFR ligands that activate JAK-STAT and EGFR signaling pathways Results in ISCs to stimulate their proliferation, thus revealing a unique non– Loss of Hpo Signaling in Precursor Cells Stimulates ISC Proliferation.
    [Show full text]
  • Hippo Signaling Pathway As a New Potential Target in Non-Melanoma Skin Cancers: a Narrative Review
    life Review Hippo Signaling Pathway as a New Potential Target in Non-Melanoma Skin Cancers: A Narrative Review Igor Aleksander Bednarski 1,*, Magdalena Ci ˛azy˙ ´nska 2 , Karolina Wódz 3, Izabela Drózd˙ z˙ 4 , Małgorzata Skibi ´nska 1, Joanna Narbutt 1 and Aleksandra Lesiak 1 1 Department of Dermatology, Pediatric Dermatology and Dermatological Oncology, Medical University of Lodz, 91-347 Lodz, Poland; [email protected] (M.S.); [email protected] (J.N.); [email protected] (A.L.) 2 Department of Proliferative Diseases, Nicolaus Copernicus Multidisciplinary Centre for Oncology and Traumatology, 93-513 Lodz, Poland; [email protected] 3 Laboratory of Molecular Biology, VET-LAB Brudzew, 62-720 Brudzew, Poland; [email protected] 4 Department of Clinical Genetics, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland; [email protected] * Correspondence: [email protected] Abstract: Non-melanoma skin cancers (NMSCs), including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), are the most frequently diagnosed cancers in humans, however, their exact pathogenesis is not fully understood. In recent years, it has been hypothesized that the recently discovered Hippo pathway could play a detrimental role in cutaneous carcinogenesis, but no direct connections have been made. The Hippo pathway and its effector, YAP, are responsible for tissue growth by accelerating cell proliferation, however, YAP upregulation and overexpression have also been reported in numerous types of tumors. There is also evidence that disrupted YAP/Hippo Citation: Bednarski, I.A.; Ci ˛azy´nska,˙ signaling is responsible for cancer growth, invasion, and metastasis.
    [Show full text]
  • Type I and II Interferon Are Associated with High Expression of the Hippo Pathway Family Members
    Cel al & lul ic ar in I l m C m f o u n l a o l n o Journal of Clinical & Cellular r g u y o J ISSN: 2155-9899 Immunology Research Article Type I and II Interferon are Associated with High Expression of the Hippo Pathway Family Members Bianca Sciescia1*, Raquel Tognon2, Natalia de Souza Nunes1, Tathiane Maistro Malta1, Fabiani Gai Frantz1, Fabiola Attie de Castro1, Maira da Costa Cacemiro1 1Department of Clinical, Toxicological and Bromatological Analysis, University of Sao Paulo - USP, Ribeirao Preto - SP, Brazil; 2Department of Pharmacy, Federal University of Juiz de Fora, Campus Governador Valadares, Governador Valadares - MG, Brazil ABSTRACT The Hippo pathway plays a regulatory role on inflammation and cell death and proliferation. Here we described a relationship between Hippo pathway components and inflammation in healthy subjects. The plasma levels of cytokines and chemokines were used to define their inflammatory profile and classify them as normal, high and low producers of cytokines. Leukocytes from healthy subjects with inflammatory profile expressed the highest levels of MSTS1/MST2, SAV1, LATS1/LATS2, MOB1A/MOB1B and YAP genes. The group that overexpressed Hippo pathway-related genes secreted more IFN-ϒ and IFN-α2. Keywords: Hippo pathway; Inflammatory process; Healthy subjects; Cytokines; Chemokines ABBREVATIONS: LATS1/LATS2 kinases (large tumor suppressor kinase 1/2) and MOB kinase activator IL: Interleukin; IFN: Interferon; LATS1/LATS2: Large tumor their adapter proteins MOB1A/MOB1B ( 1A/1B yes-associated suppressor kinase 1/2; MCP-1: Monocyte chemoattractant ), and the transcription coactivators YAP ( protein tafazzin protein protein-1; MIP: Macrophage inflammatory protein; MOB1A/ ) and TAZ ( ).
    [Show full text]
  • Hippo Signaling Antibody Sampler
    Hippo Signaling Antibody Sampler Kit Store at -20°C 3 n 1 Kit Orders n 877-616-CELL (2355) (9 x 20 µl) [email protected] Support n 877-678-TECH (8324) [email protected] Web n www.cellsignal.com rev. 06/16 #8579 For Research Use Only. Not For Use In Diagnostic Procedures. Products Included Product # Quantity Mol. Wt. Isotype Storage: Supplied in 10 mM sodium HEPES (pH 7.5), 150 mM NaCl, 100 µg/ml BSA, 50% glycerol and less than 0.02% Phospho-YAP (Ser397) (D1E7Y) Rabbit mAb 13619 20 µl 75 kDa Rabbit IgG sodium azide. Store at –20°C. Do not aliquot the antibodies. LATS1 (C66B5) Rabbit mAb 3477 20 µl 140 kDa Rabbit IgG Recommended Antibody Dilutions: Western blotting 1:1000 Phospho-MOB1 (Thr35) (D2F10) Rabbit mAb 8699 20 µl 24 kDa Rabbit IgG Please visit www.cellsignal.com for validation data MOB1 (E1N9D) Rabbit mAb 13730 20 µl 25 kDa Rabbit IgG and a complete listing of recommended companion Mst1 Antibody 3682 20 µl 59 kDa Rabbit IgG products. Mst2 Antibody 3952 20 µl 60 kDa Rabbit IgG SAV1 (D6M6X) Rabbit mAb 13301 20 µl 45 kDa Rabbit IgG Phospho-YAP (Ser127) (D9W2I) Rabbit mAb 13008 20 µl 65-75 kDa Rabbit IgG YAP/TAZ (D24E4) Rabbit mAb 8418 20 µl 50,70 kDa Rabbit IgG Anti-rabbit IgG, HRP-linked Antibody 7074 100 µl Goat See www.cellsignal.com for individual component applications, species cross-reactivity, dilutions and additional application protocols. Description: The Hippo Signaling Antibody Sampler Kit MOB1 (Thr35) (D2F10) Rabbit mAb recognizes endogenous Background References: provides an economical means of detecting target proteins levels of MOB1 protein only when phosphorylated at Thr35.
    [Show full text]
  • Modulation of Hippo Pathway by Alternative Splicing Diwas Srivastava
    Modulation of hippo pathway by alternative splicing Diwas Srivastava To cite this version: Diwas Srivastava. Modulation of hippo pathway by alternative splicing. Agricultural sciences. Uni- versité Montpellier, 2019. English. NNT : 2019MONTT015. tel-02387314 HAL Id: tel-02387314 https://tel.archives-ouvertes.fr/tel-02387314 Submitted on 29 Nov 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE POUR OBTENIR LE GRADE DE DOCTEUR DE L’UNIVERSITÉ DE M ONTPELLIER En BIOLOGIE - SANTE École doctorale- Biologiques pour la Santé (CBS2) Unité de recherche- Institut de Génétique Moléculaire de Montpellier Modulation of Hippo Pathway by Alternative Splicing Présentée par Diwas SRIVASTAVA Le 25 Juin 2019 Sous la direction de Dr. François JUGE et Dr. Jamal TAZI Devant le jury composé de Frédérique Peronnet , DR, HDR Institut de Biologie- Paris Seine RAPPORTRICE Julien Colombani, CR, HDR Université de Copenhague- Danemark RAPPORTEUR Florence Besse, DR, HDR Institute of Biology Valrose EXAMINATRICE Anne-Marie Martinez, Pr, HDR Université de Montpellier PRESIDENTE, EXAMINATRICE Francois Juge, CR,HDR Institut de Génétique Moléculaire de Montpellier DIRECTEUR DE THESE Jamal Tazi, Pr, HDR Université de Montpellier CO-DIRECTEUR DE THESE Acknowledgements First, I would like to express my deepest gratitude to my supervisor, Dr.
    [Show full text]
  • The Neurotransmitter Released at the Neuromuscular Junction Is
    The Neurotransmitter Released At The Neuromuscular Junction Is Towney congeals his bibbers manipulate jocular, but cash-and-carry Winfred never extravasating so malcontentedly. Is Norton always dipetalous and unworn when guzzled some admeasurement very untidily and adversely? Busty Dominic overexcited some close and jemmying his galluses so nautically! Hiw are four nlgs are working memory, sv hubs depending on the specific to the neurotransmitter released neuromuscular junction at institutions across brain The energy is delivered in a fractional manner. Smooth muscle NMJ is formed between the autonomic nerve fibers that branch diffusely on strength muscle in form diffuse junctions. In an intact brain, volume was observed that Cac density at AZs is indeed strongly correlated with Pr. Chemical synapses involve the transmission of chemical information from one cell as the next. Currents through the fusion pore that forms during exocytosis of a secretory vesicle. If you order something abusive or that does not lessen with surrender terms or guidelines please flag it as inappropriate. Ach in the presynaptic protein in the active secretors of the released. You can login by using one alongside your existing accounts. Many drugs and anesthetic agents also affect neuromuscular junction and impulse transmission to inside their effects. The chemical must be present within a neuron. Another route for tetanus is lockjaw, respectively, the calcium rushes out of newly opened gates. In our data presented at multiple neurotransmitters are commonly performed by abnormal nmj but the neurotransmitter released at is the neuromuscular junction, it will fail to propagate from another power stroke can have qualitatively distinct categories reflective of the resultant of development.
    [Show full text]
  • Hippo Signaling Interactions with Wnt/Β-Catenin and Notch Signaling Repress Liver Tumorigenesis
    The Journal of Clinical Investigation RESEARCH ARTICLE Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis Wantae Kim,1,2 Sanjoy Kumar Khan,1,2 Jelena Gvozdenovic-Jeremic,1 Youngeun Kim,3 Jason Dahlman,1 Hanjun Kim,1,2 Ogyi Park,4 Tohru Ishitani,5 Eek-hoon Jho,3 Bin Gao,4 and Yingzi Yang1,2 1Genetic Disease Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA. 2Department of Developmental Biology, Harvard School of Dental Medicine (HSDM), Boston, Massachusetts, USA. 3Department of Life Sciences, University of Seoul, Seoul, South Korea. 4Section on Liver Biology, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA. 5Division of Cell Regulation Systems, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. Malignant tumors develop through multiple steps of initiation and progression, and tumor initiation is of singular importance in tumor prevention, diagnosis, and treatment. However, the molecular mechanism whereby a signaling network of interacting pathways restrains proliferation in normal cells and prevents tumor initiation is still poorly understood. Here, we have reported that the Hippo, Wnt/β-catenin, and Notch pathways form an interacting network to maintain liver size and suppress hepatocellular carcinoma (HCC). Ablation of the mammalian Hippo kinases Mst1 and Mst2 in liver led to rapid HCC formation and activated Yes-associated protein/WW domain containing transcription regulator 1 (YAP/TAZ), STAT3, Wnt/β-catenin, and Notch signaling. Previous work has shown that abnormal activation of these downstream pathways can lead to HCC. Rigorous genetic experiments revealed that Notch signaling forms a positive feedback loop with the Hippo signaling effector YAP/TAZ to promote severe hepatomegaly and rapid HCC initiation and progression.
    [Show full text]
  • Role of Hippo Signaling Pathway in Early Placental Development COMMENTARY Francesca Soncina,B and Mana M
    COMMENTARY Role of Hippo signaling pathway in early placental development COMMENTARY Francesca Soncina,b and Mana M. Parasta,b,1 The placenta is an organ of fetal origin that develops at the interface with the maternal uterus (1). It per- forms numerous and diverse functions fundamental for the proper growth and development of the semi- allogeneic fetus, including gas, nutrient, and waste exchange; production of hormones; and modulation of maternal immune response. Placental development begins, following implantation of the blastocyst-stage embryo, with the expansion of the trophectoderm (TE) and establishment of a villous trophoblast progenitor population, termed cytotrophoblast (CTB) (2). As this cell layer grows and invaginates to form chorionic villi (functional units of the human placenta), the CTB fur- ther expands and differentiates into two main mature trophoblast cell types: the syncytiotrophoblast (STB), involved in gas/nutrient exchange, and extravillous trophoblast (EVT), which invades the maternal decidua and remodels maternal spiral arterioles (Fig. 1). How- ever, the mechanisms behind early events in human Fig. 1. Human placental chorionic villus showing the different trophoblast placentation, particularly CTB self-renewal and differ- subtypes: vCTB, STB, and EVTs in the maternal decidua, the latter arising from entiation, are largely unknown. Using tools recently differentiation of vCTB through the cell column. Each placental trophoblast developed to study early human placental develop- subcompartment expresses different combinations of the TEAD family members ment, two studies in PNAS address the role of the and their transcriptional cofactors, YAP1, TAZ, and VGLL family members. This particular spatial expression pattern suggests a dynamic exchange of binding Hippo pathway in trophoblast progenitor self-renewal.
    [Show full text]
  • The Hippo Signaling Pathway in Drug Resistance in Cancer
    cancers Review The Hippo Signaling Pathway in Drug Resistance in Cancer Renya Zeng and Jixin Dong * Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-402-559-5596; Fax: +1-402-559-4651 Simple Summary: Although great breakthroughs have been made in cancer treatment following the development of targeted therapy and immune therapy, resistance against anti-cancer drugs remains one of the most challenging conundrums. Considerable effort has been made to discover the underlying mechanisms through which malignant tumor cells acquire or develop resistance to anti-cancer treatment. The Hippo signaling pathway appears to play an important role in this process. This review focuses on how components in the human Hippo signaling pathway contribute to drug resistance in a variety of cancer types. This article also summarizes current pharmacological interventions that are able to target the Hippo signaling pathway and serve as potential anti-cancer therapeutics. Abstract: Chemotherapy represents one of the most efficacious strategies to treat cancer patients, bringing advantageous changes at least temporarily even to those patients with incurable malignan- cies. However, most patients respond poorly after a certain number of cycles of treatment due to the development of drug resistance. Resistance to drugs administrated to cancer patients greatly limits the benefits that patients can achieve and continues to be a severe clinical difficulty. Among the mechanisms which have been uncovered to mediate anti-cancer drug resistance, the Hippo signaling pathway is gaining increasing attention due to the remarkable oncogenic activities of its components (for example, YAP and TAZ) and their druggable properties.
    [Show full text]
  • STK3/4 Expression Is Regulated in Uterine Endometrial Cells During the Estrous Cycle
    cells Article STK3/4 Expression Is Regulated in Uterine Endometrial Cells during the Estrous Cycle 1, 2, 2 1 1 3 Sohyeon Moon y, Ok-Hee Lee y, Sujin Lee , Jihyun Lee , Haeun Park , Miseon Park , Eun Mi Chang 3 , Keun-Hong Park 2 and Youngsok Choi 1,* 1 Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Center, Konkuk University, Seoul 05029, Korea; [email protected] (S.M.); [email protected] (J.L.); [email protected] (H.P.) 2 Department of Biomedical Science, CHA University, Gyeonggi-do 13488, Korea; [email protected] (O.-H.L.); [email protected] (S.L.); [email protected] (K.-H.P.) 3 Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul 06135, Korea; [email protected] (M.P.); [email protected] (E.M.C.) * Correspondence: [email protected]; Tel.: +82-2-450-3969 These authors contributed equally to this work. y Received: 16 October 2019; Accepted: 12 December 2019; Published: 15 December 2019 Abstract: The uterus is dynamically regulated in response to various signaling triggered by hormones during the estrous cycle. The Hippo signaling pathway is known as an important signaling for regulating cellular processes during development by balancing between cell growth and apoptosis. Serine/threonine protein kinase 3/4 (STK3/4) is a key component of the Hippo signaling network. However, the regulation of STK3/4-Hippo signaling in the uterus is little known. In this study, we investigated the regulation and expression of STK3/4 in the uterine endometrium during the estrous cycle. STK3/4 expression was dynamically regulated in the uterus during the estrous cycle.
    [Show full text]