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https://www.readbyqxmd.com/read/26947063/yap-induces-human-naive-pluripotency
#1
Han Qin, Miroslav Hejna, Yanxia Liu, Michelle Percharde, Mark Wossidlo, Laure Blouin, Jens Durruthy-Durruthy, Priscilla Wong, Zhongxia Qi, Jingwei Yu, Lei S Qi, Vittorio Sebastiano, Jun S Song, Miguel Ramalho-Santos
The human naive pluripotent stem cell (PSC) state, corresponding to a pre-implantation stage of development, has been difficult to capture and sustain in vitro. We report that the Hippo pathway effector YAP is nuclearly localized in the inner cell mass of human blastocysts. Overexpression of YAP in human embryonic stem cells (ESCs) and induced PSCs (iPSCs) promotes the generation of naive PSCs. Lysophosphatidic acid (LPA) can partially substitute for YAP to generate transgene-free human naive PSCs. YAP- or LPA-induced naive PSCs have a rapid clonal growth rate, a normal karyotype, the ability to form teratomas, transcriptional similarities to human pre-implantation embryos, reduced heterochromatin levels, and other hallmarks of the naive state...
March 15, 2016: Cell Reports
https://www.readbyqxmd.com/read/26754915/yap-is-required-for-ependymal-integrity-and-is-suppressed-in-lpa-induced-hydrocephalus
#2
Raehee Park, Uk Yeol Moon, Jun Young Park, Lucinda J Hughes, Randy L Johnson, Seo-Hee Cho, Seonhee Kim
Timely generation and normal maturation of ependymal cells along the aqueduct are critical for preventing physical blockage between the third and fourth ventricles and the development of fetal non-communicating hydrocephalus. Our study identifies Yap, the downstream effector of the evolutionarily conserved Hippo pathway, as a central regulator for generating developmentally controlled ependymal cells along the ventricular lining of the aqueduct. Yap function is necessary for proper proliferation of progenitors and apical attachment of ependymal precursor cells...
January 12, 2016: Nature Communications
https://www.readbyqxmd.com/read/26393967/lysophosphatidic-acid-signaling-in-ovarian-cancer
#3
REVIEW
Anna Jesionowska, Elzbieta Cecerska-Heryc, Natalia Matoszka, Barbara Dolegowska
Lysophosphatidic acid (LPA) is a bioactive phospholipid that is involved in signal transduction between cells. Plasma and ascites levels of LPA are increased in ovarian cancer patients even in the early stages and thus LPA is considered as a potential diagnostic marker for this disease. This review presents the current knowledge regarding LPA signaling in epithelial ovarian cancer. LPA stimulates proliferation, migration and invasion of ovarian cancer cells through regulation of vascular endothelial growth factor, matrix metalloproteinases, urokinase plasminogen activator, interleukin-6, interleukin-8, CXC motif chemokine ligand 12/CXC receptor 4, COX2, cyclin D1, Hippo-Yap and growth-regulated oncogene α concentrations...
2015: Journal of Receptor and Signal Transduction Research
https://www.readbyqxmd.com/read/26299613/foxm1-is-a-downstream-target-of-lpa-and-yap-oncogenic-signaling-pathways-in-high-grade-serous-ovarian-cancer
#4
Qipeng Fan, Qingchun Cai, Yan Xu
Lysophosphatidic acid (LPA), a prototypical ligand for G protein coupled receptors, and Forkhead box protein M1 (FOXM1), a transcription factor that regulates expression of a wide array of genes involved in cancer initiation and progression, are two important oncogenic signaling molecules in human epithelial ovarian cancers (EOC). We conducted in vitro mechanistic studies using pharmacological inhibitors, genetic forms of the signaling molecules, and RNAi-mediated gene knock-down to uncover the molecular mechanisms of how these two molecules interact in EOC cells...
September 29, 2015: Oncotarget
https://www.readbyqxmd.com/read/26109050/a-yap-taz-induced-feedback-mechanism-regulates-hippo-pathway-homeostasis
#5
Toshiro Moroishi, Hyun Woo Park, Baodong Qin, Qian Chen, Zhipeng Meng, Steven W Plouffe, Koji Taniguchi, Fa-Xing Yu, Michael Karin, Duojia Pan, Kun-Liang Guan
YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are major downstream effectors of the Hippo pathway that influences tissue homeostasis, organ size, and cancer development. Aberrant hyperactivation of YAP/TAZ causes tissue overgrowth and tumorigenesis, whereas their inactivation impairs tissue development and regeneration. Dynamic and precise control of YAP/TAZ activity is thus important to ensure proper physiological regulation and homeostasis of the cells. Here, we show that YAP/TAZ activation results in activation of their negative regulators, LATS1/2 (large tumor suppressor 1/2) kinases, to constitute a negative feedback loop of the Hippo pathway in both cultured cells and mouse tissues...
June 15, 2015: Genes & Development
https://www.readbyqxmd.com/read/26029725/lysophosphatidic-acid-induces-yap-promoted-proliferation-of-human-corneal-endothelial-cells-via-pi3k-and-rock-pathways
#6
Yi-Jen Hsueh, Hung-Chi Chen, Sung-En Wu, Tze-Kai Wang, Jan-Kan Chen, David Hui-Kang Ma
The first two authors contributed equally to this work.Silence of p120-catenin has shown promise in inducing proliferation in human corneal endothelial cells (HCECs), but there is concern regarding off-target effects in potential clinical applications. We aimed to develop ex vivo expansion of HCECs using natural compounds, and we hypothesized that lysophosphatidic acid (LPA) can unlock the mitotic block in contact-inhibited HCECs via enhancing nuclear translocation of yes-associated protein (YAP). Firstly, we verified that exogenous YAP could induce cell proliferation in contact-inhibited HCEC monolayers and postconfluent B4G12 cells...
2015: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/25806284/hippo-yap-pathway-for-targeted-therapy
#7
REVIEW
Emanuela Felley-Bosco, Rolf Stahel
Malignant pleural mesothelioma (MPM) is molecularly characterized by loss of function or mutations in the neurofibromin 2 (NF2) and the cyclin-dependent kinase inhibitor 2 genes. NF2 activates a cascade of kinases, called Hippo pathway, which downregulates Yes associated protein (YAP) function as transcription co-activator for TEA domain transcription factors (TEAD). In the absence of functional NF2, the expression of genes essential for cell cycling such as survivin is increased. New therapeutic strategies aimed at interfering with YAP activity include inhibition of hedgehog pathway, which downregulates the YAP protein, verteporfin, which inhibits the assembly of a functional YAP-TEAD transcription factor, and interference with thrombin and lysophosphatidic acid (LPA) receptors downstream signalling, since upon agonist binding they activate YAP...
April 2014: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/25502757/role-of-lpa-and-the-hippo-pathway-on-apoptosis-in-salivary-gland-epithelial-cells
#8
Sung-Min Hwang, MeiHong Jin, Yong Hwan Shin, Seul Ki Choi, Eun Namkoong, MinKyoung Kim, Moon-Yong Park, Kyungpyo Park
Lysophosphatidic acid (LPA) is a bioactive lysophospholipid involved in numerous physiological responses. However, the expression of LPA receptors and the role of the Hippo signaling pathway in epithelial cells have remained elusive. In this experiment, we studied the functional expression of LPA receptors and the associated signaling pathway using reverse transcriptase-PCR, microspectrofluorimetry, western blotting and immunocytochemistry in salivary gland epithelial cells. We found that LPA receptors are functionally expressed and involved in activating the Hippo pathway mediated by YAP/TAZ through Lats/Mob1 and RhoA/ROCK...
December 12, 2014: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/25492965/neuregulin-1-activated-erbb4-interacts-with-yap-to-induce-hippo-pathway-target-genes-and-promote-cell-migration
#9
Jonathan W Haskins, Don X Nguyen, David F Stern
The receptor tyrosine kinase ERBB4, a member of the epidermal growth factor receptor (EGFR) family, is unusual in that ERBB4 can undergo intramembrane proteolysis, releasing a soluble intracellular domain (ICD) that modulates transcription in the nucleus. We found that ERBB4 activated the transcriptional coactivator YAP, which promotes organ and tissue growth and is inhibited by the Hippo tumor-suppressor pathway. Overexpressing ERBB4 in cultured mammary epithelial cells or adding the ERBB4 ligand neuregulin 1 (NRG1) to breast cancer cell cultures promoted the expression of genes regulated by YAP, such as CTGF...
December 9, 2014: Science Signaling
https://www.readbyqxmd.com/read/25294670/down-regulation-of-lpa-receptor-5-contributes-to-aberrant-lpa-signalling-in-ebv-associated-nasopharyngeal-carcinoma
#10
Lee Fah Yap, Sharmila Velapasamy, Hui Min Lee, Selvam Thavaraj, Pathmanathan Rajadurai, Wenbin Wei, Katerina Vrzalikova, Maha Hafez Ibrahim, Alan Soo-Beng Khoo, Sai Wah Tsao, Ian C Paterson, Graham S Taylor, Christopher W Dawson, Paul G Murray
Undifferentiated nasopharyngeal carcinoma (NPC) is a highly metastatic disease that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the contribution of lysophosphatidic acid (LPA) signalling to the pathogenesis of NPC. Here we demonstrate two distinct functional roles for LPA in NPC. First, we show that LPA enhances the migration of NPC cells and second, that it can inhibit the activity of EBV-specific cytotoxic T cells. Focusing on the first of these phenotypes, we show that one of the LPA receptors, LPA receptor 5 (LPAR5), is down-regulated in primary NPC tissues and that this down-regulation promotes the LPA-induced migration of NPC cell lines...
February 2015: Journal of Pathology
https://www.readbyqxmd.com/read/23942151/taz-mediates-lysophosphatidic-acid-induced-migration-and-proliferation-of-epithelial-ovarian-cancer-cells
#11
Geun Ok Jeong, Sang Hun Shin, Eun Jin Seo, Yang Woo Kwon, Soon Chul Heo, Ki-Hyung Kim, Man-Soo Yoon, Dong-Soo Suh, Jae Ho Kim
BACKGROUND: Transcriptional co-activator with PDZ-binding motif (TAZ), a downstream effector of the Hippo pathway, has been reported to regulate organ size, tissue homeostasis, and tumorigenesis by acting as a transcriptional co-activator. Lysophosphatidic acid (LPA) is a bioactive lipid implicated in tumorigenesis and metastasis of ovarian cancer through activation of G protein-coupled receptors. However, the involvement of TAZ in LPA-induced tumorigenesis of ovarian cancer has not been elucidated...
2013: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/23618389/the-role-of-lpa-and-yap-signaling-in-long-term-migration-of-human-ovarian-cancer-cells
#12
Hui Cai, Yan Xu
BACKGROUND: The Hippo-YAP signaling pathway is altered and implicated as oncogenic in many human cancers. However, extracellular signals that regulate the mammalian Hippo pathway have remained elusive until very recently when it was shown that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) ligands including lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P). LPA inhibits Lats kinase activity in HEK293 cells, but the potential involvement of a protein phosphatase was not investigated...
2013: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/22884261/identification-of-serum-derived-sphingosine-1-phosphate-as-a-small-molecule-regulator-of-yap
#13
Eric Miller, Jiayi Yang, Michael DeRan, Chunlei Wu, Andrew I Su, Ghislain M C Bonamy, Jun Liu, Eric C Peters, Xu Wu
Hippo signaling represents a tumor suppressor pathway that regulates organ size and tumorigenesis through phosphorylation and inhibition of the transcription coactivator YAP. Here, we show that serum deprivation dramatically induces YAP Ser127 phosphorylation and cytoplasmic retention, independent of cell-cell contact. Through chemical isolation and activity profiling, we identified serum-derived sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) as small molecule activators of YAP. S1P induces YAP nuclear localization through S1P(2) receptor, Rho GTPase activation, and F-actin polymerization, independent of the core Hippo pathway kinases...
August 24, 2012: Chemistry & Biology
https://www.readbyqxmd.com/read/22863277/regulation-of-the-hippo-yap-pathway-by-g-protein-coupled-receptor-signaling
#14
Fa-Xing Yu, Bin Zhao, Nattapon Panupinthu, Jenna L Jewell, Ian Lian, Lloyd H Wang, Jiagang Zhao, Haixin Yuan, Karen Tumaneng, Hairi Li, Xiang-Dong Fu, Gordon B Mills, Kun-Liang Guan
The Hippo pathway is crucial in organ size control, and its dysregulation contributes to tumorigenesis. However, upstream signals that regulate the mammalian Hippo pathway have remained elusive. Here, we report that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) signaling. Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription coactivators, which are oncoproteins repressed by Lats1/2...
August 17, 2012: Cell
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