HGF Induces Epithelial-to-Mesenchymal Transition by Modulating the Mammalian Hippo/MST2 and ISG15 Pathways
Epithelial to mesenchymal transition (EMT) is a fundamental cell differentiation/dedifferentiation process which is associated with dramatic morphological changes. Formerly polarized and immobile epithelial cells which form cell junctions and cobblestone-like cell sheets undergo a transition into hi...
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Published in | Journal of proteome research Vol. 13; no. 6; pp. 2874 - 2886 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
American Chemical Society
06.06.2014
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Abstract | Epithelial to mesenchymal transition (EMT) is a fundamental cell differentiation/dedifferentiation process which is associated with dramatic morphological changes. Formerly polarized and immobile epithelial cells which form cell junctions and cobblestone-like cell sheets undergo a transition into highly motile, elongated, mesenchymal cells lacking cell-to-cell adhesions. To explore how the proteome is affected during EMT we profiled protein expression and tracked cell biological markers in Madin-Darby kidney epithelial cells undergoing hepatocyte growth factor (HGF) induced EMT. We were able to identify and quantify over 4000 proteins by mass spectrometry. Enrichment analysis of this revealed that expression of proteins associated with the ubiquitination machinery was induced, whereas expression of proteins regulating apoptotic pathways was suppressed. We show that both the mammalian Hippo/MST2 and the ISG15 pathways are regulated at the protein level by ubiquitin ligases. Inhibition of the Hippo pathway by overexpression of either ITCH or A-Raf promotes HGF-induced EMT. Conversely, ISG15 overexpression is sufficient to induce cell scattering and an elongated morphology without external stimuli. Thus, we demonstrate for the first time that the Hippo/MST2 and ISG15 pathways are regulated during growth-factor induced EMT. |
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AbstractList | Epithelial to mesenchymal transition (EMT) is a fundamental cell differentiation/dedifferentiation process which is associated with dramatic morphological changes. Formerly polarized and immobile epithelial cells which form cell junctions and cobblestone-like cell sheets undergo a transition into highly motile, elongated, mesenchymal cells lacking cell-to-cell adhesions. To explore how the proteome is affected during EMT we profiled protein expression and tracked cell biological markers in Madin-Darby kidney epithelial cells undergoing hepatocyte growth factor (HGF) induced EMT. We were able to identify and quantify over 4000 proteins by mass spectrometry. Enrichment analysis of this revealed that expression of proteins associated with the ubiquitination machinery was induced, whereas expression of proteins regulating apoptotic pathways was suppressed. We show that both the mammalian Hippo/MST2 and the ISG15 pathways are regulated at the protein level by ubiquitin ligases. Inhibition of the Hippo pathway by overexpression of either ITCH or A-Raf promotes HGF-induced EMT. Conversely, ISG15 overexpression is sufficient to induce cell scattering and an elongated morphology without external stimuli. Thus, we demonstrate for the first time that the Hippo/MST2 and ISG15 pathways are regulated during growth-factor induced EMT. |
Author | Kida, Katarzyna Turriziani, Benedetta von Kriegsheim, Alex Kelly, Ciara Rauch, Jens Simpson, Jeremy C Monsefi, Naser Doherty, Carolanne García-Muñoz, Amaya Matallanas, David Mehta, Jai P Kolch, Walter Farrell, Jennifer |
AuthorAffiliation | School of Biology and Environmental Science School of Medicine and Medical Science Conway Institute of Biomolecular and Biomedical Research Systems Biology Ireland University College Dublin |
AuthorAffiliation_xml | – name: Systems Biology Ireland – name: University College Dublin – name: School of Biology and Environmental Science – name: Conway Institute of Biomolecular and Biomedical Research – name: School of Medicine and Medical Science |
Author_xml | – sequence: 1 givenname: Jennifer surname: Farrell fullname: Farrell, Jennifer – sequence: 2 givenname: Ciara surname: Kelly fullname: Kelly, Ciara – sequence: 3 givenname: Jens surname: Rauch fullname: Rauch, Jens – sequence: 4 givenname: Katarzyna surname: Kida fullname: Kida, Katarzyna – sequence: 5 givenname: Amaya surname: García-Muñoz fullname: García-Muñoz, Amaya – sequence: 6 givenname: Naser surname: Monsefi fullname: Monsefi, Naser – sequence: 7 givenname: Benedetta surname: Turriziani fullname: Turriziani, Benedetta – sequence: 8 givenname: Carolanne surname: Doherty fullname: Doherty, Carolanne – sequence: 9 givenname: Jai P surname: Mehta fullname: Mehta, Jai P – sequence: 10 givenname: David surname: Matallanas fullname: Matallanas, David – sequence: 11 givenname: Jeremy C surname: Simpson fullname: Simpson, Jeremy C – sequence: 12 givenname: Walter surname: Kolch fullname: Kolch, Walter – sequence: 13 givenname: Alex surname: von Kriegsheim fullname: von Kriegsheim, Alex email: alex.vonkriegsheim@ucd.ie |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24766643$$D View this record in MEDLINE/PubMed |
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Keywords | Hippo-pathway YAP1 ISG5 quantitative expression proteomics Epithelial mesenchymal transition SILAC |
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Snippet | Epithelial to mesenchymal transition (EMT) is a fundamental cell differentiation/dedifferentiation process which is associated with dramatic morphological... |
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SubjectTerms | Animals Cadherins - metabolism Cell Adhesion Dogs Epithelial-Mesenchymal Transition Hepatocyte Growth Factor - pharmacology Hepatocyte Growth Factor - physiology Integrins - metabolism Madin Darby Canine Kidney Cells Protein-Serine-Threonine Kinases - metabolism Proteome - metabolism Signal Transduction Ubiquitin-Protein Ligases - metabolism Ubiquitination Ubiquitins - metabolism |
Title | HGF Induces Epithelial-to-Mesenchymal Transition by Modulating the Mammalian Hippo/MST2 and ISG15 Pathways |
URI | http://dx.doi.org/10.1021/pr5000285 https://www.ncbi.nlm.nih.gov/pubmed/24766643 https://search.proquest.com/docview/1534102446 |
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