HGF Induces Epithelial-to-Mesenchymal Transition by Modulating the Mammalian Hippo/MST2 and ISG15 Pathways

Citations Over TimeTop 10% of 2014 papers

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.

Related Papers

• → The ISG15/USP18 ubiquitin-like pathway (ISGylation system) in Hepatitis C Virus infection and resistance to interferon therapy(2011)66 cited
• → Newly translated proteins are substrates for ubiquitin, ISG15, and FAT10(2016)7 cited
• → In Vivo Functions of Isgylation(2010)5 cited
• [Advances in ubiquitin-like protein ISG15-mediated anti-viral response].(2012)
• → Suppression of the interferon sensitive gene 15 affects the expression of proteins that play a role in HCV replication(2013)