title: Deubiquitinase activities required for hepatocyte growth factor-induced scattering of epithelial cells.
abstract: The scattering response of epithelial cells to activation of the Met receptor tyrosine kinase represents one facet of an "invasive growth" program. It is a complex event that incorporates loss of cell-cell adhesion, morphological changes, and cell motility. Ubiquitination is a reversible posttranslational modification that may target proteins for degradation or coordinate signal transduction pathways. There are approximately 79 active deubiquitinating enzymes (DUBs) predicted in the human genome. Here, via a small interfering RNA (siRNA) library approach, we have identified 12 DUBs that are necessary for aspects of the hepatocyte growth factor (HGF)-dependent scattering response of A549 cells. Different phenotypes are evident that range from full loss of scattering, similar to receptor knockdown (e.g., USP30, USP33, USP47), to loss of cell-cell contacts even in the absence of HGF but defective motility (e.g., USP3, ATXN3L). The knockdowns do not incur defective receptor, phosphatidylinositol 3-kinase, or MAP kinase activation. Our data suggest widespread involvement of the ubiquitin system at multiple stages of the Met activation response, implying significant crosstalk with phosphorylation-based transduction pathways. Development of small-molecule inhibitors of particular DUBs may offer a therapeutic approach to contain metastasis.
authors.affiliation: Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Buus
authors.forename: Monica
authors.initials: M
authors.lastname: Faronato
authors.forename: Dean E
authors.initials: DE
authors.lastname: Hammond
authors.forename: Sylvie
authors.initials: S
authors.lastname: Urbé
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clague
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D004789:Enzyme Activation; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D034622:RNA Interference; D017978:Receptors, Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination / Q000502:physiology
chemical_list: D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
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