Deubiquitinase activities required for hepatocyte growth factor-induced scattering of epithelial cells.
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.
Buus
Richard
R
Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
Faronato
Monica
M
Hammond
Dean E
DE
Urbé
Sylvie
S
Clague
Michael J
MJ
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
D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
J Biol Chem. 2000 Mar 17;275(11):7474-80
10713050
Mol Cell Biol. 1997 Feb;17(2):799-808
9001234
J Biol Chem. 2002 Feb 15;277(7):4656-62
11739384
Clin Cancer Res. 2007 Jan 1;13(1):27-37
17200335
Mol Cell Biol. 2003 Mar;23(6):2151-61
12612085
J Biol Chem. 1998 Oct 2;273(40):25777-82
9748249
Biochimie. 2008 Feb;90(2):270-83
17961905
Science. 2007 Jan 12;315(5809):201-5
17218518
Nat Rev Mol Cell Biol. 2003 Dec;4(12):915-25
14685170
Biochem Biophys Res Commun. 2004 Jan 30;314(1):54-62
14715245
Cancer Metastasis Rev. 2008 Mar;27(1):85-94
18175071
Nat Rev Mol Cell Biol. 2005 Aug;6(8):599-609
16064136
Mol Cell Biol. 2004 Nov;24(22):9752-62
15509780
Mol Biol Cell. 2008 May;19(5):1903-11
18287522
J Biol Chem. 2004 Dec 17;279(51):52835-9
15466866
Oncogene. 2001 May 17;20(22):2761-70
11420688
Mol Cell. 2005 Apr 15;18(2):143-5
15837416
Mol Biol Cell. 1998 Aug;9(8):2185-200
9693375
Cell. 2005 Dec 2;123(5):773-86
16325574
Mol Cell. 2005 Feb 4;17(3):331-9
15694335
Nat Cell Biol. 2006 Apr;8(4):339-47
16531995
Cell. 2008 Sep 5;134(5):804-16
18775313
Mol Cell. 2007 Dec 14;28(5):730-8
18082598
J Biol Chem. 2008 Mar 14;283(11):7036-45
18178551