The ubiquitin ligase Itch mediates the antiapoptotic activity of epidermal growth factor by promoting the ubiquitylation and degradation of the truncated C-terminal portion of Bid.
The truncated C-terminal portion of Bid (tBid) is an important intermediate in ligand-induced apoptosis. tBid has been shown to be sensitive to proteasomal inhibitors and downregulated by activation of the epidermal growth factor (EGF) pathway. Here, we provide evidence that tBid is a substrate of the ubiquitin ligase Itch, which can specifically interact with and ubiquitinate tBid, but not intact Bid. Consistently, overexpression of Itch increases cell survival and inhibits caspase 3 activity, whereas downregulation of Itch by RNA interference has the opposite effect, increasing cell death and apoptosis. Treatment with EGF increases Itch phosphorylation and activity, and Itch expression is important for the ability of EGF to increase cell survival after tumour necrosis factor-related apoptosis-inducing ligand treatment. Our findings identify Itch as a key molecule between EGF signalling and resistance to apoptosis through downregulation of tBid, providing further details on how EGF receptor and proteasome inhibitors can contribute to the induction of apoptosis and the treatment of cancer.
Azakir
Bilal A
BA
Département de sciences biologiques, Université de Montréal, Montréal, Québec, Canada.
Desrochers
Guillaume
G
Angers
Annie
A
D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D006801:Humans; D010446:Peptide Fragments; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D010446:Peptide Fragments; D012097:Repressor Proteins; D004815:Epidermal Growth Factor; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases