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Title: The anti-HER3 (ErbB3) therapeutic antibody 9F7-F11 induces HER3 ubiquitination and degradation in tumors through JNK1/2- dependent ITCH/AIP4 activation
Authors: Le Clorennec, C.
Lazrek, Y.
Dubreuil, O.
Larbouret, C.
Poul, M-A.
Mondon, P.
Melino, Gerry
Pèlegrin, A.
Chardès, T.
First Published: 18-May-2016
Publisher: Impact Journals
Citation: Oncotarget, Vol. 7, No. 24
Abstract: We characterized the mechanism of action of the neuregulin-non-competitive anti-HER3 therapeutic antibody 9F7-F11 that blocks the PI3K/AKT pathway, leading to cell cycle arrest and apoptosis in vitro and regression of pancreatic and breast cancer in vivo. We found that 9F7-F11 induces rapid HER3 down-regulation. Specifically, 9F7-F11-induced HER3 ubiquitination and degradation in pancreatic, breast and prostate cancer cell lines was driven mainly by the itchy E3 ubiquitin ligase (ITCH/AIP4). Overexpression of the ITCH/AIP4 inhibitor N4BP1 or small-interfering RNA-mediated knockdown of ITCH/AIP4 inhibited HER3 ubiquitination/degradation and PI3K/AKT signaling blockade induced by 9F7-F11. Moreover, 9F7-F11-mediated JNK1/2 phosphorylation led to ITCH/AIP4 activation and recruitment to HER3 for receptor ubiquitination and degradation. ITCH/AIP4 activity was activated by the deubiquitinases USP8 and USP9X, as demonstrated by RNA interference. Taken together, our results suggest that 9F7-F11-induced HER3 ubiquitination and degradation in cancer cells mainly occurs through JNK1/2-dependent ITCH/AIP4 activation.
DOI Link: 10.18632/oncotarget.9455
eISSN: 1949-2553
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Creative Commons Attribution 3.0 License
Appears in Collections:Published Articles, MRC Toxicology Unit

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