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An ERBB 3/ ERBB 2 oncogenic unit plays a key role in NRG 1 signaling and melanoma cell growth and survival
Author(s) -
Zhang Keman,
Wong Poki,
Duan Jiaqi,
Jacobs Barbara,
Borden Ernest C.,
Bedogni Barbara
Publication year - 2013
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12089
Subject(s) - erbb , neuregulin , neuregulin 1 , cancer research , melanoma , receptor tyrosine kinase , biology , signal transduction , cell growth , microbiology and biotechnology , genetics
Summary We recently identified neuregulin‐1 ( NRG 1) as a novel target of Notch1 required in Notch‐dependent melanoma growth. ERBB 3 and ERBB 4, tyrosine kinase receptors specifically activated by NRG 1, have been shown to be either elevated in melanoma cell lines and tumors or to be mutated in 20% of melanomas, respectively. While these data support key roles of NRG 1 and its receptors in the pathogenesis of melanoma, whether ERBB 3 and ERBB 4 display redundant or exclusive functions is not known. Here, we show that ERBB 3 and ERBB 4 inhibition results in distinct outcomes. ERBB 3 inhibition ablates the cellular responses to NRG 1, results in AKT inactivation and leads to cell growth arrest and apoptotic cell death. In contrast, ERBB 4 knockdown mildly affects cell growth, has no effects on cell survival and, importantly, does not alter the responses to NRG 1. Finally, we identified ERBB 2 as a key coreceptor in NRG 1‐dependent ERBB 3 signaling. ERBB 2 forms a complex with ERBB 3, and its inhibition recapitulates the phenotypes observed upon ERBB 3 ablation. We propose that an NRG 1‐ ERBB 3‐ ERBB 2 signaling unit operates in melanoma cells where it promotes growth and survival.