An ERBB 3/ ERBB 2 oncogenic unit plays a key role in NRG 1 signaling and melanoma cell growth and survival

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.