title: An ERBB3/ERBB2 oncogenic unit plays a key role in NRG1 signaling and melanoma cell growth and survival.
abstract: We recently identified neuregulin-1 (NRG1) as a novel target of Notch1 required in Notch-dependent melanoma growth. ERBB3 and ERBB4, tyrosine kinase receptors specifically activated by NRG1, 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 NRG1 and its receptors in the pathogenesis of melanoma, whether ERBB3 and ERBB4 display redundant or exclusive functions is not known. Here, we show that ERBB3 and ERBB4 inhibition results in distinct outcomes. ERBB3 inhibition ablates the cellular responses to NRG1, results in AKT inactivation and leads to cell growth arrest and apoptotic cell death. In contrast, ERBB4 knockdown mildly affects cell growth, has no effects on cell survival and, importantly, does not alter the responses to NRG1. Finally, we identified ERBB2 as a key coreceptor in NRG1-dependent ERBB3 signaling. ERBB2 forms a complex with ERBB3, and its inhibition recapitulates the phenotypes observed upon ERBB3 ablation. We propose that an NRG1-ERBB3-ERBB2 signaling unit operates in melanoma cells where it promotes growth and survival.
authors.affiliation: Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Keman
authors.initials: K
authors.lastname: Zhang
authors.forename: Poki
authors.initials: P
authors.lastname: Wong
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Duan
authors.forename: Barbara
authors.initials: B
authors.lastname: Jacobs
authors.forename: Ernest C
authors.initials: EC
authors.lastname: Borden
authors.forename: Barbara
authors.initials: B
authors.lastname: Bedogni
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D066246:ErbB Receptors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D020890:Neuregulin-1 / Q000378:metabolism*; D010766:Phosphorylation; D055503:Protein Multimerization; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D066247:Receptor, ErbB-4; D015398:Signal Transduction
chemical_list: D066246:ErbB Receptors; D020890:Neuregulin-1; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C094131:NRG1 protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C587689:ERBB4 protein, human