Autocrine activation of ErbB2/ErbB3 receptor complex by NRG-1 in non-small cell lung cancer cell lines.
Our prior studies identified co-expression of the human epidermal growth factor-like receptors 2 (ErbB2) and 3 (ErbB3), as well as the growth factor neuregulin-1 (NRG-1) in normal lung epithelium and lung cancers. As ErbB2 and ErbB3 dimerize to produce a high affinity receptor for NRG-1, we postulated that an autocrine growth loop was present in transformed and non-transformed pulmonary epithelial cells. To test this hypothesis, we examined four cell lines derived from human non-small cell carcinomas for: (1) ErbB2 and ErbB3 expression and endogenous activation; (2) NRG-1 expression and secretion/shedding; and (3) the effect of receptor blockade on autocrine receptor activation. Our studies found that ErbB2 and ErbB3 were expressed by each of these cell lines. In addition, the NRG-1 gene was also expressed with both major isoforms of NRG-1 (NRG-1alpha and NRG-1beta) found intracellularly. Only the NRG-1alpha isoform, however, was found secreted/shed into the culture medium. The secreted/shed NRG-1alpha was capable of activating the ErbB2/ErbB3 receptor complex expressed on the breast adenocarcinoma cell line MCF-7. Basal ErbB2 phosphorylation was identified in all lung cancer cell lines and was inhibited with an antibody that blocked the NRG-1 binding site on ErbB3. Taken together, these data show that secreted NRG-1alpha can activate the ErbB2/ErbB3 heterodimer in an autocrine fashion. The identification of a NRG-1alpha/ErbB2/ErbB3 autocrine loop raises the possibility that interruption of this loop may have therapeutic potential in lung cancer.
Gollamudi
Murthy
M
Department of Internal Medicine, Pulmonary and Critical Care Division, University Hospitals of Cleveland, Case Western Reserve University, Wearn 610, 11100 Euclid Avenue, Cleveland, OH 44106, USA.
Nethery
David
D
Liu
Jinbo
J
Kern
Jeffrey A
JA
D019898:Autocrine Communication; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D020890:Neuregulin-1 / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics*; D020893:Receptor, ErbB-3 / Q000096:biosynthesis* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3