Gamma-heregulin: a novel heregulin isoform that is an autocrine growth factor for the human breast cancer cell line, MDA-MB-175.
A novel neuregulin isoform, termed gamma-HRG, was cloned and characterized from the human breast cancer cell line, MDA-MB-175. As observed with other neuregulins, gamma-HRG, is a product of alternative mRNA splicing of the neuregulin gene. Gamma-HRG contains the EGF-like and immunoglobulin-like domains that are commonly found in other family members, but lacks a transmembrane and cytoplasmic region. The new isoform possesses a unique N-terminal region that includes a hydrophobic domain that may function as a secretion signal. A purified recombinant version of gamma-HRG competes for binding to soluble ErbB3- and ErbB4-IgG fusion proteins with affinities similar to those observed for rHRGbeta1(177-244). Gamma-HRG has a wide distribution in mesenchymal or neuronal tissues but in contrast to other neuregulins, it is not present in breast, lung, liver and small intestine. Expression of gamma-HRG with its cognate receptors, ErbB3 and ErbB2 suggested that the growth of the MDA-MB-175 cell line might be a result of the autocrine stimulation of a growth factor signaling pathway. Treatment of MDA-MB-175 cells with an anti-ErbB2 monoclonal antibody that interferes with the ligand-dependent formation of ErbB2-ErbB3 heterodimer complexes shows a strong growth inhibitory effect on this cell line. Moreover, incubation with a receptor-IgG fusion protein that neutralizes secreted gamma-HRG, also inhibits cell growth. These data suggest that the secretion of gamma-HRG by MDA-MB-175 cells leads to the formation of a constitutively active receptor complex and stimulates the growth of these cells in an autocrine manner.
Schaefer
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Genentech, Inc., South San Francisco, California 94080, USA.
Fitzpatrick
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Sliwkowski
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D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D002455:Cell Division; D003001:Cloning, Molecular; D019281:Dimerization; D066246:ErbB Receptors / Q000378:metabolism; D004926:Escherichia coli; D005260:Female; D006133:Growth Substances / Q000096:biosynthesis*; D006801:Humans; D008969:Molecular Sequence Data; D020890:Neuregulin-1; D009474:Neurons / Q000378:metabolism; D009928:Organ Specificity; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D066246:ErbB Receptors; D006133:Growth Substances; D020890:Neuregulin-1; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011993:Recombinant Fusion Proteins; C108697:gamma-heregulin