Neuregulin-1 activates the JAK-STAT pathway and regulates lung epithelial cell proliferation.
Neuregulin-1 (NRG-1) is part of a family of proteins whose members are structurally related to epidermal growth factor. NRG-1 induces cell proliferation through a high-affinity receptor complex composed of a heterodimer of human epidermal growth factor-like receptor (HER) 2 and 3. In this study, we show that NRG-1 activates the Janus kinases (JAK) and signal transducer and activator of transcription proteins (STAT). NRG-1 induced a rapid and transient increase in tyrosine phosphorylation of TYK2 and JAK3, but not JAK1 or JAK2, and induced STAT3 and STAT5 tyrosine phosphorylation. Upon phosphorylation, STAT3 translocated to the nucleus within 1 h. Activation of the JAK-STAT pathway was dependent on HER2/HER3 heterodimerization and was necessary for NRG-1-induced proliferation. Inhibition of HER2's ability to dimerize using the HER2-specific antibody 2C4 completely blocked NRG-1-induced JAK3, TYK2, STAT3, and STAT5 tyrosine phosphorylation. Blocking the JAK-STAT pathway with a specific JAK-STAT pathway inhibitor, AG490, inhibited NRG-1-induced JAK and STAT phosphorylation and cell proliferation. These data suggest that NRG-1 activates the JAK-STAT signal transduction pathway through its high-affinity receptor, the HER2/HER3 heterodimer. This pathway plays an important role in NRG-1-stimulated proliferation of pulmonary epithelial cells.
Department of Internal Medicine, Pulmonary and Critical Care Division, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Jinbo
J
Liu
Jeffrey A
JA
Kern
D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D008168:Lung / Q000166:cytology* / Q000378:metabolism; D008175:Lung Neoplasms; D008894:Milk Proteins; D020890:Neuregulin-1 / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D008894:Milk Proteins; D020890:Neuregulin-1; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine; D020032:Tyrphostins; C494086:STAT3 protein, human; C494101:STAT6 protein, human; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C507904:JAK1 protein, human; C507933:JAK3 protein, human