ErbB-2 kinase is required for constitutive stat 3 activation in malignant human lung epithelial cells.
Overexpression of the growth factor receptor ErbB-2/Her2/Neu has been implicated in the development of non-small-cell lung cancer. We have reported that the transformation of human lung epithelial cells by c-erbB-2 also requires an active ErbB-1 (EGF receptor) and the autocrine production of its ligand, TGF-alpha. In this report, we demonstrate that STAT 3 is constitutively activated in these cells by the TGF-alpha-stimulated ErbB-1/-2 heterodimer complex. STAT 3 activation was confirmed by mobility shift assays and nuclear localization. ErbB-1 was required, but not sufficient for the TGF-alpha-induced activation of STATs. Inhibition of ErbB-2 kinase activity by tyrphostin AG825 prevented the constitutive activation of STAT 3 in the TGF-alpha-producing, ErbB-1 expressing cell line. Our results demonstrate a requirement for ErbB-2 kinase activity to establish constitutive STAT 3 activation resulting from an autocrine ErbB-1/ TGF-alpha loop. Int. J. Cancer 83:564-570, 1999. Published 1999 Wiley-Liss, Inc.
Fernandes
A
A
Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892, USA.
Hamburger
A W
AW
Gerwin
B I
BI
D052160:Benzothiazoles; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000378:metabolism*; D008894:Milk Proteins; D011233:Precipitin Tests; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
D052160:Benzothiazoles; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D008894:Milk Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D016211:Transforming Growth Factor alpha; D020032:Tyrphostins; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C098214:tyrphostin AG825