Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Benzothiazoles
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Cell Line
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Cell Nucleus / metabolism
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DNA-Binding Proteins / metabolism*
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Dimerization
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Electrophoresis, Polyacrylamide Gel
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Epithelial Cells / metabolism*
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Humans
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Immunoblotting
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Lung Neoplasms / metabolism*
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Milk Proteins*
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Precipitin Tests
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Receptor, ErbB-2 / antagonists & inhibitors
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Receptor, ErbB-2 / metabolism*
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Receptor, ErbB-2 / physiology*
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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STAT5 Transcription Factor
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Trans-Activators / metabolism*
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Transfection
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Transforming Growth Factor alpha / pharmacology
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Tyrphostins / pharmacology
Substances
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Benzothiazoles
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DNA-Binding Proteins
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Enzyme Inhibitors
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Milk Proteins
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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STAT5 Transcription Factor
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Trans-Activators
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Transforming Growth Factor alpha
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Tyrphostins
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tyrphostin AG825
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ErbB Receptors
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Receptor, ErbB-2