ErbB-2 kinase is required for constitutive stat 3 activation in malignant human lung epithelial cells

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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‐α. In this report, we demonstrate that STAT 3 is constitutively activated in these cells by the TGF‐α–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‐α–induced activation of STATs. Inhibition of ErbB‐2 kinase activity by tyrphostin AG825 prevented the constitutive activation of STAT 3 in the TGF‐α–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‐α loop. Int. J. Cancer 83:564–570, 1999. Published 1999 Wiley‐Liss, Inc.