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

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.