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 impli cated in the development of non-small-cell lung cancer. We have reported th at the transformation of human lung epithelial cells by c-erbB-2 also requi res an active ErbB-1 (EGF receptor) and the autocrine production of its lig and, TGF-alpha. In this report, we demonstrate that STAT 3 is constitutivel y activated in these cells by the TGF-alpha-stimulated qErbB-1/-2 heterodim er complex. STAT 3 activation was confirmed by mobility shift assays and nu clear localization. ErbB-1 was required, but not sufficient for the TGF-alp ha-induced activation of STATs, Inhibition of ErbB-2 kinase activity by tyr phostin AC825 prevented the constitutive activation of STAT 3 in the TGF-al pha-producing, ErbB-1 expressing cell line. Our results demonstrate a requi rement for ErbB-2 kinase activity to establish constitutive STAT 3 activati on resulting from an autocrine ErbB-1/ TGF-alpha loop. Int. J. Cancer 83:56 4-570, 1999. Published 1999 Wiley-Liss, Inc.dagger