Association of v-ErbA with Smad4 disrupts TGF-beta signaling.

Disruption of the transforming growth factor-beta (TGF-beta) pathway is observed in the majority of cancers. To further understand TGF-beta pathway inactivation in cancer, we stably expressed the v-ErbA oncoprotein in TGF-beta responsive cells. v-ErbA participates in erythroleukemic transformation of cells induced by the avian erythroblastosis virus (AEV). Here we demonstrate that expression of v-ErbA was sufficient to antagonize TGF-beta-induced cell growth inhibition and that dysregulation of TGF-beta signaling required that v-ErbA associate with the Smad4 which sequesters Smad4 in the cytoplasm. We also show that AEV-transformed erythroleukemia cells were resistant to TGF-beta-induced growth inhibition and that TGF-beta sensitivity could be recovered by reducing v-ErbA expression. Our results reveal a novel mechanism for oncogenic disruption of TGF-beta signaling and provide a mechanistic explanation of v-ErbA activity in AEV-induced erythroleukemia.