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.
Erickson
Richard A
RA
Department of Chemistry and Biochemistry, University of Colorado-Boulder, Boulder, CO 80309, USA.
Liu
Xuedong
X
D001665:Binding Sites; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D004900:Erythroblasts / Q000378:metabolism; D006801:Humans; D009154:Mutation; D018774:Oncogene Proteins v-erbA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051901:Smad4 Protein / Q000032:analysis / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
D018774:Oncogene Proteins v-erbA; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta