TrkB-Induced Inhibition of R-SMAD/SMAD4 Activation is Essential for TGF-?-Mediated Tumor Suppressor Activity.

ABSTRACT: TrkB-mediated activation of the IL6/JAK2/STAT3 signaling pathway is associated with the induction of the epithelial-mesenchymal transition (EMT) program and the acquisition of metastatic potential by tumors. Conversely, the transforming of growth factor-? (TGF-?) is implicated in tumor suppression through the canonical SMAD-dependent signaling pathway. Hence, TrkB could play a role in disrupting the potent TGF-?-mediated growth inhibition, a concept that has not been fully explored. Here, we identified TrkB to be a crucial regulator of the TGF-? signaling pathway as it inhibits the TGF-?-mediated tumor suppression and the activation of TrkB kinase. We further show that the interactions between TrkB and SMADs inhibit TGF-?-mediated R-SMAD/SMAD4 complex formation and suppress TGF-?-induced nuclear translocation and target gene expression. Additionally, the knockdown of TrkB restored the tumor inhibitory activity of TGF-? signaling. These observations suggest that interactions between TrkB and SMADs are critical for the inhibition of TGF-? tumor suppressor activity in cancer cells.

SUBMITTER: Kim MS 

PROVIDER: S-EPMC7226331 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature