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

Min Soo Kim,Wook Jin

doi:10.3390/cancers12041048

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-β (TGF-β) is implicated in tumor suppression through the canonical SMAD-dependent signaling pathway. Hence, TrkB could play a role in disrupting the potent TGF-β-mediated growth inhibition, a concept that has not been fully explored. Here, we identified TrkB to be a crucial regulator of the TGF-β signaling pathway as it inhibits the TGF-β-mediated tumor suppression and the activation of TrkB kinase. We further show that the interactions between TrkB and SMADs inhibit TGF-β-mediated R-SMAD/SMAD4 complex formation and suppress TGF-β-induced nuclear translocation and target gene expression. Additionally, the knockdown of TrkB restored the tumor inhibitory activity of TGF-β signaling. These observations suggest that interactions between TrkB and SMADs are critical for the inhibition of TGF-β tumor suppressor activity in cancer cells.

Highlights

Transforming growth factor-β (TGF-β) plays a dual role as a potent growth inhibitor of epithelial and non-epithelial cells, inducing growth arrest and apoptosis, and as a promoter of tumor progression in advanced cancers, inducing epithelial–mesenchymal transition (EMT) [1,2]
We further demonstrate that TrkB inhibits the nuclear retention of R-SMAD/SMAD4 complexes through the formation of a TGF-β-mediated TrkB/SMAD complex
TrkB significantly inhibits the TGF-β-induced transcriptional activity of SBE and 3TP in RIE-1, HeLa, and NMuMG cells (Figure 1A,B and Figure S1A). These results suggest that TrkB could regulate the canonical TGF-β-signaling pathway

Summary

Introduction

Transforming growth factor-β (TGF-β) plays a dual role as a potent growth inhibitor of epithelial and non-epithelial cells, inducing growth arrest and apoptosis, and as a promoter of tumor progression in advanced cancers, inducing epithelial–mesenchymal transition (EMT) [1,2]. The growth-inhibitory responses of TGF-β are mediated through the activation of the canonical SMAD-dependent pathway via the induction and reshuffling of CDK inhibitors (CDKN1A). TGF-β promotes tumor progression by inducing the expression of specific EMT-associated transcription factors via both canonical SMAD-dependent and non-canonical SMAD-independent signaling pathways [1,3]. Neurotrophins and their receptors play a crucial role in the proper development, migration, maturation, survival, and differentiation of the nervous system [4]. TGF-β1 significantly of RIE-1-TrkB cells (Figure 2E–G). TGF-β1 significantly stimulated the stimulated endogenousthe endogenous phosphorylation SMAD2inand

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Conclusion