Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to its aggressive characteristics and low response to the existing clinical therapies. Distant... Show moreTriple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to its aggressive characteristics and low response to the existing clinical therapies. Distant metastasis is the main cause of death of TNBC patients. Better understanding of the mechanisms underlying TNBC metastasis may lead to new strategies of early diagnosis and more efficient treatment. In our study, we uncovered that the autophagy receptor optineurin (OPTN) plays an unexpected role in TNBC metastasis. Data mining of publicly available data bases revealed that the mRNA level of OPTN in TNBC patients positively correlates with relapse free and distance metastasis free survival. Importantly, in vitro and in vivo models demonstrated that OPTN suppresses TNBC metastasis. Mechanistically, OPTN inhibited the pro-oncogenic transforming growth factor-beta (TGF beta) signaling in TNBC cells by interacting with TGF beta type I receptor (T beta RI) and promoting its ubiquitination for degradation. Consistent with our experimental findings, the clinical TNBC samples displayed a negative correlation between OPTN mRNA expression and TGF beta gene response signature and expression of proto-typic TGF beta target genes. Altogether, our study demonstrates that OPTN is a negative regulator for TGF beta receptor/SMAD signaling and suppresses metastasis in TNBC. Show less
Li, Y.H.; Cui, C.; Xie, F.; Kielbasa, S.; Mei, H.L.; Dinther, M. van; ... ; Dijke, P. ten 2020
The transforming growth factor-beta (TGF-beta) family controls embryogenesis, stem cell differentiation, and tissue homeostasis. However, how post-translation modifications contribute to fine... Show moreThe transforming growth factor-beta (TGF-beta) family controls embryogenesis, stem cell differentiation, and tissue homeostasis. However, how post-translation modifications contribute to fine-tuning of TGF-beta family signaling responses is not well understood. Inhibitory (I)-Smads can antagonize TGF-beta/Smad signaling by recruiting Smurf E3 ubiquitin ligases to target the active TGF-beta receptor for proteasomal degradation. A proteomic interaction screen identified Vpr binding protein (VprBP) as novel binding partner of Smad7. Mis-expression studies revealed that VprBP negatively controls Smad2 phosphorylation, Smad2-Smad4 interaction, as well as TGF-beta target gene expression. VprBP was found to promote Smad7-Smurf1-T beta RI complex formation and induce proteasomal degradation of TGF-beta type I receptor (T beta RI). Moreover, VprBP appears to stabilize Smurf1 by suppressing Smurf1 poly-ubiquitination. In multiple adult and mouse embryonic stem cells, depletion of VprBP promotes TGF-beta or Activin-induced responses. In the mouse embryo VprBP expression negatively correlates with mesoderm marker expression, and VprBP attenuated mesoderm induction during zebrafish embryogenesis. Our findings thereby uncover a novel regulatory mechanism by which Smurf1 controls the TGF-beta and Activin cascade and identify VprBP as a critical determinant of embryonic mesoderm induction. Show less
Narasimhan, S.; Scherpe, S.; Paioni, A.L.; Zwan, J. van der; Folkers, G.E.; Ovaa, H.; Baldus, M. 2019
