aPKC alters the TGF beta response in NSCLC cells through both Smad-dependent and Smad-independent pathways

作者：Gunaratne Adrian^*; Chan Eddie; El Chabib Tarek H; Carter David; Di Guglielmo Gianni M

来源：Journal of Cell Science, 2015, 128(3): 487-498.

DOI：10.1242/jcs.155440

• Transforming growth factor beta
• Atypical protein kinase C
• p38 MAPK
• Apoptosis
• Nuclear translocation
• SARA

Transforming growth factor beta (TGF beta) signaling controls many cellular responses including proliferation, epithelial to mesenchymal transition and apoptosis, through the activation of canonical (Smad) as well as non-canonical (e.g. Par6) pathways. Previous studies from our lab have demonstrated that aPKC inhibition regulates TGF beta receptor trafficking and signaling. Here, we report that downstream TGF beta-dependent transcriptional responses in aPKC-silenced NSCLC cells were reduced compared with those of control cells, despite a temporal extension of Smad2 phosphorylation. We assessed SARA-Smad2-Smad4 association and observed that knockdown of aPKC increased SARA (also known as ZFYVE9) levels and SARA-Smad2 complex formation, increased cytoplasmic retention of Smad2 and reduced Smad2-Smad4 complex formation, which correlated with reduced Smad2 nuclear translocation. Interestingly, we also detected an increase in p38 MAPK phosphorylation and apoptosis in aPKC-silenced cells, which were found to be TRAF6-dependent. Taken together, our results suggest that aPKC isoforms regulate Smad and non-Smad TGF beta pathways and that aPKC inhibition sensitizes NSCLC cells to undergo TGF beta-dependent apoptosis.

• 出版日期2015-2-1