Summary.
Transforming growth factor-β (TGF-β) activates not only TGF-β type I receptor (Tβ RI) but also c-Jun N-terminal kinase (JNK), converting the mediator Smad3 to two distinct phosphoisoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker phosphorylated Smad3 (pSmad3L). While Tβ RI/pSmad3C pathway inhibits growth of normal epithelial cells, the activated mesenchymal cells invade via JNK/pSmad3L pathway. During sporadic human colorectal carcinogenesis, TGF-β signaling confers a selective advantage upon tumor cells by shifting from epithelial Tβ RI/pSmad3C pathway to mesenchymal JNK/pSmad3L pathway. Loss of epithelial homeostasis and acquisition of a migratory, mesenchymal phenotype are essential for tumor invasion. In a future, specific inhibition of the JNK/pSmad3L pathway will become a therapy for human colorectal cancer that restores the lost tumor-suppressive function observed in normal colorectal epithelial cells at the expense of effects promoting the aggressive behavior.
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Received 12 July 2006; accepted 21 August 2006
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Matsuzaki, K., Seki, T. & Okazaki, K. TGF-β during human colorectal carcinogenesis: the shift from epithelial to mesenchymal signaling. Inflammopharmacol 14, 198–203 (2006). https://doi.org/10.1007/s10787-006-1536-2
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DOI: https://doi.org/10.1007/s10787-006-1536-2