Cellular and Molecular Biology



Smad3 phosphoisoform-mediated signaling during sporadic human colorectal carcinogenesis

K. Matsuzaki

Department of Gastroenterology and Hepatology, Kansai Medical University, Moriguchi, Osaka, Japan

Offprint requests to: Koichi Matsuzaki, M.D., Department of Gastroenterology and Hepatology, Kansai Medical University, 10-15 Fumizonocho, Moriguchi, Osaka, 570-8507, Japan. e-mail: matsuzak@takii.kmu.ac.jp

Summary. Transforming growth factor-ß (TGF-ß) signaling occurring during human colorectal carcinogenesis involves a shift in TGF-ß function, reducing the cytokine’s antiproliferative effect, while increasing actions that promote invasion and metastasis. TGF-ß signaling involves phosphorylation of Smad3 at serine residues 208 and 213 in the linker region and serine residues 423 and 425 in the C-terminal region. Exogenous TGF-ß activates not only TGF-ß type I receptor (TßRI) but also c-Jun N-terminal kinase (JNK), changing unphosphorylated Smad3 to its phosphoisoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker phosphorylated Smad3 (pSmad3L). Either pSmad3C or pSmad3L oligomerizes with Smad4, and translocates into nuclei. While the TßRI/pSmad3C pathway inhibits growth of normal epithelial cells in vivo, JNK/pSmad3L-mediated signaling promotes tumor cell invasion and extracellular matrix synthesis by activated mesenchymal cells. Furthermore, hepatocyte growth factor signaling interacts with TGF-ß to activate the JNK/pSmad3L pathway, accelerating nuclear transport of cytoplasmic pSmad3L. This reduces accessibility of unphosphorylated Smad3 to membrane-anchored TßRI, preventing Smad3C phosphorylation, pSmad3C-mediated transcription, and antiproliferative effects of TGF-ß on epithelial cells. As neoplasia progresses from normal colorectal epithelium through adenoma to invasive adenocarcinoma with distant metastasis, nuclear pSmad3L gradually increases while pSmad3C decreases. The shift from TßRI/pSmad3C-mediated to JNK/pSmad3L-mediated signaling is a major mechanism orchestrating a complex transition of TGF-ß signaling during sporadic human colorectal carcinogenesis. This review summarizes the recent understanding of Smad3 phosphoisoform-mediated signaling, particularly “cross-talk” between Smad3 and JNK pathways that cooperatively promote oncogenic activities. Understanding of these actions should help to develop more effective therapy against human colorectal cancer, involving inhibition of JNK/pSmad3L pathway. Histol Histopathol 21, 645-662 (2006)

Key words: TGF-ß, Smad, JNK, p38 MAPK, Colorectal cancer

DOI: 10.14670/HH-21.645