title: Smad3 phosphoisoform-mediated signaling during sporadic human colorectal carcinogenesis.
abstract: Transforming growth factor-beta (TGF-beta) signaling occurring during human colorectal carcinogenesis involves a shift in TGF-beta function, reducing the cytokine's antiproliferative effect, while increasing actions that promote invasion and metastasis. TGF-beta 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-beta activates not only TGF-beta type I receptor (TbetaRI) 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 TbetaRI/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-beta to activate the JNK/pSmad3L pathway, accelerating nuclear transport of cytoplasmic pSmad3L. This reduces accessibility of unphosphorylated Smad3 to membrane-anchored TbetaRI, preventing Smad3C phosphorylation, pSmad3C-mediated transcription, and antiproliferative effects of TGF-beta 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 TbetaRI/pSmad3C-mediated to JNK/pSmad3L-mediated signaling is a major mechanism orchestrating a complex transition of TGF-beta 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.
authors.affiliation: Department of Gastroenterology and Hepatology, Kansai Medical University, Moriguchi, Osaka, Japan. matsuzak@takii.kmu.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Matsuzaki
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology / Q000503:physiopathology; D000236:Adenoma / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000473:pathology / Q000503:physiopathology*; D018450:Disease Progression; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D010766:Phosphorylation; D020033:Protein Isoforms; D012694:Serine / Q000032:analysis; D015398:Signal Transduction; D051900:Smad3 Protein / Q000737:chemistry / Q000276:immunology / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D020033:Protein Isoforms; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D012694:Serine; D048670:MAP Kinase Kinase 4