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Smad3 phosphoisoform-mediated signaling during sporadic human colorectal carcinogenesis

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dc.contributor.authorMatsuzaki, K.es
dc.date.accessioned2011-06-30T12:02:59Z
dc.date.available2011-06-30T12:02:59Z
dc.date.issued2006
dc.description.abstractTransforming 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, pSmad3Cmediated 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.es
dc.formatapplication/pdfes
dc.format.extent18es
dc.identifier.issn0213-3911es
dc.identifier.urihttp://hdl.handle.net/10201/22669
dc.languageenges
dc.publisherMurcia : F. Hernándezes
dc.relation.ispartofHistology and histopathologyes
dc.rightsinfo:eu-repo/semantics/openAccesses
dc.subjectSMADes
dc.subjectColorectal canceres
dc.subject.otherCDU::6 - Ciencias aplicadas::61 - Medicina::616 - Patología. Medicina clínica. Oncologíaes
dc.titleSmad3 phosphoisoform-mediated signaling during sporadic human colorectal carcinogenesises
dc.typeinfo:eu-repo/semantics/articlees
dspace.entity.typePublicationes
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Histology and histopathology Vol.21, nº 6 (2006)