Publication: Smad3 phosphoisoform-mediated signaling during sporadic human colorectal carcinogenesis
Authors
Matsuzaki, K.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
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, 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.
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