Single Nucleotide Polymorphism in SMAD7 and CHI3L1 and Colorectal Cancer Risk

Table 10

TGF-β-induced non-Smad signaling pathways.

c-Jun N-terminal kinases (JNK)/p38 activation	(i) TGF-β can rapidly activate JNK and p38 through MAPK kinases (MKK4, MKK 3/6) in various cell lines [133, 134]. Activation of JNK/P38 plays a role in TGF-β-induced apoptosis and in TGF-β-induced EMT [135].
Extracellular signal-regulatedkinase (ERK) activation	(i) TGF-β was found to activate the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway which are important for TGF-β mediated EMT [125, 136].
Phosphoinositide 3-kinase(PI3-K)/AKT activation	(i) TGF-β was reported to rapidly activate phosphoinositide 3-kinase (PI3-K) as indicated by the phosphorylation of its downstream effector Akt [137]; (ii) Although the PI3-K/Akt pathway is a non-Smad pathway contributing to TGF-β-induced EMT, it can antagonize Smad-induced apoptosis and growth inhibition [138]
Rho-like GTPases	(i) The Rho-like GTPases, such as Ras homolog gene family, member A (RhoA) plays an important role in controlling dynamic cytoskeletal organization, cell motility, and gene expression and is a key player in TGF-β-induced EMT [139]; (ii) TGF-β regulates RhoA activity in two different modes as it induces a rapid activation of RhoA during the early phase of stimulation and then downregulates the level of RhoA protein at later stages, both of these modes of regulation appear to be essential for TGF-β-induced EMT [140]