Transforming Growth Factor-Beta and Urokinase-Type Plasminogen Activator: Dangerous Partners in Tumorigenesis—Implications in Skin Cancer
Figure 1
TGF-β signaling. TGF-β signaling comprises two groups of a set of intracellular transduction pathway: SMADs signals and Non-SMADs signals. When the active TGF-β1 binds to its cell surface type II receptor (TBR2), it induces the activation of TGF-β type I receptor (ALK5 or TBRI) and forms a heterotetrameric complex. (a) SMADs signals: active ALK5 in the complex phosphorylates SMAD2/3 which in turn promotes the SMADs release from complexes with SARA from the inner face of the plasmatic membrane. Phosphorylated SMADs interact with co-SMAD4 forming a heteromeric complex to be translocated into the cell nucleus, where, by interacting with other transcription factors and/or co-repressors or co-activators, they modulate gene expression. (b) Non-SMAD signals: active TGF-β receptors complex interacts with ubiquitin ligase tumor necrosis factor receptor-associated factor 6 (TRAF6) which in turn recruits TGF-β-activated kinase 1 (TAK1) to activate p38, JNK, and NFκB pathways. Additionally, TGF-β binding provokes the phosphorylation of ALK at tyrosine residues which enable the formation of Shc-Grb2/SoS complex to activate Ras-Raf1-MEK1,2-ERK1,2 signaling. On the other hand, receptor-activated complexes can activate PI3K provoking the activation of AKT and the small Rho GTPases. The activation of Non-SMAD signals pathways in turn initiates transcriptional or nontranscriptional activities to regulate cellular responses.
