Transforming Growth Factor-Beta and Oxidative Stress Interplay: Implications in Tumorigenesis and Cancer Progression

Figure 1

TGF- signaling. Active TGF-β1 binds to its cell surface type II receptor (TRII) inducing the activation of TGF- type I receptor (ALK5/TRI) forming a heterotetrameric complex. Active TRI from the complex then triggers the activation of the Smad pathway: TRI phosphorylates the receptor associated-Smads (R-Smads) Smad2,3 which in turn promotes their release from the complex with SARA from the inner face of plasma membrane. Phosphorylated Smads interact with co-Smad4 forming a heteromeric complex to be translocated into the cell nucleus, where, through the interaction with other transcription factors and corepressors or coactivators, it modulates gene expression. Active TGF-β-receptors can also activate the non-Smad signaling pathways, such as ERK1,2, p38, JNK, and NF-B. Furthermore, the active receptor complex can activate PI3K provoking the activation of AKT and the small Rho GTPases. The activation of non-Smad signaling pathways can, in turn, initiate transcriptional or nontranscriptional activity to regulate gene and cellular responses.