Transforming Growth Factor-Beta and Matrix Metalloproteinases: Functional Interactions in Tumor Stroma-Infiltrating Myeloid Cells
Figure 1
TGF-β signaling and MMPs interplay. Active TGF-β binds to its cell-surface type II receptor (TBRII), inducing the activation of TGF-β type I receptor (ALK5 or TBRI) and forming a heterotetrameric complex. Then two sets of signaling pathways can be stimulated: the Smad pathway, where ALK5 phosphorylates Smad2,3 and promotes the release of Smads from the complex with SARA from the inner face of the plasma membrane (phosphorylated Smad2,3 interact with co-Smad4, forming a heteromeric complex to be translocated into the cell nucleus) and non-Smad pathways, where active TGF-β-receptor 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, or NFB pathway. On the other hand, TGF-β binding provokes the phosphorylation of ALK5 at tyrosine residues which enable the formation of Shc-Grb2/SoS complex to activate Ras-Raf1-MEK1,2-ERK1,2 signaling. Finally, receptor activated complexes can activate PI3K, provoking the activation of AKT and the small Rho GTPases. The activation of both Smad and non-Smad signaling pathways in turn initiate transcriptional or nontranscriptional activity to regulate MMPs expression, thus incrementing the protein levels in tumor microenvironment. When membrane bound MMPs or soluble MMPs are expressed, they may promote the activation of latent TGF-β by proteolytic cleavage within the N-terminal region of the latency-associated peptide (LAP) or the large latent complex (LLC).
