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Review
. 2012 Sep 3:10:183.
doi: 10.1186/1479-5876-10-183.

TGF-β - an excellent servant but a bad master

Lenka Kubiczkova  1 , Lenka Sedlarikova, Roman Hajek, Sabina Sevcikova
Affiliations
Review

TGF-β - an excellent servant but a bad master

Lenka Kubiczkova et al. J Transl Med. .

Abstract

The transforming growth factor (TGF-β) family of growth factors controls an immense number of cellular responses and figures prominently in development and homeostasis of most human tissues. Work over the past decades has revealed significant insight into the TGF-β signal transduction network, such as activation of serine/threonine receptors through ligand binding, activation of SMAD proteins through phosphorylation, regulation of target genes expression in association with DNA-binding partners and regulation of SMAD activity and degradation. Disruption of the TGF-β pathway has been implicated in many human diseases, including solid and hematopoietic tumors. As a potent inhibitor of cell proliferation, TGF-β acts as a tumor suppressor; however in tumor cells, TGF-β looses anti-proliferative response and become an oncogenic factor. This article reviews current understanding of TGF-β signaling and different mechanisms that lead to its impairment in various solid tumors and hematological malignancies.

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Figures

Figure 1
Figure 1
TGF-β synthesis and activation. TGF-βs are synthesized as inactive precursors that contain pre-region (Signal peptide) and pro-region (N terminal peptide - LAP). Processing of inactive form starts with proteolytic cleavage that removes signal peptide from pre-pro-TGF-βs form. After dimerization, TGF-βs are cleaved by proteases (eg. Furin) into C-terminal mature peptides and N-terminal LAP (Latency Associated Peptide). TGF-βs with LAP form small latent complexes (SLP) that are transported to extracellular matrix where can further covalently bind to latent TGF-β binding protein (LTBP) to form a large latent complexes (LLC). LTBP is able to connect inactive TGF-β forms to ECM proteins. This interaction is further supported by covalent transglutaminase-induced (TGase) crosslinks. Activation of TGF-β starts with release of LCC from ECM by proteases. Then, the mature protein is cleaved from LTBP, which is provided in vitro by acidic condition, pH or plasmin or in vivo by thrombospondin (TSP). Once the active TGF-β family member is released from the ECM, it is capable of signaling
Figure 2
Figure 2
TGF-β canonical signaling pathway. After ligand binding, TGF-β receptors dimerize and phosphorylate intracellular SMAD proteins. Complex of SMAD2 and/or SMAD3 becomes phosphorylated by TβRI and forms a complex with SMAD4 which is subsequently transported into the nucleus where it binds with specific transcription factors (TF) and induces a transcription of TGF-β dependent genes
Figure 3
Figure 3
TGF-β non-canonical signaling pathway. After ligand binding, several different branching signaling pathways can be activated in malignant cells, such as Notch signaling, MAP kinases, AKT/PKB pathway, GTP-binding proteins pathway, PTK pathway, NF-κB and Wnt/β-catenin pathway
Figure 4
Figure 4
Role of TGF-β in regulation of cell cycle. Physiologically, TGF-β is a potent inhibitor of cell cycle; it induces expression of p15INK4B and represses expression of c-Myc. p15INK4B is able to prevent cyclin D-CDK4/6 complex formation; moreover, it displaces p21CIP1 and p27KIP1 from cyclin D-CDK4/6 complexes. These CIP/KIP inhibitors are subsequently able to inactivate other complexes of G1 and S phase and thereby inhibit cell cycle. Moreover, low levels of c-Myc allows for TGF-β induced p15INK4B and p21CIP1 transcription
Figure 5
Figure 5
The E2F1/miR-106b-25/p21 pathway. In gastric cancer, miR-106b-25 cluster is activated by E2F1 in parallel with its host gene, Mcm7. In turn, miR-106b and miR-93 regulate E2F1 expression, establishing a miRNA negative feedback loop. Over-expressed miR-106b, miR-93, and miR-25 inhibit the synthesis of p21CIP1 and Bim (TGF-β downstream effectors) and therefore prevent cell cycle inhibition and apoptosis
Figure 6
Figure 6
TGF-β signaling in APL. Cytoplasmic isoform of PML (cPML) protein interacts with SMAD2/3 and SARA and is required for accumulation of SARA-SMAD2/3 and TGF-β receptors in early endosome. However, the PML-RARα oncoprotein physically interacts with cPML and thus leads to impaired TGF-β signaling
Figure 7
Figure 7
TGF-β signaling in the bone marrow microenvironment of multiple myeloma. Myeloma cells are able to produce TGF-β cytokine which influence cells of bone marrow microenvironment such as osteoblast progenitors, bone marrow stromal cells. Moreover, it disrupts T cell proliferation and activation
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