Vilar et al. (2006), TGF-β
September 2008, model of the month by Noriko Hiroi
Original model: BIOMD0000000101
Under normal physiological conditions, members of the transforming growth factor-β (TGF-β) family help control tissue growth. In particular, TGF-β triggers antiproliferative response in epithelial, endothelial, neuronal and haematopoietic cells. In normal cells, TGF-β induces sustained signals that last more than 6 h. In contrast, certain tumours develop a resistance to the growth-suppressive effects of TGF-β, which is not based on mutations. In this case, TGF-β promotes cancer progression in tumour microenvironments. In cancer cells, TGF-β-induced signals are much shorter than in normal cells, lasting usually about 1-2 h [1, 2]. The computational model [BIOMD0000000101, 3] set out to study the mechanisms underlying these paradoxical characteristics of TGF-β family-induced signals.
The model encompasses the detection and transduction of the extracellular signals to transcription factors (Smad2 etc.), as well as TGF-β receptor trafficking. The authors' main conclusion is that the key quantity which determines the qualitative behaviour of the pathway is the ratio between the ligand-induced degradation of active complexes and their constitutive degradation. When ligand-induced degradation is dominant, the activated (phosphorylated) form of the final target of this signal (Smad2) exhibits a short activation (Figure 2 A, B). On the other hand, when the constitutive degradation process is dominant, activated Smad2 lasts longer (Figure 2 E, F). These two different behaviours can be compared to the phenotypes shown by cancerous and normal epithelial cells.
Figure 1: Model of receptor trafficking and signalling. Figure taken from  and modified by N.H. to facilitate comparison with the version in BioModels database (BIOMD0000000101).
By considering the large variation of ligand-receptor combinations within the TGF-β family, the authors proposed an hypothesis to explain how TGF-β could work both as a suppressive signal and also as a stimulus for cell proliferation. TGF-β receptors activate different downstream pathways according to the upstream signal. By competitive inhibition, one ligand can potentially inhibit the effects of another one (Figure 3). Thus, if TGF-β loses its growth suppressor properties, it could promote growth by inhibiting the other growth suppressor pathways.
Figure 2: Control of Kinetic Signalling Behaviour. Smad2 activity over time is shown at different constitutive-to-induced degradation ratios (CIR) (low for A, B, medium for C, D, high for E, F) and different shapes of TGF-β input (stepwise increase for A, C, E, slow increase for B, D, F). Figure taken from .
Figure 3: Control of Signal Integration. Formation of ligand-receptor complexes at different CIR and input shapes of TGF-β. Figure taken from .
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