01 juillet 2007
Le texte scientifique en Anglais
Specificity and plasticity of cellular signalling networks
The signalling routes described previously are part of the dynamic systems whose components interact by molecular interactions and phosphorylation reactions.
Towards a semi-solid circuitry - The protein–protein interactions brought into play involve either modules specifically recognising phosphorylated tyrosine residues in a specific context, either by protein-rich sequences or lipids. These molecular assemblies which are like « Lego », enable a circuitry to be established where the idea of proximity between proteins seems to represent a principle as important as the passive diffusion of secondary messengers.
Cellular Specificity - One of the problems for this type of signalling is to understand how hundreds of different membrane receptors can generate specific cellular responses when there are relatively limited numbers of signaling pathways linking the membrane with the nucleus One solution to this problem resides in the fact that different specific signalling networks are used in a combinatorial way, each receptor utilizing a specific combination of « integrators ». Another possibility implies that the cellular response to a given receptor is dictated by the availability at the membrane level in the close environment of the receptor, of the components of different signaling pathways. This supposes that it is necessary to consider the existence of microdomains in the environment of the membrane and in which the traffic of proteins is limited. As has already been mentioned, the components found at the same « stages » of different signalling pathways have structural homologies but also very important functional homologies. In spite of this, we observe that each pathway is specific for a given stimulus (also the activation of the specific pathway of cellular stress will never make the cell proliferate).
Multiple combinations for specific responses Beyond this specific linear signalling from the membrane to the nucleus, it is clear that the majority of circuits are equipped with extraordinary plasticity. This property enables them to cooperate in a spatio-temporal way (MAP pathway JAK pathway) and also to activate multiple transcription factors whose simultaneous presence is necessary for the activity of numerous promoters.
Intensity of signals: notion of threshold - Conflicting observations have shown that according to the cell type, the same growth factors can induce either proliferation or differentiation. Thus, FGF ( fibroblast growth factor ) which is a powerful mitogen for numerous cell types, induces differentiation of a specific cell line ( PC12 cells). Another factor, EGF (epidermal growth factor) stimulates the proliferation of these cells. Overall, the two growth factors follow the same signalling pathways. However, a detailed analysis has enabled it to be shown that the difference observed in response to FGF is correlated with persistent activation of Ras-GTP AND MAP kinases which relocate in the nucleus for several hours. On the contrary, the proliferation of PC12 cells in response to EGF is correlated with an activation of Ras-GTP AND MAP kinases which remains localized in the cytoplasm. Thus, the modulation of the intensity and/or of the duration of the activation caused by two growth factors seems to represent an important component of the final cellular response. This concept highlights the effects of threshold, well known in developmental biology, where gradual variations in the concentration of ligand or that of a nuclear factor cause fundamental differences in gene expression.
Towards a multitude of signalling networks - The techniques of molecular biology have recently revealed the existence of new protein homologues of kinase proteins of the MAP kinase cascade. These results have enabled the elucidation of several parallel pathways of signal transduction which, by activating kinase proteins in a sequential way, function in a manner analogous to the classic mitogenic pathway.These types of signalling modules were set up very early in the evolutionary process since they exist in yeast. It should be noted that the MAP kinase pathway is activated by the majority of growth factors and plays a role in cellular proliferation and activation of other pathways. This is observed in response to factors which « stress » the cell, such as ultraviolet rays, thermal shocks, changes in osmolarity or the exposure to inhibitors of protein synthesis.