Abstract
In mammalian and bacterial cells simple phosphorylation circuits play an important role in signaling. Bacteria have hundreds of two-component signaling systems that involve phosphotransfer between a receptor and a response regulator. In mammalian cells a similar pathway is the TGF-beta pathway, where extracellular TGF-beta ligands activate cell surface receptors that phosphorylate Smad proteins, which in turn activate many genes. In TGF-beta signaling the multiplicity of ligands begs the question as to whether cells can distinguish signals coming from different ligands, but transduced through a small set of Smads. Here we use information theory with stochastic simulations of networks to address this question. We find that when signals are transduced through only one Smad, the cell cannot distinguish between different levels of the external ligands. Increasing the number of Smads from one to two significantly improves information transmission as well as the ability to discriminate between ligands. Surprisingly, both total information transmitted and the capacity to discriminate between ligands are quite insensitive to high levels of cross-talk between the two Smads. Robustness against cross-talk requires that the average amplitude of the signals are large. We find that smaller systems, as exemplified by some two-component systems in bacteria, are significantly much less robust against cross-talk. For such system sizes phosphotransfer is also less robust against cross-talk than phosphorylation. This suggests that mammalian signal transduction can tolerate a high amount of cross-talk without degrading information content. This may have played a role in the evolution of new functionalities from small mutations in signaling pathways, allowed for the development of cross-regulation and led to increased overall robustness due to redundancy in signaling pathways. On the other hand the lack of cross-regulation observed in many bacterial two-component systems may partly be due to the loss of information content due to cross-talk.
Highlights
Phosphorylation reactions make up a large part of signal transduction processes
The TGF-b subfamily promotes the formation of a Type I/Type II complex after binding, while the BMP subfamily is believed to bind to a preformed complex of Type I/Type II receptors [2]
We have used information theoretic methods to study the transmission of information in simple signaling networks based on the Smad signaling pathway of the TGF-b proteins in mammalian cells and two-component systems in bacteria
Summary
Phosphorylation reactions make up a large part of signal transduction processes. TGF-b family members constitute a large class of related secreted polypeptides that are very important, especially during growth and development processes [1]. These proteins have been classified into several sub-families, of which the TGF-b subfamily of TGF-b’s 1, 2 and 3 and the BMP sub-family, consisting of BMPs 2, 4, 5, 6, 8 and 9, is the most important. The phosphorylated Type I receptor recruits a subfamily of Smad proteins, called receptor Smads (or RSmads), that are phosphorylated by the Type I receptor. Smads 6 and 7 are a class of Smads called inhibitory Smads, or ISmads, and they negatively regulate Smad signaling [1]
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