Abstract
Many proteins and signaling pathways are present in most cell types and tissues and yet perform specialized functions. To elucidate mechanisms by which these ubiquitous pathways are modulated, we overlaid information about cross-cell line protein abundance and variability, and evolutionary conservation onto functional pathway components and topological layers in the pathway hierarchy. We found that the input (receptors) and the output (transcription factors) layers evolve more rapidly than proteins in the intermediary transmission layer. In contrast, protein expression variability decreases from the input to the output layer. We observed that the differences in protein variability between the input and transmission layer can be attributed to both the network position and the tendency of variable proteins to physically interact with constitutively expressed proteins. Differences in protein expression variability and conservation are also accompanied by the tendency of conserved and constitutively expressed proteins to acquire somatic mutations, while germline mutations tend to occur in cell type-specific proteins. Thus, conserved core proteins in the transmission layer could perform a fundamental role in most cell types and are therefore less tolerant to germline mutations. In summary, we propose that the core signal transmission machinery is largely modulated by a variable input layer through physical protein interactions. We hypothesize that the bow-tie organization of cellular signaling on the level of protein abundance variability contributes to the specificity of the signal response in different cell types.
Highlights
Proteins do not act in isolation but interact with other proteins to fulfill important cellular functions
It is largely unknown how this flexibility is achieved and how this flexibility is balanced with the high degree of evolutionary conservation of some signaling proteins and the need for robustness against intra- and extra-cellular perturbations.We show how functional roles of signaling proteins determine patterns of evolutionary conservation, protein abundance and disease mutations
Projecting pathway annotations on protein-protein interaction (PPI) networks, a picture emerges in which PPIs between variable and less conserved receptors and stable and conserved proteins of the core signal transmission machinery largely modulate signaling activity in a tissuespecific manner
Summary
Proteins do not act in isolation but interact with other proteins to fulfill important cellular functions. One important cellular function controlled by pathways is the transmission of extra-cellular signals from the cell membrane to the nucleus to provoke a response to changes in the environment of the cell. Signaling pathways are often active in many different cell types and are conserved at a large evolutionary scale [1]. The characterization of mechanisms by which these ubiquitous pathways achieve specificity and fulfill largely different functions in different cell types or organisms is of crucial importance. One characteristic of signaling pathways is the bow-tie (or hourglass) architecture in which signals sensed by receptors converge onto a core consisting of a smaller number of proteins followed by a diverse response of transcription factors. The bow-tie property has been observed in different human signaling pathways such as those downstream of epidermal growth factor receptor [2] and of toll-like receptor [3]. Robustness by hierarchy comes to a price: mutations in the central core proteins might hijack the behavior of the entire system [5]
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