Protein conservation and variation suggest mechanisms of cell type-specific modulation of signaling pathways

PLoS Comput Biol. 2014 Jun 12;10(6):e1003659. doi: 10.1371/journal.pcbi.1003659. eCollection 2014 Jun.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Gene Expression Profiling
  • Humans
  • Mice
  • Models, Biological*
  • Mutation / physiology
  • Organ Specificity / physiology*
  • Proteins / chemistry*
  • Proteins / physiology*
  • Proteomics
  • Signal Transduction / physiology*

Substances

  • Proteins

Grant support

The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007/2013) under grant agreements Nr. (PROSPECTS_201648 and PRIMES_278568). This work was supported by the Spanish Ministerio de Economía y Competitividad, Plan Nacional BIO2012-39754 and the European Fund for Regional Development. We acknowledge support of the Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa 2013-2017’ (SEV-2012-0208). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.