Protein evolution on a human signaling network

Background: The architectural structure of cellular networks provides a framework for innovations as well as constraints for protein evolution. This issue has previously been studied extensively by analyzing protein interaction networks. However, it is unclear how signaling networks influence and constrain protein evolution and conversely, how protein evolution modifies and shapes the functional consequences of signaling networks. In this study, we constructed a human signaling network containing more than 1,600 nodes and 5,000 links through manual curation of signaling pathways, and analyzed the d(N)/d(S) values of human-mouse orthologues on the network. Results: We revealed that the protein d(N)/d(S) value decreases along the signal information flow from the extracellular space to nucleus. In the network, neighbor proteins tend to have similar d(N)/d(S) ratios, indicating neighbor proteins have similar evolutionary rates: co-fast or co-slow. However, different types of relationships (activating, inhibitory and neutral) between proteins have different effects on protein evolutionary rates, i.e., physically interacting protein pairs have the closest evolutionary rates. Furthermore, for directed shortest paths, the more distant two proteins are, the less chance they share similar evolutionary rates. However, such behavior was not observed for neutral shortest paths. Fast evolving signaling proteins have two modes of evolution: immunological proteins evolve more independently, while apoptotic proteins tend to form network components with other signaling proteins and share more similar evolutionary rates, possibly enhancing rapid information exchange between apoptotic and other signaling pathways. Conclusion: Major network constraints on protein evolution in protein interaction networks previously described have been found for signaling networks. We further uncovered how network characteristics affect the evolutionary and co-evolutionary behavior of proteins and how protein evolution can modify the existing functionalities of signaling networks. These new insights provide some general principles for understanding protein evolution in the context of signaling networks.