Protein evolution on a human signaling network

We revealed that the protein dN/dS value decreases along the signal information flow from the extracellular space to nucleus. In the network, neighbor proteins tend to have similar dN/dS 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.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.Proteins in cells tend to form a complex cellular signaling network that responds to various signals, ranging from environmental conditions, hormones or neurotransmitters to ions, and perform a series of tasks such as cell growth, maintenance of cell survival, proliferation, differentiation, development and apoptosis [1-4]. Cellular signaling networks are ubiquitous in various prokaryotes and eukaryotes and play pivotal roles in fundamental processes. Most studies on signaling have so f