Global analysis of phosphorylation networks in humans

• A conserved kinase-to-kinase backbone exists in the phosphorylation networks.
• Functions of homologous kinases are often conserved, even with distinct substrates.
• Phosphorylation networks are inherently wired with gene regulatory networks.

Phosphorylation-mediated signaling plays a crucial role in nearly every aspect of cellular physiology. A recent study based on protein microarray experiments identified a large number of kinase–substrate relationships (KSRs), and built a comprehensive and reliable phosphorylation network in humans. Analysis of this network, in conjunction with additional resources, revealed several key features. First, comparison of the human and yeast phosphorylation networks uncovered an evolutionarily conserved signaling backbone dominated by kinase-to-kinase relationships. Second, although most of the KSRs themselves are not conserved, the functions enriched in the substrates for a given kinase are often conserved. Third, the prevalence of kinase-transcription factor regulatory modules suggests that phosphorylation and transcriptional regulatory networks are inherently wired together to form integrated regulatory circuits. Overall, the phosphorylation networks described in this work promise to offer new insights into the properties of kinase signaling pathways, at both the global and the protein levels. This article is part of a Special Issue entitled: Computational Proteomics, Systems Biology & Clinical Implications. Guest Editor: Yudong Cai.