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Open Access Research article

Elucidation of the evolutionary expansion of phosphorylation signaling networks using comparative phosphomotif analysis

Hisayoshi Yoshizaki12 and Shujiro Okuda3

Author Affiliations

1 Department of Pathology I, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan

2 Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga 525-0058, Japan

3 Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan

BMC Genomics 2014, 15:546  doi:10.1186/1471-2164-15-546

Published: 1 July 2014



Protein phosphorylation is catalyzed by kinases and is involved in the regulation of a wide range of processes. The phosphosites in protein sequence motifs determine the types of kinases involved. The development of phosphoproteomics has allowed the identification of huge numbers of phosphosites, some of which are not involved in physiological functions.


We developed a method for extracting phosphosites with important roles in cellular functions and determined 178 phosphomotifs based on the analysis of 34,366 phosphosites. We compared the conservation of serine/threonine/tyrosine residues observed in humans and seven other species. Consequently, we identified 16 phosphomotifs, where the level of conservation increased among species. The highly conserved phosphomotifs in humans and the worm were kinase regulatory sites. The motifs present in the fly were novel phosphomotifs, including zinc finger motifs involved in the regulation of gene expression. Subsequently, we found that this zinc finger motif contributed to subcellular protein localization. The motifs identified in fish allowed us to detect the expansion of phosphorylation signals related to alternative splicing. We also showed that the motifs present in specific species functioned in an additional network that interacted directly with the core signaling network conserved from yeast to humans.


Our method may facilitate the efficient extraction of novel phosphomotifs with physiological functions, thereby contributing greatly to the analysis of complex phosphorylation signaling cascades. Our study suggests that the phosphorylation networks acquired during evolution have added signaling network modules to the core signaling networks.