Molecular Systems Biology (Apr 2013)
Construction of human activity‐based phosphorylation networks
- Robert H Newman,
- Jianfei Hu,
- Hee‐Sool Rho,
- Zhi Xie,
- Crystal Woodard,
- John Neiswinger,
- Christopher Cooper,
- Matthew Shirley,
- Hillary M Clark,
- Shaohui Hu,
- Woochang Hwang,
- Jun Seop Jeong,
- George Wu,
- Jimmy Lin,
- Xinxin Gao,
- Qiang Ni,
- Renu Goel,
- Shuli Xia,
- Hongkai Ji,
- Kevin N Dalby,
- Morris J Birnbaum,
- Philip A Cole,
- Stefan Knapp,
- Alexey G Ryazanov,
- Donald J Zack,
- Seth Blackshaw,
- Tony Pawson,
- Anne‐Claude Gingras,
- Stephen Desiderio,
- Akhilesh Pandey,
- Benjamin E Turk,
- Jin Zhang,
- Heng Zhu,
- Jiang Qian
Affiliations
- Robert H Newman
- Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine
- Jianfei Hu
- Department of Ophthalmology, Johns Hopkins School of Medicine
- Hee‐Sool Rho
- Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine
- Zhi Xie
- Department of Ophthalmology, Johns Hopkins School of Medicine
- Crystal Woodard
- Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine
- John Neiswinger
- Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine
- Christopher Cooper
- Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine
- Matthew Shirley
- Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine
- Hillary M Clark
- Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine
- Shaohui Hu
- Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine
- Woochang Hwang
- Department of Ophthalmology, Johns Hopkins School of Medicine
- Jun Seop Jeong
- Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine
- George Wu
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health
- Jimmy Lin
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine
- Xinxin Gao
- Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine
- Qiang Ni
- Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine
- Renu Goel
- Institute of Bioinformatics, International Tech Park
- Shuli Xia
- Hugo W. Moser Kennedy Krieger Institute
- Hongkai Ji
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health
- Kevin N Dalby
- Division of Medicinal Chemistry, College of Pharmacy, University of Texas at Austin
- Morris J Birnbaum
- Department of Medicine, University of Pennsylvania School of Medicine
- Philip A Cole
- Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine
- Stefan Knapp
- Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford
- Alexey G Ryazanov
- Department of Pharmacology, University of Medicine and Dentistry of New Jersey
- Donald J Zack
- Department of Ophthalmology, Johns Hopkins School of Medicine
- Seth Blackshaw
- Center for High‐Throughput Biology, Johns Hopkins School of Medicine
- Tony Pawson
- Centre for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital Toronto
- Anne‐Claude Gingras
- Centre for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital Toronto
- Stephen Desiderio
- Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine
- Akhilesh Pandey
- Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine
- Benjamin E Turk
- Department of Pharmacology, Yale University School of Medicine
- Jin Zhang
- Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine
- Heng Zhu
- Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine
- Jiang Qian
- Department of Ophthalmology, Johns Hopkins School of Medicine
- DOI
- https://doi.org/10.1038/msb.2013.12
- Journal volume & issue
-
Vol. 9,
no. 1
pp. 1 – 12
Abstract
Abstract The landscape of human phosphorylation networks has not been systematically explored, representing vast, unchartered territories within cellular signaling networks. Although a large number of in vivo phosphorylated residues have been identified by mass spectrometry (MS)‐based approaches, assigning the upstream kinases to these residues requires biochemical analysis of kinase‐substrate relationships (KSRs). Here, we developed a new strategy, called CEASAR, based on functional protein microarrays and bioinformatics to experimentally identify substrates for 289 unique kinases, resulting in 3656 high‐quality KSRs. We then generated consensus phosphorylation motifs for each of the kinases and integrated this information, along with information about in vivo phosphorylation sites determined by MS, to construct a high‐resolution map of phosphorylation networks that connects 230 kinases to 2591 in vivo phosphorylation sites in 652 substrates. The value of this data set is demonstrated through the discovery of a new role for PKA downstream of Btk (Bruton's tyrosine kinase) during B‐cell receptor signaling. Overall, these studies provide global insights into kinase‐mediated signaling pathways and promise to advance our understanding of cellular signaling processes in humans.
Keywords
