A Global Protein Kinase and Phosphatase Interaction Network in Yeast

Ashton Breitkreutz*1, Hyungwon Choi*2, Jeff Sharom*1,3, Lorrie Boucher*1, Victor Neduva*4, Brett Larsen1, Zhen-Yuan Lin1, Bobby-Joe Breitkreutz1, Chris Stark1, Guomin Liu1, Jessica Ahn1, Danielle Dewar-Darch1, Teresa Reguly1, Xiaojing Tang1, Ricardo Almeida4, Zhaohui Steve Qin6, Tony Pawson1,4, Anne-Claude Gingras1,3+, Alexey I. Nesvizhskii2,5+, Mike Tyers1,3,4+

The interactions of protein kinases and phosphatases with their regulatory subunits and substrates underpin cellular regulation. We identified a kinase and phosphatase interaction (KPI) network of 1,844 interactions in budding yeast by mass spectrometric analysis of protein complexes. The KPI network contained many dense local regions of interactions that suggested new functions. Notably, the cell cycle phosphatase Cdc14 associated with multiple kinases that revealed roles for Cdc14 in mitogen-activated protein kinase signaling, the DNA damage response and metabolism, while interactions of the target of rapamycin complex 1 (TORC1) uncovered new effector kinases in nitrogen and carbon metabolism. An extensive backbone of kinase-kinase interactions cross-connects the proteome and may serve to coordinate diverse cellular responses.

Data generated in this study and interaction annotation notes are available at the custom database search where all interactions can be filtered with user-defined SAINT thresholds. Data supporting this study is also available for download. The open source Significance Analysis of Interactome (SAINT) software is available for download at Sourceforge and from the Nesvizhskii Lab homepage.

Supported by research grants from:

CIHR to A.C.G. (MOP-84314), T.P. (MOP-57793) and M.T. (MOP 12246), the Ontario Research Fund to T.P. and A.C.G. (REO#-044), the NIH to M.T. (5R01RR024031) and A.I.N. (CA-126239), an NCIC doctoral student award to J.S., Canada Research Chairs in Functional Genomics and Bioinformatics to M.T and in Functional Proteomics to A.C.G. and a Scottish Universities Life Sciences Alliance Research Professorship and a Royal Society Wolfson Research Merit Award to M.T.

Canadian Institutes of Health Research National Institutes of Health Ontario Research Fund
1 Centre for Systems Biology, Samuel Lunenfeld Research Institute, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada
2 Department of Pathology and Biostatistics, University of Michigan, Ann Arbor, Michigan USA, 48109-0602
3 Department of Molecular Genetics, University of Toronto, 1 Kings College Circle, Toronto, Ontario, M5S 1A8 Canada
4 Wellcome Trust Centre for Cell Biology and Centre for Systems Biology, University of Edinburgh, Mayfield Road, Edinburgh, EH9 3JR Scotland UK
5 Center for Computational Medicine and Biology, University of Michigan, Ann Arbor, Michigan, USA, 48109-0602
6 Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA, 48109-0602
* These authors contributed equally to this work.
+ To whom correspondence should be addressed. E-mail: gingras@lunenfeld.ca, nesvi@med.umich.edu, tyers@lunenfeld.ca
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