Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 328 (5981): 1043-1046

Copyright © 2010 by the American Association for the Advancement of Science

A Global Protein Kinase and Phosphatase Interaction Network in Yeast

Ashton Breitkreutz,1,* Hyungwon Choi,2,* Jeffrey R. Sharom,1,3,* Lorrie Boucher,1,* Victor Neduva,4,* Brett Larsen,1 Zhen-Yuan Lin,1 Bobby-Joe Breitkreutz,1 Chris Stark,1 Guomin Liu,1 Jessica Ahn,1 Danielle Dewar-Darch,1 Teresa Reguly,1 Xiaojing Tang,1 Ricardo Almeida,4 Zhaohui Steve Qin,5 Tony Pawson,1,3 Anne-Claude Gingras,1,3,{dagger} Alexey I. Nesvizhskii,2,6,{dagger} Mike Tyers1,3,4,{dagger}

Abstract: 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 1844 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, whereas 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.

1 Centre for Systems Biology, Samuel Lunenfeld Research Institute, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada.
2 Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
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 School of Biological Sciences, University of Edinburgh, Mayfield Road, Edinburgh, EH9 3JR Scotland, UK.
5 Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
6 Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: gingras{at}lunenfeld.ca (A.C.G.), nesvi{at}med.umich.edu (A.I.N.), tyers{at}lunenfeld.ca, m.tyers{at}ed.ac.uk (M.T.)

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The PhosphoGRID Saccharomyces cerevisiae protein phosphorylation site database: version 2.0 update.
I. Sadowski, B.-J. Breitkreutz, C. Stark, T.-C. Su, M. Dahabieh, S. Raithatha, W. Bernhard, R. Oughtred, K. Dolinski, K. Barreto, et al. (2013)
Database 2013, bat026
   Abstract »    Full Text »    PDF »
Response regulator-mediated MAPKKK heteromer promotes stress signaling to the Spc1 MAPK in fission yeast.
S. Morigasaki, A. Ikner, H. Tatebe, and K. Shiozaki (2013)
Mol. Biol. Cell 24, 1083-1092
   Abstract »    Full Text »    PDF »
Defective in Mitotic Arrest 1 (Dma1) Ubiquitin Ligase Controls G1 Cyclin Degradation.
S. Hernandez-Ortega, S. Bru, N. Ricco, S. Ramirez, N. Casals, J. Jimenez, M. Isasa, B. Crosas, and J. Clotet (2013)
J. Biol. Chem. 288, 4704-4714
   Abstract »    Full Text »    PDF »
gln3 Mutations Dissociate Responses to Nitrogen Limitation (Nitrogen Catabolite Repression) and Rapamycin Inhibition of TorC1.
R. Rai, J. J. Tate, D. R. Nelson, and T. G. Cooper (2013)
J. Biol. Chem. 288, 2789-2804
   Abstract »    Full Text »    PDF »
Popular Computational Methods to Assess Multiprotein Complexes Derived From Label-Free Affinity Purification and Mass Spectrometry (AP-MS) Experiments.
I. M. Armean, K. S. Lilley, and M. W. B. Trotter (2013)
Mol. Cell. Proteomics 12, 1-13
   Abstract »    Full Text »    PDF »
Physical and functional interaction between yeast Pif1 helicase and Rim1 single-stranded DNA binding protein.
R. Ramanagoudr-Bhojappa, L. P. Blair, A. J. Tackett, and K. D. Raney (2013)
Nucleic Acids Res. 41, 1029-1046
   Abstract »    Full Text »    PDF »
The BioGRID interaction database: 2013 update.
A. Chatr-aryamontri, B.-J. Breitkreutz, S. Heinicke, L. Boucher, A. Winter, C. Stark, J. Nixon, L. Ramage, N. Kolas, L. O'Donnell, et al. (2013)
Nucleic Acids Res. 41, D816-D823
   Abstract »    Full Text »    PDF »
RACK1/Asc1p, a Ribosomal Node in Cellular Signaling.
N. Rachfall, K. Schmitt, S. Bandau, N. Smolinski, A. Ehrenreich, O. Valerius, and G. H. Braus (2013)
Mol. Cell. Proteomics 12, 87-105
   Abstract »    Full Text »    PDF »
Mitotic Exit and Separation of Mother and Daughter Cells.
E. L. Weiss (2012)
Genetics 192, 1165-1202
   Abstract »    Full Text »    PDF »
Internal Amino Acids Promote Gap1 Permease Ubiquitylation via TORC1/Npr1/14-3-3-Dependent Control of the Bul Arrestin-Like Adaptors.
A. Merhi and B. Andre (2012)
Mol. Cell. Biol. 32, 4510-4522
   Abstract »    Full Text »    PDF »
Role of Scd5, a protein phosphatase-1 targeting protein, in phosphoregulation of Sla1 during endocytosis.
R. J. Chi, O. T. Torres, V. A. Segarra, T. Lansley, J. S. Chang, T. M. Newpher, and S. K. Lemmon (2012)
J. Cell Sci. 125, 4728-4739
   Abstract »    Full Text »    PDF »
Functional Analysis With a Barcoder Yeast Gene Overexpression System.
A. C. Douglas, A. M. Smith, S. Sharifpoor, Z. Yan, T. Durbic, L. E. Heisler, A. Y. Lee, O. Ryan, H. Gottert, A. Surendra, et al. (2012)
g3 2, 1279-1289
   Abstract »    Full Text »    PDF »
Protein abundance is key to distinguish promiscuous from functional phosphorylation based on evolutionary information.
E. D. Levy, S. W. Michnick, and C. R. Landry (2012)
Phil Trans R Soc B 367, 2594-2606
   Abstract »    Full Text »    PDF »
High-Resolution Protein Interaction Map of the Drosophila melanogaster p38 Mitogen-Activated Protein Kinases Reveals Limited Functional Redundancy.
V. E. Belozerov, Z.-Y. Lin, A.-C. Gingras, J. C. McDermott, and K. W. Michael Siu (2012)
Mol. Cell. Biol. 32, 3695-3706
   Abstract »    Full Text »    PDF »
Global Gene Deletion Analysis Exploring Yeast Filamentous Growth.
O. Ryan, R. S. Shapiro, C. F. Kurat, D. Mayhew, A. Baryshnikova, B. Chin, Z.-Y. Lin, M. J. Cox, F. Vizeacoumar, D. Cheung, et al. (2012)
Science 337, 1353-1356
   Abstract »    Full Text »    PDF »
Nutritional Control of Growth and Development in Yeast.
J. R. Broach (2012)
Genetics 192, 73-105
   Abstract »    Full Text »    PDF »
Yeast Adaptor Protein, Nbp2p, Is Conserved Regulator of Fungal Ptc1p Phosphatases and Is Involved in Multiple Signaling Pathways.
K. Stanger, M. Gorelik, and A. R. Davidson (2012)
J. Biol. Chem. 287, 22133-22141
   Abstract »    Full Text »    PDF »
Diversity in Genetic In Vivo Methods for Protein-Protein Interaction Studies: from the Yeast Two-Hybrid System to the Mammalian Split-Luciferase System.
B. Stynen, H. Tournu, J. Tavernier, and P. Van Dijck (2012)
Microbiol. Mol. Biol. Rev. 76, 331-382
   Abstract »    Full Text »    PDF »
Vacuolar H+-ATPase (V-ATPase) Promotes Vacuolar Membrane Permeabilization and Nonapoptotic Death in Stressed Yeast.
H. Kim, A. Kim, and K. W. Cunningham (2012)
J. Biol. Chem. 287, 19029-19039
   Abstract »    Full Text »    PDF »
Ksp1 Kinase Regulates Autophagy via the Target of Rapamycin Complex 1 (TORC1) Pathway.
M. Umekawa and D. J. Klionsky (2012)
J. Biol. Chem. 287, 16300-16310
   Abstract »    Full Text »    PDF »
Mapping the Protein Interaction Network of the Human COP9 Signalosome Complex Using a Label-free QTAX Strategy.
L. Fang, R. M. Kaake, V. R. Patel, Y. Yang, P. Baldi, and L. Huang (2012)
Mol. Cell. Proteomics 11, 138-147
   Abstract »    Full Text »    PDF »
Predicting the Fission Yeast Protein Interaction Network.
V. Pancaldi, O. S. Sarac, C. Rallis, J. R. McLean, M. Prevorovsky, K. Gould, A. Beyer, and J. Bahler (2012)
g3 2, 453-467
   Abstract »    Full Text »    PDF »
Functional wiring of the yeast kinome revealed by global analysis of genetic network motifs.
S. Sharifpoor, D. van Dyk, M. Costanzo, A. Baryshnikova, H. Friesen, A. C. Douglas, J.-Y. Youn, B. VanderSluis, C. L. Myers, B. Papp, et al. (2012)
Genome Res. 22, 791-801
   Abstract »    Full Text »    PDF »
Proteome-Wide Discovery of Evolutionary Conserved Sequences in Disordered Regions.
A. N. Nguyen Ba, B. J. Yeh, D. van Dyk, A. R. Davidson, B. J. Andrews, E. L. Weiss, and A. M. Moses (2012)
Science Signaling 5, rs1
   Abstract »    Full Text »    PDF »
Joining Forces: Integrating Proteomics and Cross-linking with the Mass Spectrometry of Intact Complexes.
F. Stengel, R. Aebersold, and C. V. Robinson (2012)
Mol. Cell. Proteomics 11, R111.014027
   Abstract »    Full Text »    PDF »
Unraveling interactions of cell cycle-regulating proteins Sic1 and B-type cyclins in living yeast cells: a FLIM-FRET approach.
G. Schreiber, M. Barberis, S. Scolari, C. Klaus, A. Herrmann, and E. Klipp (2012)
FASEB J 26, 546-554
   Abstract »    Full Text »    PDF »
Direct regulation of nucleosome density by the conserved AAA-ATPase Yta7.
L. M. Lombardi, A. Ellahi, and J. Rine (2011)
PNAS 108, E1302-E1311
   Abstract »    Full Text »    PDF »
Restriction of histone gene transcription to S phase by phosphorylation of a chromatin boundary protein.
C. F. Kurat, J.-P. Lambert, D. van Dyk, K. Tsui, H. van Bakel, S. Kaluarachchi, H. Friesen, P. Kainth, C. Nislow, D. Figeys, et al. (2011)
Genes & Dev. 25, 2489-2501
   Abstract »    Full Text »    PDF »
Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control.
R. Loewith and M. N. Hall (2011)
Genetics 189, 1177-1201
   Abstract »    Full Text »    PDF »
Reg1 Protein Regulates Phosphorylation of All Three Snf1 Isoforms but Preferentially Associates with the Gal83 Isoform.
Y. Zhang, R. R. McCartney, D. G. Chandrashekarappa, S. Mangat, and M. C. Schmidt (2011)
Eukaryot. Cell 10, 1628-1636
   Abstract »    Full Text »    PDF »
iProphet: Multi-level Integrative Analysis of Shotgun Proteomic Data Improves Peptide and Protein Identification Rates and Error Estimates.
D. Shteynberg, E. W. Deutsch, H. Lam, J. K. Eng, Z. Sun, N. Tasman, L. Mendoza, R. L. Moritz, R. Aebersold, and A. I. Nesvizhskii (2011)
Mol. Cell. Proteomics 10, M111.007690
   Abstract »    Full Text »    PDF »
Vascular ligand-receptor mapping by direct combinatorial selection in cancer patients.
F. I. Staquicini, M. Cardo-Vila, M. G. Kolonin, M. Trepel, J. K. Edwards, D. N. Nunes, A. Sergeeva, E. Efstathiou, J. Sun, N. F. Almeida, et al. (2011)
PNAS 108, 18637-18642
   Abstract »    Full Text »    PDF »
Discovery of a Novel Class of Orally Active Antifungal {beta}-1,3-D-Glucan Synthase Inhibitors.
S. S. Walker, Y. Xu, I. Triantafyllou, M. F. Waldman, C. Mendrick, N. Brown, P. Mann, A. Chau, R. Patel, N. Bauman, et al. (2011)
Antimicrob. Agents Chemother. 55, 5099-5106
   Abstract »    Full Text »    PDF »
Proteomic and Functional Genomic Landscape of Receptor Tyrosine Kinase and Ras to Extracellular Signal-Regulated Kinase Signaling.
A. A. Friedman, G. Tucker, R. Singh, D. Yan, A. Vinayagam, Y. Hu, R. Binari, P. Hong, X. Sun, M. Porto, et al. (2011)
Science Signaling 4, rs10
   Abstract »    Full Text »    PDF »
Phosphorylation of Right Open Reading Frame 2 (Rio2) Protein Kinase by Polo-like Kinase 1 Regulates Mitotic Progression.
T. Liu, M. Deng, J. Li, X. Tong, Q. Wei, and X. Ye (2011)
J. Biol. Chem. 286, 36352-36360
   Abstract »    Full Text »    PDF »
Phosphorylation and Stabilization of Topoisomerase II{alpha} Protein by p38{gamma} Mitogen-activated Protein Kinase Sensitize Breast Cancer Cells to Its Poisons.
X. Qi, S. Hou, A. Lepp, R. Li, Z. Basir, Z. Lou, and G. Chen (2011)
J. Biol. Chem. 286, 35883-35890
   Abstract »    Full Text »    PDF »
A Role for the Poly(A)-binding Protein Pab1p in PUF Protein-mediated Repression.
J. J. Chritton and M. Wickens (2011)
J. Biol. Chem. 286, 33268-33278
   Abstract »    Full Text »    PDF »
Functional interaction between dynein light chain and intermediate chain is required for mitotic spindle positioning.
M. D. Stuchell-Brereton, A. Siglin, J. Li, J. K. Moore, S. Ahmed, J. C. Williams, and J. A. Cooper (2011)
Mol. Biol. Cell 22, 2690-2701
   Abstract »    Full Text »    PDF »
Sequence, Structure, and Network Evolution of Protein Phosphorylation.
C. S. H. Tan (2011)
Science Signaling 4, mr6
   Abstract »    Full Text »    PDF »
Building Protein-Protein Interaction Networks with Proteomics and Informatics Tools.
M. E. Sardiu and M. P. Washburn (2011)
J. Biol. Chem. 286, 23645-23651
   Abstract »    Full Text »    PDF »
Physical Module Networks: an integrative approach for reconstructing transcription regulation.
N. Novershtern, A. Regev, and N. Friedman (2011)
Bioinformatics 27, i177-i185
   Abstract »    Full Text »    PDF »
ResponseNet: revealing signaling and regulatory networks linking genetic and transcriptomic screening data.
A. Lan, I. Y. Smoly, G. Rapaport, S. Lindquist, E. Fraenkel, and E. Yeger-Lotem (2011)
Nucleic Acids Res. 39, W424-W429
   Abstract »    Full Text »    PDF »
Cdc55 coordinates spindle assembly and chromosome disjunction during meiosis.
F. Bizzari and A. L. Marston (2011)
J. Cell Biol. 193, 1213-1228
   Abstract »    Full Text »    PDF »
CyClus3D: a Cytoscape plugin for clustering network motifs in integrated networks.
P. Audenaert, T. Van Parys, F. Brondel, M. Pickavet, P. Demeester, Y. Van de Peer, and T. Michoel (2011)
Bioinformatics 27, 1587-1588
   Abstract »    Full Text »    PDF »
A Conserved Coatomer-related Complex Containing Sec13 and Seh1 Dynamically Associates With the Vacuole in Saccharomyces cerevisiae.
S. Dokudovskaya, F. Waharte, A. Schlessinger, U. Pieper, D. P. Devos, I. M. Cristea, R. Williams, J. Salamero, B. T. Chait, A. Sali, et al. (2011)
Mol. Cell. Proteomics 10, M110.006478
   Abstract »    Full Text »    PDF »
Inferring Physical Protein Contacts from Large-Scale Purification Data of Protein Complexes.
S.-E. Schelhorn, J. Mestre, M. Albrecht, and E. Zotenko (2011)
Mol. Cell. Proteomics 10, M110.004929
   Abstract »    Full Text »    PDF »
Aspen Lung Conference 2010: Systems Biology of Lung Diseases--Progress in the Omics Era.
D. Sheppard (2011)
8, 199-202
   Abstract »    Full Text »    PDF »
Roles of two protein phosphatases, Reg1-Glc7 and Sit4, and glycogen synthesis in regulation of SNF1 protein kinase.
A. Ruiz, X. Xu, and M. Carlson (2011)
PNAS 108, 6349-6354
   Abstract »    Full Text »    PDF »
Diverse protein kinase interactions identified by protein microarrays reveal novel connections between cellular processes.
J. Fasolo, A. Sboner, M. G. F. Sun, H. Yu, R. Chen, D. Sharon, P. M. Kim, M. Gerstein, and M. Snyder (2011)
Genes & Dev. 25, 767-778
   Abstract »    Full Text »    PDF »
The Yak1 Protein Kinase Lies at the Center of a Regulatory Cascade Affecting Adhesive Growth and Stress Resistance in Saccharomyces cerevisiae.
M. Malcher, S. Schladebeck, and H.-U. Mosch (2011)
Genetics 187, 717-730
   Abstract »    Full Text »    PDF »
2010: Signaling Breakthroughs of the Year.
E. M. Adler (2011)
Science Signaling 4, eg1
   Abstract »    Full Text »    PDF »
A constraint network of interactions: protein-protein interaction analysis of the yeast type II phosphatase Ptc1p and its adaptor protein Nbp2p.
A. Hruby, M. Zapatka, S. Heucke, L. Rieger, Y. Wu, U. Nussbaumer, S. Timmermann, A. Dunkler, and N. Johnsson (2011)
J. Cell Sci. 124, 35-46
   Abstract »    Full Text »    PDF »
The BioGRID Interaction Database: 2011 update.
C. Stark, B.-J. Breitkreutz, A. Chatr-aryamontri, L. Boucher, R. Oughtred, M. S. Livstone, J. Nixon, K. Van Auken, X. Wang, X. Shi, et al. (2011)
Nucleic Acids Res. 39, D698-D704
   Abstract »    Full Text »    PDF »
Phospho.ELM: a database of phosphorylation sites--update 2011.
H. Dinkel, C. Chica, A. Via, C. M. Gould, L. J. Jensen, T. J. Gibson, and F. Diella (2011)
Nucleic Acids Res. 39, D261-D267
   Abstract »    Full Text »    PDF »
Elm1 kinase activates the spindle position checkpoint kinase Kin4.
A. K. Caydasi, B. Kurtulmus, M. I. L. Orrico, A. Hofmann, B. Ibrahim, and G. Pereira (2010)
J. Cell Biol. 190, 975-989
   Abstract »    Full Text »    PDF »
Comprehensive Expression Profiles of Genes for Protein Tyrosine Phosphatases in Immune Cells.
Y. Arimura and J. Yagi (2010)
Science Signaling 3, rs1
   Abstract »    Full Text »    PDF »
Signaling Through Cooperation.
E. D. Levy, C. R. Landry, and S. W. Michnick (2010)
Science 328, 983-984
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882