Functional Organization of the S. cerevisiae Phosphorylation Network

Dorothea Fiedler; Hannes Braberg; Monika Mehta; Gal Chechik; Gerard Cagney; Paromita Mukherjee; Andrea C. Silva; Michael Shales; Sean R. Collins; Sake van Wageningen; Patrick Kemmeren; Frank C.P. Holstege; Jonathan S. Weissman; Michael Christopher Keogh; Daphne Koller; Kevan M. Shokat; Nevan J. Krogan

doi:10.1016/j.cell.2008.12.039

Functional Organization of the S. cerevisiae Phosphorylation Network

Dorothea Fiedler, Hannes Braberg, Monika Mehta, Gal Chechik, Gerard Cagney, Paromita Mukherjee, Andrea C. Silva, Michael Shales, Sean R. Collins, Sake van Wageningen, Patrick Kemmeren, Frank C.P. Holstege, Jonathan S. Weissman, Michael Christopher Keogh, Daphne Koller, Kevan M. Shokat, Nevan J. Krogan

Research output: Contribution to journal › Article › peer-review

210 Scopus citations

Abstract

Reversible protein phosphorylation is a signaling mechanism involved in all cellular processes. To create a systems view of the signaling apparatus in budding yeast, we generated an epistatic miniarray profile (E-MAP) comprised of 100,000 pairwise, quantitative genetic interactions, including virtually all protein and small-molecule kinases and phosphatases as well as key cellular regulators. Quantitative genetic interaction mapping reveals factors working in compensatory pathways (negative genetic interactions) or those operating in linear pathways (positive genetic interactions). We found an enrichment of positive genetic interactions between kinases, phosphatases, and their substrates. In addition, we assembled a higher-order map from sets of three genes that display strong interactions with one another: triplets enriched for functional connectivity. The resulting network view provides insights into signaling pathway regulation and reveals a link between the cell-cycle kinase, Cak1, the Fus3 MAP kinase, and a pathway that regulates chromatin integrity during transcription by RNA polymerase II.

Original language	English
Pages (from-to)	952-963
Number of pages	12
Journal	Cell
Volume	136
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2008.12.039
State	Published - 6 Mar 2009
Externally published	Yes

Bibliographical note

Funding Information:
The authors thank A. Roguev, C. Kaplan, C.J. Ingles, P. Aguilar, T. Walther, J.H. Morris, and members of the Krogan, Shokat, and Keogh labs for advice and comments. We also thank W.A. Lim for discussion on MAP kinase cascades. We are grateful to A. Chan, E. Cheng, Y. Nijati, and Li Jieying for technical assistance. We thank F. Winston and S. Buratowski for providing yeast strains and B. Strahl, S. Hahn, and D. Morgan for sharing unpublished data. The work was supported by an Ernst Schering Postdoctoral Fellowship (D.F.), the Biophysics Graduate Group at UCSF (H.B.), the National Science Foundation (G.C. and D.K.), the New York Speakers Fund for Biomedical Research (M.-C.K.), the Howard Hughes Medical Institute (K.M.S.), the NIH (N.J.K. and K.M.S.), and Sandler Family Funding (N.J.K.).

Keywords

SIGNALING

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10.1016/j.cell.2008.12.039

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Fiedler, D., Braberg, H., Mehta, M., Chechik, G., Cagney, G., Mukherjee, P., Silva, A. C., Shales, M., Collins, S. R., van Wageningen, S., Kemmeren, P., Holstege, F. C. P., Weissman, J. S., Keogh, M. C., Koller, D., Shokat, K. M., & Krogan, N. J. (2009). Functional Organization of the S. cerevisiae Phosphorylation Network. Cell, 136(5), 952-963. https://doi.org/10.1016/j.cell.2008.12.039

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title = "Functional Organization of the S. cerevisiae Phosphorylation Network",

abstract = "Reversible protein phosphorylation is a signaling mechanism involved in all cellular processes. To create a systems view of the signaling apparatus in budding yeast, we generated an epistatic miniarray profile (E-MAP) comprised of 100,000 pairwise, quantitative genetic interactions, including virtually all protein and small-molecule kinases and phosphatases as well as key cellular regulators. Quantitative genetic interaction mapping reveals factors working in compensatory pathways (negative genetic interactions) or those operating in linear pathways (positive genetic interactions). We found an enrichment of positive genetic interactions between kinases, phosphatases, and their substrates. In addition, we assembled a higher-order map from sets of three genes that display strong interactions with one another: triplets enriched for functional connectivity. The resulting network view provides insights into signaling pathway regulation and reveals a link between the cell-cycle kinase, Cak1, the Fus3 MAP kinase, and a pathway that regulates chromatin integrity during transcription by RNA polymerase II.",

keywords = "SIGNALING",

author = "Dorothea Fiedler and Hannes Braberg and Monika Mehta and Gal Chechik and Gerard Cagney and Paromita Mukherjee and Silva, {Andrea C.} and Michael Shales and Collins, {Sean R.} and {van Wageningen}, Sake and Patrick Kemmeren and Holstege, {Frank C.P.} and Weissman, {Jonathan S.} and Keogh, {Michael Christopher} and Daphne Koller and Shokat, {Kevan M.} and Krogan, {Nevan J.}",

note = "Funding Information: The authors thank A. Roguev, C. Kaplan, C.J. Ingles, P. Aguilar, T. Walther, J.H. Morris, and members of the Krogan, Shokat, and Keogh labs for advice and comments. We also thank W.A. Lim for discussion on MAP kinase cascades. We are grateful to A. Chan, E. Cheng, Y. Nijati, and Li Jieying for technical assistance. We thank F. Winston and S. Buratowski for providing yeast strains and B. Strahl, S. Hahn, and D. Morgan for sharing unpublished data. The work was supported by an Ernst Schering Postdoctoral Fellowship (D.F.), the Biophysics Graduate Group at UCSF (H.B.), the National Science Foundation (G.C. and D.K.), the New York Speakers Fund for Biomedical Research (M.-C.K.), the Howard Hughes Medical Institute (K.M.S.), the NIH (N.J.K. and K.M.S.), and Sandler Family Funding (N.J.K.). ",

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doi = "10.1016/j.cell.2008.12.039",

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T1 - Functional Organization of the S. cerevisiae Phosphorylation Network

AU - Fiedler, Dorothea

AU - Braberg, Hannes

AU - Mehta, Monika

AU - Chechik, Gal

AU - Cagney, Gerard

AU - Mukherjee, Paromita

AU - Silva, Andrea C.

AU - Shales, Michael

AU - Collins, Sean R.

AU - van Wageningen, Sake

AU - Kemmeren, Patrick

AU - Holstege, Frank C.P.

AU - Weissman, Jonathan S.

AU - Keogh, Michael Christopher

AU - Koller, Daphne

AU - Shokat, Kevan M.

AU - Krogan, Nevan J.

N1 - Funding Information: The authors thank A. Roguev, C. Kaplan, C.J. Ingles, P. Aguilar, T. Walther, J.H. Morris, and members of the Krogan, Shokat, and Keogh labs for advice and comments. We also thank W.A. Lim for discussion on MAP kinase cascades. We are grateful to A. Chan, E. Cheng, Y. Nijati, and Li Jieying for technical assistance. We thank F. Winston and S. Buratowski for providing yeast strains and B. Strahl, S. Hahn, and D. Morgan for sharing unpublished data. The work was supported by an Ernst Schering Postdoctoral Fellowship (D.F.), the Biophysics Graduate Group at UCSF (H.B.), the National Science Foundation (G.C. and D.K.), the New York Speakers Fund for Biomedical Research (M.-C.K.), the Howard Hughes Medical Institute (K.M.S.), the NIH (N.J.K. and K.M.S.), and Sandler Family Funding (N.J.K.).

PY - 2009/3/6

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N2 - Reversible protein phosphorylation is a signaling mechanism involved in all cellular processes. To create a systems view of the signaling apparatus in budding yeast, we generated an epistatic miniarray profile (E-MAP) comprised of 100,000 pairwise, quantitative genetic interactions, including virtually all protein and small-molecule kinases and phosphatases as well as key cellular regulators. Quantitative genetic interaction mapping reveals factors working in compensatory pathways (negative genetic interactions) or those operating in linear pathways (positive genetic interactions). We found an enrichment of positive genetic interactions between kinases, phosphatases, and their substrates. In addition, we assembled a higher-order map from sets of three genes that display strong interactions with one another: triplets enriched for functional connectivity. The resulting network view provides insights into signaling pathway regulation and reveals a link between the cell-cycle kinase, Cak1, the Fus3 MAP kinase, and a pathway that regulates chromatin integrity during transcription by RNA polymerase II.

AB - Reversible protein phosphorylation is a signaling mechanism involved in all cellular processes. To create a systems view of the signaling apparatus in budding yeast, we generated an epistatic miniarray profile (E-MAP) comprised of 100,000 pairwise, quantitative genetic interactions, including virtually all protein and small-molecule kinases and phosphatases as well as key cellular regulators. Quantitative genetic interaction mapping reveals factors working in compensatory pathways (negative genetic interactions) or those operating in linear pathways (positive genetic interactions). We found an enrichment of positive genetic interactions between kinases, phosphatases, and their substrates. In addition, we assembled a higher-order map from sets of three genes that display strong interactions with one another: triplets enriched for functional connectivity. The resulting network view provides insights into signaling pathway regulation and reveals a link between the cell-cycle kinase, Cak1, the Fus3 MAP kinase, and a pathway that regulates chromatin integrity during transcription by RNA polymerase II.

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IS - 5

ER -

Functional Organization of the S. cerevisiae Phosphorylation Network

Abstract

Bibliographical note

Keywords

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