Functional overlap and regulatory links shape genetic interactions between signaling pathways

Sake Van Wageningen; Patrick Kemmeren; Philip Lijnzaad; Thanasis Margaritis; Joris J. Benschop; Inês J. De Castro; Dik Van Leenen; Marian J.A. Groot Koerkamp; Cheuk W. Ko; Antony J. Miles; Nathalie Brabers; Mariel O. Brok; Tineke L. Lenstra; Dorothea Fiedler; Like Fokkens; Rodrigo Aldecoa; Eva Apweiler; Virginia Taliadouros; Katrin Sameith; Loes A.L. Van De Pasch; Sander R. Van Hooff; Linda V. Bakker; Nevan J. Krogan; Berend Snel; Frank C.P. Holstege

doi:10.1016/j.cell.2010.11.021

Functional overlap and regulatory links shape genetic interactions between signaling pathways

Sake Van Wageningen, Patrick Kemmeren, Philip Lijnzaad, Thanasis Margaritis, Joris J. Benschop, Inês J. De Castro, Dik Van Leenen, Marian J.A. Groot Koerkamp, Cheuk W. Ko, Antony J. Miles, Nathalie Brabers, Mariel O. Brok, Tineke L. Lenstra, Dorothea Fiedler, Like Fokkens, Rodrigo Aldecoa, Eva Apweiler, Virginia Taliadouros, Katrin Sameith, Loes A.L. Van De PaschSander R. Van Hooff, Linda V. Bakker, Nevan J. Krogan, Berend Snel, Frank C.P. Holstege

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

110 Citations (Scopus)

Abstract

To understand relationships between phosphorylation-based signaling pathways, we analyzed 150 deletion mutants of protein kinases and phosphatases in S. cerevisiae using DNA microarrays. Downstream changes in gene expression were treated as a phenotypic readout. Double mutants with synthetic genetic interactions were included to investigate genetic buffering relationships such as redundancy. Three types of genetic buffering relationships are identified: mixed epistasis, complete redundancy, and quantitative redundancy. In mixed epistasis, the most common buffering relationship, different gene sets respond in different epistatic ways. Mixed epistasis arises from pairs of regulators that have only partial overlap in function and that are coupled by additional regulatory links such as repression of one by the other. Such regulatory modules confer the ability to control different combinations of processes depending on condition or context. These properties likely contribute to the evolutionary maintenance of paralogs and indicate a way in which signaling pathways connect for multiprocess control.

Original language	English
Pages (from-to)	991-1004
Number of pages	14
Journal	Cell
Volume	143
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2010.11.021
Publication status	Published - 10 Dec 2010
Externally published	Yes

Keywords

CELLBIO
SIGNALING

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10.1016/j.cell.2010.11.021

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Van Wageningen, S., Kemmeren, P., Lijnzaad, P., Margaritis, T., Benschop, J. J., De Castro, I. J., Van Leenen, D., Groot Koerkamp, M. J. A., Ko, C. W., Miles, A. J., Brabers, N., Brok, M. O., Lenstra, T. L., Fiedler, D., Fokkens, L., Aldecoa, R., Apweiler, E., Taliadouros, V., Sameith, K., ... Holstege, F. C. P. (2010). Functional overlap and regulatory links shape genetic interactions between signaling pathways. Cell, 143(6), 991-1004. https://doi.org/10.1016/j.cell.2010.11.021

@article{85a9c88e9c8344839c356165fb700af4,

title = "Functional overlap and regulatory links shape genetic interactions between signaling pathways",

abstract = "To understand relationships between phosphorylation-based signaling pathways, we analyzed 150 deletion mutants of protein kinases and phosphatases in S. cerevisiae using DNA microarrays. Downstream changes in gene expression were treated as a phenotypic readout. Double mutants with synthetic genetic interactions were included to investigate genetic buffering relationships such as redundancy. Three types of genetic buffering relationships are identified: mixed epistasis, complete redundancy, and quantitative redundancy. In mixed epistasis, the most common buffering relationship, different gene sets respond in different epistatic ways. Mixed epistasis arises from pairs of regulators that have only partial overlap in function and that are coupled by additional regulatory links such as repression of one by the other. Such regulatory modules confer the ability to control different combinations of processes depending on condition or context. These properties likely contribute to the evolutionary maintenance of paralogs and indicate a way in which signaling pathways connect for multiprocess control.",

keywords = "CELLBIO, SIGNALING",

author = "{Van Wageningen}, Sake and Patrick Kemmeren and Philip Lijnzaad and Thanasis Margaritis and Benschop, {Joris J.} and {De Castro}, {In{\^e}s J.} and {Van Leenen}, Dik and {Groot Koerkamp}, {Marian J.A.} and Ko, {Cheuk W.} and Miles, {Antony J.} and Nathalie Brabers and Brok, {Mariel O.} and Lenstra, {Tineke L.} and Dorothea Fiedler and Like Fokkens and Rodrigo Aldecoa and Eva Apweiler and Virginia Taliadouros and Katrin Sameith and {Van De Pasch}, {Loes A.L.} and {Van Hooff}, {Sander R.} and Bakker, {Linda V.} and Krogan, {Nevan J.} and Berend Snel and Holstege, {Frank C.P.}",

note = "Funding Information: This work was supported by the Netherlands Bioinformatics Centre (NBIC) and the Netherlands Organization of Scientific Research (NWO), grants 016.108.607, 817.02.015, 050.71.057, 911.06.009, 021.002.035 (T.L.L.), 863.07.007 (P.K.), 700.57.407 (J.J.B.). ",

year = "2010",

month = dec,

day = "10",

doi = "10.1016/j.cell.2010.11.021",

language = "English",

volume = "143",

pages = "991--1004",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "6",

}

Van Wageningen, S, Kemmeren, P , Lijnzaad, P , Margaritis, T, Benschop, JJ, De Castro, IJ, Van Leenen, D, Groot Koerkamp, MJA, Ko, CW, Miles, AJ, Brabers, N, Brok, MO, Lenstra, TL, Fiedler, D, Fokkens, L, Aldecoa, R, Apweiler, E, Taliadouros, V, Sameith, K, Van De Pasch, LAL, Van Hooff, SR, Bakker, LV, Krogan, NJ, Snel, B & Holstege, FCP 2010, 'Functional overlap and regulatory links shape genetic interactions between signaling pathways', Cell, vol. 143, no. 6, pp. 991-1004. https://doi.org/10.1016/j.cell.2010.11.021

TY - JOUR

T1 - Functional overlap and regulatory links shape genetic interactions between signaling pathways

AU - Van Wageningen, Sake

AU - Kemmeren, Patrick

AU - Lijnzaad, Philip

AU - Margaritis, Thanasis

AU - Benschop, Joris J.

AU - De Castro, Inês J.

AU - Van Leenen, Dik

AU - Groot Koerkamp, Marian J.A.

AU - Ko, Cheuk W.

AU - Miles, Antony J.

AU - Brabers, Nathalie

AU - Brok, Mariel O.

AU - Lenstra, Tineke L.

AU - Fiedler, Dorothea

AU - Fokkens, Like

AU - Aldecoa, Rodrigo

AU - Apweiler, Eva

AU - Taliadouros, Virginia

AU - Sameith, Katrin

AU - Van De Pasch, Loes A.L.

AU - Van Hooff, Sander R.

AU - Bakker, Linda V.

AU - Krogan, Nevan J.

AU - Snel, Berend

AU - Holstege, Frank C.P.

N1 - Funding Information: This work was supported by the Netherlands Bioinformatics Centre (NBIC) and the Netherlands Organization of Scientific Research (NWO), grants 016.108.607, 817.02.015, 050.71.057, 911.06.009, 021.002.035 (T.L.L.), 863.07.007 (P.K.), 700.57.407 (J.J.B.).

PY - 2010/12/10

Y1 - 2010/12/10

N2 - To understand relationships between phosphorylation-based signaling pathways, we analyzed 150 deletion mutants of protein kinases and phosphatases in S. cerevisiae using DNA microarrays. Downstream changes in gene expression were treated as a phenotypic readout. Double mutants with synthetic genetic interactions were included to investigate genetic buffering relationships such as redundancy. Three types of genetic buffering relationships are identified: mixed epistasis, complete redundancy, and quantitative redundancy. In mixed epistasis, the most common buffering relationship, different gene sets respond in different epistatic ways. Mixed epistasis arises from pairs of regulators that have only partial overlap in function and that are coupled by additional regulatory links such as repression of one by the other. Such regulatory modules confer the ability to control different combinations of processes depending on condition or context. These properties likely contribute to the evolutionary maintenance of paralogs and indicate a way in which signaling pathways connect for multiprocess control.

AB - To understand relationships between phosphorylation-based signaling pathways, we analyzed 150 deletion mutants of protein kinases and phosphatases in S. cerevisiae using DNA microarrays. Downstream changes in gene expression were treated as a phenotypic readout. Double mutants with synthetic genetic interactions were included to investigate genetic buffering relationships such as redundancy. Three types of genetic buffering relationships are identified: mixed epistasis, complete redundancy, and quantitative redundancy. In mixed epistasis, the most common buffering relationship, different gene sets respond in different epistatic ways. Mixed epistasis arises from pairs of regulators that have only partial overlap in function and that are coupled by additional regulatory links such as repression of one by the other. Such regulatory modules confer the ability to control different combinations of processes depending on condition or context. These properties likely contribute to the evolutionary maintenance of paralogs and indicate a way in which signaling pathways connect for multiprocess control.

KW - CELLBIO

KW - SIGNALING

UR - http://www.scopus.com/inward/record.url?scp=78649938122&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2010.11.021

DO - 10.1016/j.cell.2010.11.021

M3 - Article

C2 - 21145464

AN - SCOPUS:78649938122

SN - 0092-8674

VL - 143

SP - 991

EP - 1004

JO - Cell

JF - Cell

IS - 6

ER -

Functional overlap and regulatory links shape genetic interactions between signaling pathways

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Keywords

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