Systematic interactome mapping and genetic perturbation analysis of a C. elegans TGF-β signaling network

Muneesh Tewari; Patrick J. Hu; Jin Sook Ahn; Nono Ayivi-Guedehoussou; Pierre Olivier Vidalain; Siming Li; Stuart Milstein; Chris M. Armstrong; Mike Boxem; Maurice D. Butler; Svetlana Busiguina; Jean François Rual; Nieves Ibarrola; Sabrina T. Chaklos; Nicolas Bertin; Philippe Vaglio; Mark L. Edgley; Kevin V. King; Patrice S. Albert; Jean Vandenhaute; Akhilesh Pandey; Donald L. Riddle; Gary Ruvkun; Marc Vidal

doi:10.1016/S1097-2765(04)00033-4

Systematic interactome mapping and genetic perturbation analysis of a C. elegans TGF-β signaling network

Muneesh Tewari, Patrick J. Hu, Jin Sook Ahn, Nono Ayivi-Guedehoussou, Pierre Olivier Vidalain, Siming Li, Stuart Milstein, Chris M. Armstrong, Mike Boxem, Maurice D. Butler, Svetlana Busiguina, Jean François Rual, Nieves Ibarrola, Sabrina T. Chaklos, Nicolas Bertin, Philippe Vaglio, Mark L. Edgley, Kevin V. King, Patrice S. Albert, Jean VandenhauteAkhilesh Pandey, Donald L. Riddle, Gary Ruvkun, Marc Vidal

School of Medicine

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

104 Scopus citations

Abstract

To initiate a system-level analysis of C. elegans DAF-7/TGF-β signaling, we combined interactome mapping with single and double genetic perturbations. Yeast two-hybrid (Y2H) screens starting with known DAF-7/TGF-β pathway components defined a network of 71 interactions among 59 proteins. Coaffinity purification (co-AP) assays in mammalian cells confirmed the overall quality of this network. Systematic perturbations of the network using RNAi, both in wild-type and daf-7/TGF-β pathway mutant animals, identified nine DAF-7/TGF-β signaling modifiers, seven of which are conserved in humans. We show that one of these has functional homology to human SNO/SKI oncoproteins and that mutations at the corresponding genetic locus daf-5 confer defects in DAF-7/TGF-β signaling. Our results reveal substantial molecular complexity in DAF-7/TGF-β signal transduction. Integrating interactome maps with systematic genetic perturbations may be useful for developing a systems biology approach to this and other signaling modules.

Original language	English (US)
Pages (from-to)	469-482
Number of pages	14
Journal	Molecular Cell
Volume	13
Issue number	4
DOIs	https://doi.org/10.1016/S1097-2765(04)00033-4
State	Published - Feb 27 2004

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Molecular Biology

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Tewari, M., Hu, P. J., Ahn, J. S., Ayivi-Guedehoussou, N., Vidalain, P. O., Li, S., Milstein, S., Armstrong, C. M., Boxem, M., Butler, M. D., Busiguina, S., Rual, J. F., Ibarrola, N., Chaklos, S. T., Bertin, N., Vaglio, P., Edgley, M. L., King, K. V., Albert, P. S., ... Vidal, M. (2004). Systematic interactome mapping and genetic perturbation analysis of a C. elegans TGF-β signaling network. Molecular Cell, 13(4), 469-482. https://doi.org/10.1016/S1097-2765(04)00033-4

Tewari, M, Hu, PJ, Ahn, JS, Ayivi-Guedehoussou, N, Vidalain, PO, Li, S, Milstein, S, Armstrong, CM, Boxem, M, Butler, MD, Busiguina, S, Rual, JF, Ibarrola, N, Chaklos, ST, Bertin, N, Vaglio, P, Edgley, ML, King, KV, Albert, PS, Vandenhaute, J, Pandey, A, Riddle, DL, Ruvkun, G & Vidal, M 2004, 'Systematic interactome mapping and genetic perturbation analysis of a C. elegans TGF-β signaling network', Molecular Cell, vol. 13, no. 4, pp. 469-482. https://doi.org/10.1016/S1097-2765(04)00033-4

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abstract = "To initiate a system-level analysis of C. elegans DAF-7/TGF-β signaling, we combined interactome mapping with single and double genetic perturbations. Yeast two-hybrid (Y2H) screens starting with known DAF-7/TGF-β pathway components defined a network of 71 interactions among 59 proteins. Coaffinity purification (co-AP) assays in mammalian cells confirmed the overall quality of this network. Systematic perturbations of the network using RNAi, both in wild-type and daf-7/TGF-β pathway mutant animals, identified nine DAF-7/TGF-β signaling modifiers, seven of which are conserved in humans. We show that one of these has functional homology to human SNO/SKI oncoproteins and that mutations at the corresponding genetic locus daf-5 confer defects in DAF-7/TGF-β signaling. Our results reveal substantial molecular complexity in DAF-7/TGF-β signal transduction. Integrating interactome maps with systematic genetic perturbations may be useful for developing a systems biology approach to this and other signaling modules.",

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AU - Tewari, Muneesh

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AU - Ahn, Jin Sook

AU - Ayivi-Guedehoussou, Nono

AU - Vidalain, Pierre Olivier

AU - Li, Siming

AU - Milstein, Stuart

AU - Armstrong, Chris M.

AU - Boxem, Mike

AU - Butler, Maurice D.

AU - Busiguina, Svetlana

AU - Rual, Jean François

AU - Ibarrola, Nieves

AU - Chaklos, Sabrina T.

AU - Bertin, Nicolas

AU - Vaglio, Philippe

AU - Edgley, Mark L.

AU - King, Kevin V.

AU - Albert, Patrice S.

AU - Vandenhaute, Jean

AU - Pandey, Akhilesh

AU - Riddle, Donald L.

AU - Ruvkun, Gary

AU - Vidal, Marc

PY - 2004/2/27

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N2 - To initiate a system-level analysis of C. elegans DAF-7/TGF-β signaling, we combined interactome mapping with single and double genetic perturbations. Yeast two-hybrid (Y2H) screens starting with known DAF-7/TGF-β pathway components defined a network of 71 interactions among 59 proteins. Coaffinity purification (co-AP) assays in mammalian cells confirmed the overall quality of this network. Systematic perturbations of the network using RNAi, both in wild-type and daf-7/TGF-β pathway mutant animals, identified nine DAF-7/TGF-β signaling modifiers, seven of which are conserved in humans. We show that one of these has functional homology to human SNO/SKI oncoproteins and that mutations at the corresponding genetic locus daf-5 confer defects in DAF-7/TGF-β signaling. Our results reveal substantial molecular complexity in DAF-7/TGF-β signal transduction. Integrating interactome maps with systematic genetic perturbations may be useful for developing a systems biology approach to this and other signaling modules.

AB - To initiate a system-level analysis of C. elegans DAF-7/TGF-β signaling, we combined interactome mapping with single and double genetic perturbations. Yeast two-hybrid (Y2H) screens starting with known DAF-7/TGF-β pathway components defined a network of 71 interactions among 59 proteins. Coaffinity purification (co-AP) assays in mammalian cells confirmed the overall quality of this network. Systematic perturbations of the network using RNAi, both in wild-type and daf-7/TGF-β pathway mutant animals, identified nine DAF-7/TGF-β signaling modifiers, seven of which are conserved in humans. We show that one of these has functional homology to human SNO/SKI oncoproteins and that mutations at the corresponding genetic locus daf-5 confer defects in DAF-7/TGF-β signaling. Our results reveal substantial molecular complexity in DAF-7/TGF-β signal transduction. Integrating interactome maps with systematic genetic perturbations may be useful for developing a systems biology approach to this and other signaling modules.

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Systematic interactome mapping and genetic perturbation analysis of a C. elegans TGF-β signaling network

Abstract

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