Abstract
Background:Mutation of the epidermal growth factor receptor (EGFR) results in a discordant cell signaling, leading to the development of various diseases. However, the mechanism underlying the alteration of downstream signaling due to such mutation has not yet been completely understood at the system level. Here, we report a phosphoproteomics-based methodology for characterizing the regulatory mechanism underlying aberrant EGFR signaling using computational network modeling. Methodology/Principal Findings: Our phosphoproteomic analysis of the mutation at tyrosine 992 (Y992), one of the multifunctional docking sites of EGFR, revealed network-wide effects of the mutation on EGF signaling in a time-resolved manner. Computational modeling based on the temporal activation profiles enabled us to not only rediscover already-known protein interactions with Y992 and internalization property of mutated EGFR but also further gain model-driven insights into the effect of cellular content and the regulation of EGFR degradation. Our kinetic model also suggested critical reactions facilitating the reconstruction of the diverse effects of the mutation on phosphoproteome dynamics. Conclusions/Significance:Our integrative approach provided a mechanistic description of the disorders of mutated EGFR signaling networks, which could facilitate the development of a systematic strategy toward controlling disease-related cell signaling.
| Original language | English |
|---|---|
| Article number | e13926 |
| Journal | PLoS One |
| Volume | 5 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 2010 |
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ASJC Scopus subject areas
- Agricultural and Biological Sciences(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
Phosphoproteomics-Based modeling defines the regulatory mechanism underlying aberrant EGFR signaling. / Tasaki, Shinya; Nagasaki, Masao; Kozuka-Hata, Hiroko; Senba, Kentaro; Gotoh, Noriko; Hattori, Seisuke; Inoue, Jun ichiro; Yamamoto, Tadashi; Miyano, Satoru; Sugano, Sumio; Oyama, Masaaki.
In: PLoS One, Vol. 5, No. 11, e13926, 2010.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Phosphoproteomics-Based modeling defines the regulatory mechanism underlying aberrant EGFR signaling
AU - Tasaki, Shinya
AU - Nagasaki, Masao
AU - Kozuka-Hata, Hiroko
AU - Senba, Kentaro
AU - Gotoh, Noriko
AU - Hattori, Seisuke
AU - Inoue, Jun ichiro
AU - Yamamoto, Tadashi
AU - Miyano, Satoru
AU - Sugano, Sumio
AU - Oyama, Masaaki
PY - 2010
Y1 - 2010
N2 - Background:Mutation of the epidermal growth factor receptor (EGFR) results in a discordant cell signaling, leading to the development of various diseases. However, the mechanism underlying the alteration of downstream signaling due to such mutation has not yet been completely understood at the system level. Here, we report a phosphoproteomics-based methodology for characterizing the regulatory mechanism underlying aberrant EGFR signaling using computational network modeling. Methodology/Principal Findings: Our phosphoproteomic analysis of the mutation at tyrosine 992 (Y992), one of the multifunctional docking sites of EGFR, revealed network-wide effects of the mutation on EGF signaling in a time-resolved manner. Computational modeling based on the temporal activation profiles enabled us to not only rediscover already-known protein interactions with Y992 and internalization property of mutated EGFR but also further gain model-driven insights into the effect of cellular content and the regulation of EGFR degradation. Our kinetic model also suggested critical reactions facilitating the reconstruction of the diverse effects of the mutation on phosphoproteome dynamics. Conclusions/Significance:Our integrative approach provided a mechanistic description of the disorders of mutated EGFR signaling networks, which could facilitate the development of a systematic strategy toward controlling disease-related cell signaling.
AB - Background:Mutation of the epidermal growth factor receptor (EGFR) results in a discordant cell signaling, leading to the development of various diseases. However, the mechanism underlying the alteration of downstream signaling due to such mutation has not yet been completely understood at the system level. Here, we report a phosphoproteomics-based methodology for characterizing the regulatory mechanism underlying aberrant EGFR signaling using computational network modeling. Methodology/Principal Findings: Our phosphoproteomic analysis of the mutation at tyrosine 992 (Y992), one of the multifunctional docking sites of EGFR, revealed network-wide effects of the mutation on EGF signaling in a time-resolved manner. Computational modeling based on the temporal activation profiles enabled us to not only rediscover already-known protein interactions with Y992 and internalization property of mutated EGFR but also further gain model-driven insights into the effect of cellular content and the regulation of EGFR degradation. Our kinetic model also suggested critical reactions facilitating the reconstruction of the diverse effects of the mutation on phosphoproteome dynamics. Conclusions/Significance:Our integrative approach provided a mechanistic description of the disorders of mutated EGFR signaling networks, which could facilitate the development of a systematic strategy toward controlling disease-related cell signaling.
UR - http://www.scopus.com/inward/record.url?scp=78649723147&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78649723147&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0013926
DO - 10.1371/journal.pone.0013926
M3 - Article
C2 - 21085658
AN - SCOPUS:78649723147
VL - 5
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 11
M1 - e13926
ER -