Oncogenic Mutations Rewire Signaling Pathways by Switching Protein Recruitment to Phosphotyrosine Sites
Research output: Contribution to journal › Journal article › peer-review
Standard
Oncogenic Mutations Rewire Signaling Pathways by Switching Protein Recruitment to Phosphotyrosine Sites. / Lundby, Alicia; Franciosa, Giulia; Emdal, Kristina B; Refsgaard, Jan C; Gnosa, Sebastian P; Bekker-Jensen, Dorte B; Secher, Anna; Maurya, Svetlana R; Paul, Indranil; Mendez, Blanca L; Kelstrup, Christian D; Francavilla, Chiara; Kveiborg, Marie; Montoya, Guillermo; Jensen, Lars J; Olsen, Jesper V.
In: Cell, Vol. 179, No. 2, 2019, p. 543-560.Research output: Contribution to journal › Journal article › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Oncogenic Mutations Rewire Signaling Pathways by Switching Protein Recruitment to Phosphotyrosine Sites
AU - Lundby, Alicia
AU - Franciosa, Giulia
AU - Emdal, Kristina B
AU - Refsgaard, Jan C
AU - Gnosa, Sebastian P
AU - Bekker-Jensen, Dorte B
AU - Secher, Anna
AU - Maurya, Svetlana R
AU - Paul, Indranil
AU - Mendez, Blanca L
AU - Kelstrup, Christian D
AU - Francavilla, Chiara
AU - Kveiborg, Marie
AU - Montoya, Guillermo
AU - Jensen, Lars J
AU - Olsen, Jesper V
N1 - Copyright © 2019 Elsevier Inc. All rights reserved.
PY - 2019
Y1 - 2019
N2 - Tyrosine phosphorylation regulates multi-layered signaling networks with broad implications in (patho)physiology, but high-throughput methods for functional annotation of phosphotyrosine sites are lacking. To decipher phosphotyrosine signaling directly in tissue samples, we developed a mass-spectrometry-based interaction proteomics approach. We measured the in vivo EGF-dependent signaling network in lung tissue quantifying >1,000 phosphotyrosine sites. To assign function to all EGF-regulated sites, we determined their recruited protein signaling complexes in lung tissue by interaction proteomics. We demonstrated how mutations near tyrosine residues introduce molecular switches that rewire cancer signaling networks, and we revealed oncogenic properties of such a lung cancer EGFR mutant. To demonstrate the scalability of the approach, we performed >1,000 phosphopeptide pulldowns and analyzed them by rapid mass spectrometric analysis, revealing tissue-specific differences in interactors. Our approach is a general strategy for functional annotation of phosphorylation sites in tissues, enabling in-depth mechanistic insights into oncogenic rewiring of signaling networks.
AB - Tyrosine phosphorylation regulates multi-layered signaling networks with broad implications in (patho)physiology, but high-throughput methods for functional annotation of phosphotyrosine sites are lacking. To decipher phosphotyrosine signaling directly in tissue samples, we developed a mass-spectrometry-based interaction proteomics approach. We measured the in vivo EGF-dependent signaling network in lung tissue quantifying >1,000 phosphotyrosine sites. To assign function to all EGF-regulated sites, we determined their recruited protein signaling complexes in lung tissue by interaction proteomics. We demonstrated how mutations near tyrosine residues introduce molecular switches that rewire cancer signaling networks, and we revealed oncogenic properties of such a lung cancer EGFR mutant. To demonstrate the scalability of the approach, we performed >1,000 phosphopeptide pulldowns and analyzed them by rapid mass spectrometric analysis, revealing tissue-specific differences in interactors. Our approach is a general strategy for functional annotation of phosphorylation sites in tissues, enabling in-depth mechanistic insights into oncogenic rewiring of signaling networks.
U2 - 10.1016/j.cell.2019.09.008
DO - 10.1016/j.cell.2019.09.008
M3 - Journal article
C2 - 31585087
VL - 179
SP - 543
EP - 560
JO - Cell
JF - Cell
SN - 0092-8674
IS - 2
ER -
ID: 228455146