Phosphorylation site dynamics of early T-cell receptor signaling

Lily A Chylek, Vyacheslav Akimov, Jörn Dengjel, Kristoffer T G Rigbolt, Bin Hu, William S Hlavacek, Blagoy Blagoev

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

In adaptive immune responses, T-cell receptor (TCR) signaling impacts multiple cellular processes and results in T-cell differentiation, proliferation, and cytokine production. Although individual protein-protein interactions and phosphorylation events have been studied extensively, we lack a systems-level understanding of how these components cooperate to control signaling dynamics, especially during the crucial first seconds of stimulation. Here, we used quantitative proteomics to characterize reshaping of the T-cell phosphoproteome in response to TCR/CD28 co-stimulation, and found that diverse dynamic patterns emerge within seconds. We detected phosphorylation dynamics as early as 5 s and observed widespread regulation of key TCR signaling proteins by 30 s. Development of a computational model pointed to the presence of novel regulatory mechanisms controlling phosphorylation of sites with central roles in TCR signaling. The model was used to generate predictions suggesting unexpected roles for the phosphatase PTPN6 (SHP-1) and shortcut recruitment of the actin regulator WAS. Predictions were validated experimentally. This integration of proteomics and modeling illustrates a novel, generalizable framework for solidifying quantitative understanding of a signaling network and for elucidating missing links.

OriginalsprogEngelsk
TidsskriftPLOS ONE
Vol/bind9
Udgave nummer8
Sider (fra-til)e104240
ISSN1932-6203
DOI
StatusUdgivet - 2014

Fingeraftryk

Phosphorylation
T-Cell Antigen Receptor
phosphorylation
T-lymphocytes
receptors
T-cells
Non-Receptor Type 6 Protein Tyrosine Phosphatase
proteomics
Proteins
Actins
Cell Differentiation
prediction
Phosphoric Monoester Hydrolases
Cell Proliferation
protein-protein interactions
cell differentiation
actin
Cytokines
cytokines
proteins

Citer dette

Chylek, L. A., Akimov, V., Dengjel, J., Rigbolt, K. T. G., Hu, B., Hlavacek, W. S., & Blagoev, B. (2014). Phosphorylation site dynamics of early T-cell receptor signaling. PLOS ONE, 9(8), e104240. https://doi.org/10.1371/journal.pone.0104240
Chylek, Lily A ; Akimov, Vyacheslav ; Dengjel, Jörn ; Rigbolt, Kristoffer T G ; Hu, Bin ; Hlavacek, William S ; Blagoev, Blagoy. / Phosphorylation site dynamics of early T-cell receptor signaling. I: PLOS ONE. 2014 ; Bind 9, Nr. 8. s. e104240.
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title = "Phosphorylation site dynamics of early T-cell receptor signaling",
abstract = "In adaptive immune responses, T-cell receptor (TCR) signaling impacts multiple cellular processes and results in T-cell differentiation, proliferation, and cytokine production. Although individual protein-protein interactions and phosphorylation events have been studied extensively, we lack a systems-level understanding of how these components cooperate to control signaling dynamics, especially during the crucial first seconds of stimulation. Here, we used quantitative proteomics to characterize reshaping of the T-cell phosphoproteome in response to TCR/CD28 co-stimulation, and found that diverse dynamic patterns emerge within seconds. We detected phosphorylation dynamics as early as 5 s and observed widespread regulation of key TCR signaling proteins by 30 s. Development of a computational model pointed to the presence of novel regulatory mechanisms controlling phosphorylation of sites with central roles in TCR signaling. The model was used to generate predictions suggesting unexpected roles for the phosphatase PTPN6 (SHP-1) and shortcut recruitment of the actin regulator WAS. Predictions were validated experimentally. This integration of proteomics and modeling illustrates a novel, generalizable framework for solidifying quantitative understanding of a signaling network and for elucidating missing links.",
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Chylek, LA, Akimov, V, Dengjel, J, Rigbolt, KTG, Hu, B, Hlavacek, WS & Blagoev, B 2014, 'Phosphorylation site dynamics of early T-cell receptor signaling', PLOS ONE, bind 9, nr. 8, s. e104240. https://doi.org/10.1371/journal.pone.0104240

Phosphorylation site dynamics of early T-cell receptor signaling. / Chylek, Lily A; Akimov, Vyacheslav; Dengjel, Jörn; Rigbolt, Kristoffer T G; Hu, Bin; Hlavacek, William S; Blagoev, Blagoy.

I: PLOS ONE, Bind 9, Nr. 8, 2014, s. e104240.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Phosphorylation site dynamics of early T-cell receptor signaling

AU - Chylek, Lily A

AU - Akimov, Vyacheslav

AU - Dengjel, Jörn

AU - Rigbolt, Kristoffer T G

AU - Hu, Bin

AU - Hlavacek, William S

AU - Blagoev, Blagoy

PY - 2014

Y1 - 2014

N2 - In adaptive immune responses, T-cell receptor (TCR) signaling impacts multiple cellular processes and results in T-cell differentiation, proliferation, and cytokine production. Although individual protein-protein interactions and phosphorylation events have been studied extensively, we lack a systems-level understanding of how these components cooperate to control signaling dynamics, especially during the crucial first seconds of stimulation. Here, we used quantitative proteomics to characterize reshaping of the T-cell phosphoproteome in response to TCR/CD28 co-stimulation, and found that diverse dynamic patterns emerge within seconds. We detected phosphorylation dynamics as early as 5 s and observed widespread regulation of key TCR signaling proteins by 30 s. Development of a computational model pointed to the presence of novel regulatory mechanisms controlling phosphorylation of sites with central roles in TCR signaling. The model was used to generate predictions suggesting unexpected roles for the phosphatase PTPN6 (SHP-1) and shortcut recruitment of the actin regulator WAS. Predictions were validated experimentally. This integration of proteomics and modeling illustrates a novel, generalizable framework for solidifying quantitative understanding of a signaling network and for elucidating missing links.

AB - In adaptive immune responses, T-cell receptor (TCR) signaling impacts multiple cellular processes and results in T-cell differentiation, proliferation, and cytokine production. Although individual protein-protein interactions and phosphorylation events have been studied extensively, we lack a systems-level understanding of how these components cooperate to control signaling dynamics, especially during the crucial first seconds of stimulation. Here, we used quantitative proteomics to characterize reshaping of the T-cell phosphoproteome in response to TCR/CD28 co-stimulation, and found that diverse dynamic patterns emerge within seconds. We detected phosphorylation dynamics as early as 5 s and observed widespread regulation of key TCR signaling proteins by 30 s. Development of a computational model pointed to the presence of novel regulatory mechanisms controlling phosphorylation of sites with central roles in TCR signaling. The model was used to generate predictions suggesting unexpected roles for the phosphatase PTPN6 (SHP-1) and shortcut recruitment of the actin regulator WAS. Predictions were validated experimentally. This integration of proteomics and modeling illustrates a novel, generalizable framework for solidifying quantitative understanding of a signaling network and for elucidating missing links.

U2 - 10.1371/journal.pone.0104240

DO - 10.1371/journal.pone.0104240

M3 - Journal article

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VL - 9

SP - e104240

JO - P L o S One

JF - P L o S One

SN - 1932-6203

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ER -

Chylek LA, Akimov V, Dengjel J, Rigbolt KTG, Hu B, Hlavacek WS et al. Phosphorylation site dynamics of early T-cell receptor signaling. PLOS ONE. 2014;9(8):e104240. https://doi.org/10.1371/journal.pone.0104240