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Protein phosphorylation events during T cell receptor (TCR) signaling control the formation of complexes among proteins proximal to the TCR, the activation of kinase cascades, and the activation of transcription factors; however, the mode and extent of the influence of phosphorylation in coordinating the diverse phenomena associated with T cell activation are unclear. Therefore, we used the human Jurkat T cell leukemia cell line as a model system and performed large-scale quantitative phosphoproteomic analyses of TCR signaling. We identified 10,665 unique phosphorylation sites, of which 696 showed TCR-responsive changes. In addition, we analyzed broad trends in phosphorylation data sets to uncover underlying mechanisms associated with T cell activation. We found that, upon stimulation of the TCR, phosphorylation events extensively targeted protein modules involved in all of the salient phenomena associated with T cell activation: patterning of surface proteins, endocytosis of the TCR, formation of the F-actin cup, inside-out activation of integrins, polarization of microtubules, production of cytokines, and alternative splicing of messenger RNA. Further, case-by-case analysis of TCR-responsive phosphorylation sites on proteins belonging to relevant functional modules together with network analysis allowed us to deduce that serine-threonine (S-T) phosphorylation modulated protein-protein interactions (PPIs) in a system-wide fashion. We also provide experimental support for this inference by showing that phosphorylation of tubulin on six distinct serine residues abrogated PPIs during the assembly of microtubules. We propose that modulation of PPIs by stimulus-dependent changes in S-T phosphorylation state is a widespread phenomenon applicable to many other signaling systems.

Original publication

DOI

10.1126/scisignal.2000007

Type

Journal article

Journal

Sci Signal

Publication Date

18/08/2009

Volume

2

Keywords

Actins, Amino Acid Sequence, Binding Sites, Biological Transport, Cytokines, Endocytosis, Extracellular Signal-Regulated MAP Kinases, Humans, Jurkat Cells, Microtubules, Models, Biological, Molecular Sequence Data, Phosphoproteins, Phosphorylation, Protein Binding, Protein Interaction Mapping, Proteomics, RNA Splicing, Receptors, Antigen, T-Cell, Sequence Homology, Amino Acid, Serine, Signal Transduction, Threonine, Transcription Factors, Tyrosine