Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.
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Mayya V, Lundgren DH, Hwang SI, Rezaul K, Wu L, Eng JK, Rodionov V, Han DK
Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.
Sci Signal. 2009 Aug 18;2(84):ra46. doi: 10.1126/scisignal.2000007.
- PubMed ID
- 19690332 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Polypeptides
Name UniProt ID Voltage-dependent T-type calcium channel subunit alpha-1I Q9P0X4 Details Tyrosine-protein kinase ABL1 P00519 Details NADH dehydrogenase [ubiquinone] flavoprotein 3, mitochondrial P56181 Details 7-dehydrocholesterol reductase Q9UBM7 Details RAF proto-oncogene serine/threonine-protein kinase P04049 Details Transketolase P29401 Details Coagulation factor V P12259 Details L-lactate dehydrogenase B chain P07195 Details Pyruvate kinase PKM P14618 Details Voltage-gated inwardly rectifying potassium channel KCNH2 Q12809 Details Organic cation/carnitine transporter 2 O76082 Details Solute carrier family 12 member 6 Q9UHW9 Details DNA ligase 3 P49916 Details Bifunctional glutamate/proline--tRNA ligase P07814 Details DNA ligase 1 P18858 Details Neutral amino acid transporter B(0) Q15758 Details 5'-AMP-activated protein kinase subunit beta-1 Q9Y478 Details T-cell surface glycoprotein CD3 epsilon chain P07766 Details Solute carrier family 12 member 7 Q9Y666 Details GMP synthase [glutamine-hydrolyzing] P49915 Details Thymidylate synthase P04818 Details Peroxisomal multifunctional enzyme type 2 P51659 Details L-lactate dehydrogenase A chain P00338 Details Serine/threonine-protein kinase A-Raf P10398 Details Tyrosine-protein kinase ABL2 P42684 Details Neutral amino acid transporter A P43007 Details Albumin P02768 Details Chromodomain-helicase-DNA-binding protein 1 O14646 Details Glyceraldehyde-3-phosphate dehydrogenase P04406 Details DNA polymerase alpha catalytic subunit P09884 Details Integrin alpha-4 P13612 Details Solute carrier family 12 member 4 Q9UP95 Details Choline-phosphate cytidylyltransferase A P49585 Details Acetyl-CoA carboxylase 1 Q13085 Details 3',5'-cyclic-AMP phosphodiesterase 7B Q9NP56 Details Serine/threonine-protein kinase B-raf P15056 Details NADH-ubiquinone oxidoreductase chain 2 P03891 Details Interferon alpha/beta receptor 1 P17181 Details 5'-AMP-activated protein kinase catalytic subunit alpha-1 Q13131 Details DNA polymerase alpha subunit B Q14181 Details Sodium/potassium-transporting ATPase subunit alpha-1 P05023 Details Biliverdin reductase A P53004 Details DNA topoisomerase 2-alpha P11388 Details Sodium/hydrogen exchanger 1 P19634 Details 5'-AMP-activated protein kinase subunit beta-2 O43741 Details Sphingosine-1-phosphate lyase 1 O95470 Details Malate dehydrogenase, mitochondrial P40926 Details Multidrug resistance-associated protein 1 P33527 Details Glucocorticoid receptor P04150 Details Proto-oncogene tyrosine-protein kinase Src P12931 Details Tyrosine-protein kinase Lck P06239 Details CTP synthase 1 P17812 Details Histone deacetylase 9 Q9UKV0 Details Signal transducer and activator of transcription 5B P51692 Details DNA (cytosine-5)-methyltransferase 1 P26358 Details Growth factor receptor-bound protein 2 P62993 Details Mitogen-activated protein kinase 1 P28482 Details Phosphatidylinositol 3-kinase regulatory subunit alpha P27986 Details Cyclic AMP-responsive element-binding protein 1 P16220 Details Insulin receptor substrate 1 P35568 Details Catenin beta-1 P35222 Details Thiopurine S-methyltransferase P51580 Details Synaptic vesicle glycoprotein 2A Q7L0J3 Details Phospholipid-transporting ATPase IA Q9Y2Q0 Details E3 ubiquitin-protein ligase Mdm2 Q00987 Details Calnexin P27824 Details Rho-associated protein kinase 1 Q13464 Details Mitogen-activated protein kinase 14 Q16539 Details Transcription factor Jun P05412 Details GTP cyclohydrolase 1 P30793 Details Mitogen-activated protein kinase 3 P27361 Details Glycogen synthase kinase-3 beta P49841 Details Tyrosine-protein phosphatase non-receptor type 11 Q06124 Details Cyclin-dependent kinase 2 P24941 Details Cyclin-dependent kinase 1 P06493 Details Nuclear factor NF-kappa-B p105 subunit P19838 Details CD44 antigen P16070 Details Heat shock protein HSP 90-alpha P07900 Details Protein c-Fos P01100 Details Protein kinase C alpha type P17252 Details 3',5'-cyclic-AMP phosphodiesterase 4A P27815 Details Inositol monophosphatase 1 P29218 Details Inhibitor of nuclear factor kappa-B kinase subunit beta O14920 Details Microtubule-associated protein 1A P78559 Details RAC-beta serine/threonine-protein kinase P31751 Details 14-3-3 protein zeta/delta P63104 Details Phosphatidylethanolamine-binding protein 1 P30086 Details ATP-binding cassette sub-family C member 4 O15439 Details 3-phosphoinositide-dependent protein kinase 1 O15530 Details Glucose-6-phosphate isomerase P06744 Details Protein-glutamine gamma-glutamyltransferase E Q08188 Details Tyrosine-protein kinase ZAP-70 P43403 Details Tyrosine-protein kinase SYK P43405 Details Tyrosine-protein kinase ITK/TSK Q08881 Details Protein kinase C theta type Q04759 Details Tubulin alpha-1C chain Q9BQE3 Details DNA repair protein XRCC4 Q13426 Details Fructose-bisphosphate aldolase A P04075 Details M-phase inducer phosphatase 2 P30305 Details Poly [ADP-ribose] polymerase 1 P09874 Details Cyclin-dependent kinase 7 P50613 Details Thioredoxin reductase 1, cytoplasmic Q16881 Details Cytokine receptor common subunit gamma P31785 Details Laminin subunit alpha-5 O15230 Details Retinoblastoma-associated protein P06400 Details Cyanocobalamin reductase / alkylcobalamin dealkylase Q9Y4U1 Details Methionine adenosyltransferase 2 subunit beta Q9NZL9 Details Cyclin-dependent kinase 6 Q00534 Details Adenosine deaminase P00813 Details Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase P22234 Details Multifunctional protein CAD P27708 Details Phosphoribosylformylglycinamidine synthase O15067 Details N-acetyl-D-glucosamine kinase Q9UJ70 Details Peptidyl-prolyl cis-trans isomerase G Q13427 Details Histone deacetylase 1 Q13547 Details Histone deacetylase 2 Q92769 Details Histone deacetylase 3 O15379 Details Phosphatidylinositol 3-kinase regulatory subunit beta O00459 Details DNA-dependent protein kinase catalytic subunit P78527 Details Protein kinase C delta type Q05655 Details DNA topoisomerase 2-beta Q02880 Details Ribonucleoside-diphosphate reductase subunit M2 P31350 Details E3 ubiquitin-protein ligase UBR4 Q5T4S7 Details NAD-dependent protein deacetylase sirtuin-1 Q96EB6 Details Telomerase-binding protein EST1A Q86US8 Details Prostaglandin E synthase 3 Q15185 Details Actin nucleation-promoting factor WAS P42768 Details Gephyrin Q9NQX3 Details Anthrax toxin receptor 2 P58335 Details Pleckstrin homology domain-containing family A member 1 Q9HB21 Details Casein kinase I isoform gamma-2 P78368 Details Wee1-like protein kinase P30291 Details Serine/threonine-protein kinase Chk1 O14757 Details Tubulin beta-6 chain Q9BUF5 Details Bcl-2-like protein 2 Q92843 Details Bcl2-associated agonist of cell death Q92934 Details Far upstream element-binding protein 1 Q96AE4 Details cAMP-dependent protein kinase type II-alpha regulatory subunit P13861 Details cAMP-dependent protein kinase type I-alpha regulatory subunit P10644 Details T-cell surface glycoprotein CD3 delta chain P04234 Details T-cell surface glycoprotein CD3 gamma chain P09693 Details T-cell surface glycoprotein CD3 zeta chain P20963 Details Microtubule-associated protein 4 P27816 Details Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 P16615 Details Tumor necrosis factor receptor superfamily member 8 P28908 Details Tyrosine-protein kinase JAK3 P52333 Details Transmembrane anterior posterior transformation protein 1 homolog Q6NXT6 Details Casein kinase I isoform epsilon P49674 Details Heat shock factor protein 1 Q00613 Details Histone deacetylase 4 P56524 Details Histone deacetylase 7 Q8WUI4 Details Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A Q9HCR9 Details Serum paraoxonase/lactonase 3 Q15166 Details Receptor-type tyrosine-protein phosphatase epsilon P23469 Details Integrin beta-1 P05556 Details Nischarin Q9Y2I1 Details Cation-independent mannose-6-phosphate receptor P11717 Details Copper-transporting ATPase 1 Q04656 Details Nuclear receptor coactivator 2 Q15596 Details cAMP-dependent protein kinase catalytic subunit alpha P17612 Details Uracil-DNA glycosylase P13051 Details Heat shock cognate 71 kDa protein P11142 Details Dual specificity protein kinase TTK P33981 Details Endothelin-converting enzyme 1 P42892 Details Serine/threonine-protein kinase haspin Q8TF76 Details Inner centromere protein Q9NQS7 Details Large ribosomal subunit protein eL37 P61927 Details Triosephosphate isomerase P60174 Details Protein kinase C iota type P41743 Details Proteasome subunit alpha type-2 P25787 Details Proteasome subunit alpha type-3 P25788 Details Proteasome subunit alpha type-5 P28066 Details Dual specificity tyrosine-phosphorylation-regulated kinase 1A Q13627 Details STE20-like serine/threonine-protein kinase Q9H2G2 Details Calcium/calmodulin-dependent protein kinase type IV Q16566 Details Dual specificity protein kinase CLK3 P49761 Details Nuclear receptor coactivator 5 Q9HCD5 Details Hydroxymethylglutaryl-CoA synthase, cytoplasmic Q01581 Details Calcium/calmodulin-dependent protein kinase type II subunit delta Q13557 Details Serine/threonine-protein kinase 26 Q9P289 Details Profilin-1 P07737 Details Myocardin-related transcription factor A Q969V6 Details Cofilin-1 P23528 Details Rho-associated protein kinase 2 O75116 Details Actin-related protein 2/3 complex subunit 1B O15143 Details Actin-related protein 2/3 complex subunit 3 O15145 Details SRSF protein kinase 2 P78362 Details Serine/threonine-protein kinase 17B O94768 Details Afadin P55196 Details Interleukin-1 receptor-associated kinase 4 Q9NWZ3 Details CREB-binding protein Q92793 Details Mediator of RNA polymerase II transcription subunit 1 Q15648 Details Protein arginine N-methyltransferase 3 O60678 Details Epsin-1 Q9Y6I3 Details Phosphoglucomutase-1 P36871 Details Vimentin P08670 Details cAMP-dependent protein kinase catalytic subunit beta P22694 Details Ras-related protein Rab-8B Q92930 Details cAMP-dependent protein kinase type II-beta regulatory subunit P31323 Details Poly(A) polymerase alpha P51003 Details 3-ketoacyl-CoA thiolase, peroxisomal P09110 Details NAD-dependent protein deacetylase sirtuin-3, mitochondrial Q9NTG7 Details T-complex protein 1 subunit gamma P49368 Details Carboxypeptidase D O75976 Details Transitional endoplasmic reticulum ATPase P55072 Details Ubiquitin-like modifier-activating enzyme 1 P22314 Details Histone acetyltransferase KAT5 Q92993 Details SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 O60264 Details Uridine-cytidine kinase-like 1 Q9NWZ5 Details Spectrin beta chain, non-erythrocytic 1 Q01082 Details Kinesin-like protein KIF2C Q99661 Details Acetylcholine receptor subunit alpha P02708 Details Sodium bicarbonate cotransporter 3 Q9Y6M7 Details Breakpoint cluster region protein P11274 Details Dual specificity mitogen-activated protein kinase kinase 2 P36507 Details Mitogen-activated protein kinase kinase kinase 2 Q9Y2U5 Details RalA-binding protein 1 Q15311 Details 5'(3')-deoxyribonucleotidase, cytosolic type Q8TCD5 Details Transferrin receptor protein 1 P02786 Details Ribosomal protein S6 kinase alpha-3 P51812 Details Membrane-associated progesterone receptor component 1 O00264 Details Inositol 1,4,5-trisphosphate-gated calcium channel ITPR3 Q14573 Details Cyclic AMP-dependent transcription factor ATF-1 P18846 Details Cyclic AMP-dependent transcription factor ATF-2 P15336 Details Complement component 1 Q subcomponent-binding protein, mitochondrial Q07021 Details Mitogen-activated protein kinase kinase kinase 20 Q9NYL2 Details Alpha-enolase P06733 Details Protein PML P29590 Details Nucleolar and coiled-body phosphoprotein 1 Q14978 Details TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 Q15750 Details Protein O-GlcNAcase O60502 Details Utrophin P46939 Details Nucleobindin-2 P80303 Details Calmodulin-2 P0DP24 Details Calmodulin-3 P0DP25 Details 60 kDa heat shock protein, mitochondrial P10809 Details Small ribosomal subunit protein uS5 P15880 Details Heterogeneous nuclear ribonucleoproteins A2/B1 P22626 Details Heterogeneous nuclear ribonucleoprotein H P31943 Details Heterogeneous nuclear ribonucleoprotein H3 P31942 Details Splicing factor, proline- and glutamine-rich P23246 Details Eukaryotic translation initiation factor 6 P56537 Details 14-3-3 protein beta/alpha P31946 Details Hepatoma-derived growth factor P51858 Details Phosphoglycerate mutase 1 P18669 Details Ran-specific GTPase-activating protein P43487 Details Protein disulfide-isomerase A3 P30101 Details Phosphatidylinositol 4-kinase type 2-beta Q8TCG2 Details Huntingtin P42858 Details Lymphoid enhancer-binding factor 1 Q9UJU2 Details Eukaryotic translation initiation factor 3 subunit F O00303 Details Heterogeneous nuclear ribonucleoprotein K P61978 Details Heat shock 70 kDa protein 4 P34932 Details Splicing factor 3A subunit 3 Q12874 Details SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1 Q969G3 Details Tumor protein D54 O43399 Details Ubiquitin carboxyl-terminal hydrolase 14 P54578 Details 14-3-3 protein eta Q04917 Details 14-3-3 protein theta P27348 Details Chromobox protein homolog 5 P45973 Details Keratin, type II cytoskeletal 1 P04264 Details Desmoplakin P15924 Details Hornerin Q86YZ3 Details KAT8 regulatory NSL complex subunit 3 Q9P2N6 Details Far upstream element-binding protein 2 Q92945 Details Cysteine and glycine-rich protein 1 P21291 Details Filamin-A P21333 Details Heterogeneous nuclear ribonucleoprotein D0 Q14103 Details Heterochromatin protein 1-binding protein 3 Q5SSJ5 Details Nucleophosmin P06748 Details Large ribosomal subunit protein eL14 P50914 Details Small ribosomal subunit protein eS17 P08708 Details Small ribosomal subunit protein eS8 P62241 Details Splicing factor 1 Q15637 Details Transgelin-2 P37802 Details Zyxin Q15942 Details Survival motor neuron protein B4DP61 Details Myosin-9 P35579 Details Splicing factor 3B subunit 1 O75533 Details Serine/threonine-protein kinase 3 Q13188 Details Tyrosine-protein kinase Tec P42680 Details Serine/threonine-protein kinase 38 Q15208 Details STE20/SPS1-related proline-alanine-rich protein kinase Q9UEW8 Details Serine/threonine-protein kinase TAO1 Q7L7X3 Details Serine/threonine-protein kinase tousled-like 1 Q9UKI8 Details Serine/threonine-protein kinase tousled-like 2 Q86UE8 Details Serine/threonine-protein kinase ULK1 O75385 Details AP2-associated protein kinase 1 Q2M2I8 Details BMP-2-inducible protein kinase Q9NSY1 Details Citron Rho-interacting kinase O14578 Details Interferon-induced, double-stranded RNA-activated protein kinase P19525 Details Cyclin-G-associated kinase O14976 Details Glycogen synthase kinase-3 alpha P49840 Details Serine/threonine-protein kinase SIK3 Q9Y2K2 Details Serine/threonine-protein kinase LATS1 O95835 Details Mitogen-activated protein kinase kinase kinase 10 Q02779 Details Mitogen-activated protein kinase kinase kinase 11 Q16584 Details Mitogen-activated protein kinase kinase kinase 12 Q12852 Details Mitogen-activated protein kinase kinase kinase 3 Q99759 Details Mitogen-activated protein kinase kinase kinase 4 Q9Y6R4 Details Mitogen-activated protein kinase kinase kinase kinase 1 Q92918 Details Mitogen-activated protein kinase kinase kinase kinase 2 Q12851 Details Mitogen-activated protein kinase kinase kinase kinase 4 O95819 Details MAP kinase-activated protein kinase 5 Q8IW41 Details MAP/microtubule affinity-regulating kinase 3 P27448 Details CLIP-associating protein 1 Q7Z460 Details Megakaryocyte-associated tyrosine-protein kinase P42679 Details Maternal embryonic leucine zipper kinase Q14680 Details Misshapen-like kinase 1 Q8N4C8 Details MAP kinase-interacting serine/threonine-protein kinase 2 Q9HBH9 Details Serine/threonine-protein kinase Nek4 P51957 Details Serine/threonine-protein kinase Nek9 Q8TD19 Details Serine/threonine-protein kinase OSR1 O95747 Details Serine/threonine-protein kinase PAK 1 Q13153 Details Serine/threonine-protein kinase PAK 2 Q13177 Details Serine/threonine-protein kinase PAK 4 O96013 Details Cyclin-dependent kinase 17 Q00537 Details Phosphatidylinositol 4-kinase beta Q9UBF8 Details Serine/threonine-protein kinase N1 Q16512 Details Serine/threonine-protein kinase N2 Q16513 Details Serine/threonine-protein kinase PRP4 homolog Q13523 Details Serine/threonine-protein kinase RIO1 Q9BRS2 Details Serine/threonine-protein kinase RIO2 Q9BVS4 Details Serine/threonine-protein kinase SIK2 Q9H0K1 Details SNF-related serine/threonine-protein kinase Q9NRH2 Details Serine/threonine-protein kinase 10 O94804 Details Histone-lysine N-methyltransferase EZH2 Q15910 Details Phosphoglycerate kinase 2 P07205 Details Mitogen-activated protein kinase 6 Q16659 Details NAD-dependent protein deacetylase sirtuin-2 Q8IXJ6 Details Sulfotransferase 4A1 Q9BR01 Details Voltage-gated potassium channel subunit beta-2 Q13303 Details Plasma membrane ascorbate-dependent reductase CYBRD1 Q53TN4 Details ATP-citrate synthase P53396 Details Solute carrier family 23 member 2 Q9UGH3 Details Sodium-coupled neutral amino acid symporter 2 Q96QD8 Details Zinc transporter ZIP3 Q9BRY0 Details Tyrosine-protein phosphatase non-receptor type 6 P29350 Details Molybdopterin synthase catalytic subunit O96007 Details Eukaryotic translation initiation factor 4E-binding protein 1 Q13541 Details 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 P16885 Details Lysine-specific histone demethylase 1A O60341 Details Signal transducer and activator of transcription 1-alpha/beta P42224 Details Proliferation marker protein Ki-67 P46013 Details G1/S-specific cyclin-D3 P30281 Details Histone acetyltransferase p300 Q09472 Details ELAV-like protein 1 Q15717 Details cAMP-dependent protein kinase type I-beta regulatory subunit P31321 Details Bcl-2-like protein 11 O43521 Details