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
NameUniProt ID
Voltage-dependent T-type calcium channel subunit alpha-1IQ9P0X4Details
Tyrosine-protein kinase ABL1P00519Details
NADH dehydrogenase [ubiquinone] flavoprotein 3, mitochondrialP56181Details
7-dehydrocholesterol reductaseQ9UBM7Details
RAF proto-oncogene serine/threonine-protein kinaseP04049Details
TransketolaseP29401Details
Coagulation factor VP12259Details
L-lactate dehydrogenase B chainP07195Details
Pyruvate kinase PKMP14618Details
Voltage-gated inwardly rectifying potassium channel KCNH2Q12809Details
Organic cation/carnitine transporter 2O76082Details
Solute carrier family 12 member 6Q9UHW9Details
DNA ligase 3P49916Details
Bifunctional glutamate/proline--tRNA ligaseP07814Details
DNA ligase 1P18858Details
Neutral amino acid transporter B(0)Q15758Details
5'-AMP-activated protein kinase subunit beta-1Q9Y478Details
T-cell surface glycoprotein CD3 epsilon chainP07766Details
Solute carrier family 12 member 7Q9Y666Details
GMP synthase [glutamine-hydrolyzing]P49915Details
Thymidylate synthaseP04818Details
Peroxisomal multifunctional enzyme type 2P51659Details
L-lactate dehydrogenase A chainP00338Details
Serine/threonine-protein kinase A-RafP10398Details
Tyrosine-protein kinase ABL2P42684Details
Neutral amino acid transporter AP43007Details
AlbuminP02768Details
Chromodomain-helicase-DNA-binding protein 1O14646Details
Glyceraldehyde-3-phosphate dehydrogenaseP04406Details
DNA polymerase alpha catalytic subunitP09884Details
Integrin alpha-4P13612Details
Solute carrier family 12 member 4Q9UP95Details
Choline-phosphate cytidylyltransferase AP49585Details
Acetyl-CoA carboxylase 1Q13085Details
3',5'-cyclic-AMP phosphodiesterase 7BQ9NP56Details
Serine/threonine-protein kinase B-rafP15056Details
NADH-ubiquinone oxidoreductase chain 2P03891Details
Interferon alpha/beta receptor 1P17181Details
5'-AMP-activated protein kinase catalytic subunit alpha-1Q13131Details
DNA polymerase alpha subunit BQ14181Details
Sodium/potassium-transporting ATPase subunit alpha-1P05023Details
Biliverdin reductase AP53004Details
DNA topoisomerase 2-alphaP11388Details
Sodium/hydrogen exchanger 1P19634Details
5'-AMP-activated protein kinase subunit beta-2O43741Details
Sphingosine-1-phosphate lyase 1O95470Details
Malate dehydrogenase, mitochondrialP40926Details
Multidrug resistance-associated protein 1P33527Details
Glucocorticoid receptorP04150Details
Proto-oncogene tyrosine-protein kinase SrcP12931Details
Tyrosine-protein kinase LckP06239Details
CTP synthase 1P17812Details
Histone deacetylase 9Q9UKV0Details
Signal transducer and activator of transcription 5BP51692Details
DNA (cytosine-5)-methyltransferase 1P26358Details
Growth factor receptor-bound protein 2P62993Details
Mitogen-activated protein kinase 1P28482Details
Phosphatidylinositol 3-kinase regulatory subunit alphaP27986Details
Cyclic AMP-responsive element-binding protein 1P16220Details
Insulin receptor substrate 1P35568Details
Catenin beta-1P35222Details
Thiopurine S-methyltransferaseP51580Details
Synaptic vesicle glycoprotein 2AQ7L0J3Details
Phospholipid-transporting ATPase IAQ9Y2Q0Details
E3 ubiquitin-protein ligase Mdm2Q00987Details
CalnexinP27824Details
Rho-associated protein kinase 1Q13464Details
Mitogen-activated protein kinase 14Q16539Details
Transcription factor JunP05412Details
GTP cyclohydrolase 1P30793Details
Mitogen-activated protein kinase 3P27361Details
Glycogen synthase kinase-3 betaP49841Details
Tyrosine-protein phosphatase non-receptor type 11Q06124Details
Cyclin-dependent kinase 2P24941Details
Cyclin-dependent kinase 1P06493Details
Nuclear factor NF-kappa-B p105 subunitP19838Details
CD44 antigenP16070Details
Heat shock protein HSP 90-alphaP07900Details
Protein c-FosP01100Details
Protein kinase C alpha typeP17252Details
3',5'-cyclic-AMP phosphodiesterase 4AP27815Details
Inositol monophosphatase 1P29218Details
Inhibitor of nuclear factor kappa-B kinase subunit betaO14920Details
Microtubule-associated protein 1AP78559Details
RAC-beta serine/threonine-protein kinaseP31751Details
14-3-3 protein zeta/deltaP63104Details
Phosphatidylethanolamine-binding protein 1P30086Details
ATP-binding cassette sub-family C member 4O15439Details
3-phosphoinositide-dependent protein kinase 1O15530Details
Glucose-6-phosphate isomeraseP06744Details
Protein-glutamine gamma-glutamyltransferase EQ08188Details
Tyrosine-protein kinase ZAP-70P43403Details
Tyrosine-protein kinase SYKP43405Details
Tyrosine-protein kinase ITK/TSKQ08881Details
Protein kinase C theta typeQ04759Details
Tubulin alpha-1C chainQ9BQE3Details
DNA repair protein XRCC4Q13426Details
Fructose-bisphosphate aldolase AP04075Details
M-phase inducer phosphatase 2P30305Details
Poly [ADP-ribose] polymerase 1P09874Details
Cyclin-dependent kinase 7P50613Details
Thioredoxin reductase 1, cytoplasmicQ16881Details
Cytokine receptor common subunit gammaP31785Details
Laminin subunit alpha-5O15230Details
Retinoblastoma-associated proteinP06400Details
Cyanocobalamin reductase / alkylcobalamin dealkylaseQ9Y4U1Details
Methionine adenosyltransferase 2 subunit betaQ9NZL9Details
Cyclin-dependent kinase 6Q00534Details
Adenosine deaminaseP00813Details
Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetaseP22234Details
Multifunctional protein CADP27708Details
Phosphoribosylformylglycinamidine synthaseO15067Details
N-acetyl-D-glucosamine kinaseQ9UJ70Details
Peptidyl-prolyl cis-trans isomerase GQ13427Details
Histone deacetylase 1Q13547Details
Histone deacetylase 2Q92769Details
Histone deacetylase 3O15379Details
Phosphatidylinositol 3-kinase regulatory subunit betaO00459Details
DNA-dependent protein kinase catalytic subunitP78527Details
Protein kinase C delta typeQ05655Details
DNA topoisomerase 2-betaQ02880Details
Ribonucleoside-diphosphate reductase subunit M2P31350Details
E3 ubiquitin-protein ligase UBR4Q5T4S7Details
NAD-dependent protein deacetylase sirtuin-1Q96EB6Details
Telomerase-binding protein EST1AQ86US8Details
Prostaglandin E synthase 3Q15185Details
Actin nucleation-promoting factor WASP42768Details
GephyrinQ9NQX3Details
Anthrax toxin receptor 2P58335Details
Pleckstrin homology domain-containing family A member 1Q9HB21Details
Casein kinase I isoform gamma-2P78368Details
Wee1-like protein kinaseP30291Details
Serine/threonine-protein kinase Chk1O14757Details
Tubulin beta-6 chainQ9BUF5Details
Bcl-2-like protein 2Q92843Details
Bcl2-associated agonist of cell deathQ92934Details
Far upstream element-binding protein 1Q96AE4Details
cAMP-dependent protein kinase type II-alpha regulatory subunitP13861Details
cAMP-dependent protein kinase type I-alpha regulatory subunitP10644Details
T-cell surface glycoprotein CD3 delta chainP04234Details
T-cell surface glycoprotein CD3 gamma chainP09693Details
T-cell surface glycoprotein CD3 zeta chainP20963Details
Microtubule-associated protein 4P27816Details
Sarcoplasmic/endoplasmic reticulum calcium ATPase 2P16615Details
Tumor necrosis factor receptor superfamily member 8P28908Details
Tyrosine-protein kinase JAK3P52333Details
Transmembrane anterior posterior transformation protein 1 homologQ6NXT6Details
Casein kinase I isoform epsilonP49674Details
Heat shock factor protein 1Q00613Details
Histone deacetylase 4P56524Details
Histone deacetylase 7Q8WUI4Details
Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11AQ9HCR9Details
Serum paraoxonase/lactonase 3Q15166Details
Receptor-type tyrosine-protein phosphatase epsilonP23469Details
Integrin beta-1P05556Details
NischarinQ9Y2I1Details
Cation-independent mannose-6-phosphate receptorP11717Details
Copper-transporting ATPase 1Q04656Details
Nuclear receptor coactivator 2Q15596Details
cAMP-dependent protein kinase catalytic subunit alphaP17612Details
Uracil-DNA glycosylaseP13051Details
Heat shock cognate 71 kDa proteinP11142Details
Dual specificity protein kinase TTKP33981Details
Endothelin-converting enzyme 1P42892Details
Serine/threonine-protein kinase haspinQ8TF76Details
Inner centromere proteinQ9NQS7Details
Large ribosomal subunit protein eL37P61927Details
Triosephosphate isomeraseP60174Details
Protein kinase C iota typeP41743Details
Proteasome subunit alpha type-2P25787Details
Proteasome subunit alpha type-3P25788Details
Proteasome subunit alpha type-5P28066Details
Dual specificity tyrosine-phosphorylation-regulated kinase 1AQ13627Details
STE20-like serine/threonine-protein kinaseQ9H2G2Details
Calcium/calmodulin-dependent protein kinase type IVQ16566Details
Dual specificity protein kinase CLK3P49761Details
Nuclear receptor coactivator 5Q9HCD5Details
Hydroxymethylglutaryl-CoA synthase, cytoplasmicQ01581Details
Calcium/calmodulin-dependent protein kinase type II subunit deltaQ13557Details
Serine/threonine-protein kinase 26Q9P289Details
Profilin-1P07737Details
Myocardin-related transcription factor AQ969V6Details
Cofilin-1P23528Details
Rho-associated protein kinase 2O75116Details
Actin-related protein 2/3 complex subunit 1BO15143Details
Actin-related protein 2/3 complex subunit 3O15145Details
SRSF protein kinase 2P78362Details
Serine/threonine-protein kinase 17BO94768Details
AfadinP55196Details
Interleukin-1 receptor-associated kinase 4Q9NWZ3Details
CREB-binding proteinQ92793Details
Mediator of RNA polymerase II transcription subunit 1Q15648Details
Protein arginine N-methyltransferase 3O60678Details
Epsin-1Q9Y6I3Details
Phosphoglucomutase-1P36871Details
VimentinP08670Details
cAMP-dependent protein kinase catalytic subunit betaP22694Details
Ras-related protein Rab-8BQ92930Details
cAMP-dependent protein kinase type II-beta regulatory subunitP31323Details
Poly(A) polymerase alphaP51003Details
3-ketoacyl-CoA thiolase, peroxisomalP09110Details
NAD-dependent protein deacetylase sirtuin-3, mitochondrialQ9NTG7Details
T-complex protein 1 subunit gammaP49368Details
Carboxypeptidase DO75976Details
Transitional endoplasmic reticulum ATPaseP55072Details
Ubiquitin-like modifier-activating enzyme 1P22314Details
Histone acetyltransferase KAT5Q92993Details
SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5O60264Details
Uridine-cytidine kinase-like 1Q9NWZ5Details
Spectrin beta chain, non-erythrocytic 1Q01082Details
Kinesin-like protein KIF2CQ99661Details
Acetylcholine receptor subunit alphaP02708Details
Sodium bicarbonate cotransporter 3Q9Y6M7Details
Breakpoint cluster region proteinP11274Details
Dual specificity mitogen-activated protein kinase kinase 2P36507Details
Mitogen-activated protein kinase kinase kinase 2Q9Y2U5Details
RalA-binding protein 1Q15311Details
5'(3')-deoxyribonucleotidase, cytosolic typeQ8TCD5Details
Transferrin receptor protein 1P02786Details
Ribosomal protein S6 kinase alpha-3P51812Details
Membrane-associated progesterone receptor component 1O00264Details
Inositol 1,4,5-trisphosphate-gated calcium channel ITPR3Q14573Details
Cyclic AMP-dependent transcription factor ATF-1P18846Details
Cyclic AMP-dependent transcription factor ATF-2P15336Details
Complement component 1 Q subcomponent-binding protein, mitochondrialQ07021Details
Mitogen-activated protein kinase kinase kinase 20Q9NYL2Details
Alpha-enolaseP06733Details
Protein PMLP29590Details
Nucleolar and coiled-body phosphoprotein 1Q14978Details
TGF-beta-activated kinase 1 and MAP3K7-binding protein 1Q15750Details
Protein O-GlcNAcaseO60502Details
UtrophinP46939Details
Nucleobindin-2P80303Details
Calmodulin-2P0DP24Details
Calmodulin-3P0DP25Details
60 kDa heat shock protein, mitochondrialP10809Details
Small ribosomal subunit protein uS5P15880Details
Heterogeneous nuclear ribonucleoproteins A2/B1P22626Details
Heterogeneous nuclear ribonucleoprotein HP31943Details
Heterogeneous nuclear ribonucleoprotein H3P31942Details
Splicing factor, proline- and glutamine-richP23246Details
Eukaryotic translation initiation factor 6P56537Details
14-3-3 protein beta/alphaP31946Details
Hepatoma-derived growth factorP51858Details
Phosphoglycerate mutase 1P18669Details
Ran-specific GTPase-activating proteinP43487Details
Protein disulfide-isomerase A3P30101Details
Phosphatidylinositol 4-kinase type 2-betaQ8TCG2Details
HuntingtinP42858Details
Lymphoid enhancer-binding factor 1Q9UJU2Details
Eukaryotic translation initiation factor 3 subunit FO00303Details
Heterogeneous nuclear ribonucleoprotein KP61978Details
Heat shock 70 kDa protein 4P34932Details
Splicing factor 3A subunit 3Q12874Details
SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1Q969G3Details
Tumor protein D54O43399Details
Ubiquitin carboxyl-terminal hydrolase 14P54578Details
14-3-3 protein etaQ04917Details
14-3-3 protein thetaP27348Details
Chromobox protein homolog 5P45973Details
Keratin, type II cytoskeletal 1P04264Details
DesmoplakinP15924Details
HornerinQ86YZ3Details
KAT8 regulatory NSL complex subunit 3Q9P2N6Details
Far upstream element-binding protein 2Q92945Details
Cysteine and glycine-rich protein 1P21291Details
Filamin-AP21333Details
Heterogeneous nuclear ribonucleoprotein D0Q14103Details
Heterochromatin protein 1-binding protein 3Q5SSJ5Details
NucleophosminP06748Details
Large ribosomal subunit protein eL14P50914Details
Small ribosomal subunit protein eS17P08708Details
Small ribosomal subunit protein eS8P62241Details
Splicing factor 1Q15637Details
Transgelin-2P37802Details
ZyxinQ15942Details
Survival motor neuron proteinB4DP61Details
Myosin-9P35579Details
Splicing factor 3B subunit 1O75533Details
Serine/threonine-protein kinase 3Q13188Details
Tyrosine-protein kinase TecP42680Details
Serine/threonine-protein kinase 38Q15208Details
STE20/SPS1-related proline-alanine-rich protein kinaseQ9UEW8Details
Serine/threonine-protein kinase TAO1Q7L7X3Details
Serine/threonine-protein kinase tousled-like 1Q9UKI8Details
Serine/threonine-protein kinase tousled-like 2Q86UE8Details
Serine/threonine-protein kinase ULK1O75385Details
AP2-associated protein kinase 1Q2M2I8Details
BMP-2-inducible protein kinaseQ9NSY1Details
Citron Rho-interacting kinaseO14578Details
Interferon-induced, double-stranded RNA-activated protein kinaseP19525Details
Cyclin-G-associated kinaseO14976Details
Glycogen synthase kinase-3 alphaP49840Details
Serine/threonine-protein kinase SIK3Q9Y2K2Details
Serine/threonine-protein kinase LATS1O95835Details
Mitogen-activated protein kinase kinase kinase 10Q02779Details
Mitogen-activated protein kinase kinase kinase 11Q16584Details
Mitogen-activated protein kinase kinase kinase 12Q12852Details
Mitogen-activated protein kinase kinase kinase 3Q99759Details
Mitogen-activated protein kinase kinase kinase 4Q9Y6R4Details
Mitogen-activated protein kinase kinase kinase kinase 1Q92918Details
Mitogen-activated protein kinase kinase kinase kinase 2Q12851Details
Mitogen-activated protein kinase kinase kinase kinase 4O95819Details
MAP kinase-activated protein kinase 5Q8IW41Details
MAP/microtubule affinity-regulating kinase 3P27448Details
CLIP-associating protein 1Q7Z460Details
Megakaryocyte-associated tyrosine-protein kinaseP42679Details
Maternal embryonic leucine zipper kinaseQ14680Details
Misshapen-like kinase 1Q8N4C8Details
MAP kinase-interacting serine/threonine-protein kinase 2Q9HBH9Details
Serine/threonine-protein kinase Nek4P51957Details
Serine/threonine-protein kinase Nek9Q8TD19Details
Serine/threonine-protein kinase OSR1O95747Details
Serine/threonine-protein kinase PAK 1Q13153Details
Serine/threonine-protein kinase PAK 2Q13177Details
Serine/threonine-protein kinase PAK 4O96013Details
Cyclin-dependent kinase 17Q00537Details
Phosphatidylinositol 4-kinase betaQ9UBF8Details
Serine/threonine-protein kinase N1Q16512Details
Serine/threonine-protein kinase N2Q16513Details
Serine/threonine-protein kinase PRP4 homologQ13523Details
Serine/threonine-protein kinase RIO1Q9BRS2Details
Serine/threonine-protein kinase RIO2Q9BVS4Details
Serine/threonine-protein kinase SIK2Q9H0K1Details
SNF-related serine/threonine-protein kinaseQ9NRH2Details
Serine/threonine-protein kinase 10O94804Details
Histone-lysine N-methyltransferase EZH2Q15910Details
Phosphoglycerate kinase 2P07205Details
Mitogen-activated protein kinase 6Q16659Details
NAD-dependent protein deacetylase sirtuin-2Q8IXJ6Details
Sulfotransferase 4A1Q9BR01Details
Voltage-gated potassium channel subunit beta-2Q13303Details
Plasma membrane ascorbate-dependent reductase CYBRD1Q53TN4Details
ATP-citrate synthaseP53396Details
Solute carrier family 23 member 2Q9UGH3Details
Sodium-coupled neutral amino acid symporter 2Q96QD8Details
Zinc transporter ZIP3Q9BRY0Details
Tyrosine-protein phosphatase non-receptor type 6P29350Details
Molybdopterin synthase catalytic subunitO96007Details
Eukaryotic translation initiation factor 4E-binding protein 1Q13541Details
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2P16885Details
Lysine-specific histone demethylase 1AO60341Details
Signal transducer and activator of transcription 1-alpha/betaP42224Details
Proliferation marker protein Ki-67P46013Details
G1/S-specific cyclin-D3P30281Details
Histone acetyltransferase p300Q09472Details
ELAV-like protein 1Q15717Details
cAMP-dependent protein kinase type I-beta regulatory subunitP31321Details
Bcl-2-like protein 11O43521Details