Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.

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Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M

Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.

Cell. 2006 Nov 3;127(3):635-48.

PubMed ID
17081983 [ View in PubMed
]
Abstract

Cell signaling mechanisms often transmit information via posttranslational protein modifications, most importantly reversible protein phosphorylation. Here we develop and apply a general mass spectrometric technology for identification and quantitation of phosphorylation sites as a function of stimulus, time, and subcellular location. We have detected 6,600 phosphorylation sites on 2,244 proteins and have determined their temporal dynamics after stimulating HeLa cells with epidermal growth factor (EGF) and recorded them in the Phosida database. Fourteen percent of phosphorylation sites are modulated at least 2-fold by EGF, and these were classified by their temporal profiles. Surprisingly, a majority of proteins contain multiple phosphorylation sites showing different kinetics, suggesting that they serve as platforms for integrating signals. In addition to protein kinase cascades, the targets of reversible phosphorylation include ubiquitin ligases, guanine nucleotide exchange factors, and at least 46 different transcriptional regulators. The dynamic phosphoproteome provides a missing link in a global, integrative view of cellular regulation.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Tyrosine-protein kinase ABL1P00519Details
Pyruvate kinase PKMP14618Details
DNA ligase 3P49916Details
Monocarboxylate transporter 7O15403Details
Bifunctional glutamate/proline--tRNA ligaseP07814Details
DNA ligase 1P18858Details
Neutral amino acid transporter B(0)Q15758Details
Ferritin heavy chainP02794Details
RAC-alpha serine/threonine-protein kinaseP31749Details
Serine/threonine-protein kinase A-RafP10398Details
Monocarboxylate transporter 4O15427Details
Receptor tyrosine-protein kinase erbB-2P04626Details
Chromodomain-helicase-DNA-binding protein 1O14646Details
Glyceraldehyde-3-phosphate dehydrogenaseP04406Details
Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrialP08559Details
Choline-phosphate cytidylyltransferase AP49585Details
Acetyl-CoA carboxylase 1Q13085Details
Cytosolic phospholipase A2P47712Details
Monocarboxylate transporter 1P53985Details
Inosine-5'-monophosphate dehydrogenase 2P12268Details
Heme oxygenase 1P09601Details
DNA topoisomerase 2-alphaP11388Details
Epidermal growth factor receptorP00533Details
Activated CDC42 kinase 1Q07912Details
Multidrug resistance-associated protein 1P33527Details
CTP synthase 1P17812Details
DNA (cytosine-5)-methyltransferase 1P26358Details
CalpastatinP20810Details
Growth factor receptor-bound protein 2P62993Details
C-X-C chemokine receptor type 4P61073Details
Mitogen-activated protein kinase 1P28482Details
DNA topoisomerase 1P11387Details
Insulin receptor substrate 1P35568Details
Catenin beta-1P35222Details
CalnexinP27824Details
Mitogen-activated protein kinase 3P27361Details
Phosphatidylserine synthase 1P48651Details
Microtubule-associated protein 2P11137Details
CD44 antigenP16070Details
Heat shock protein HSP 90-alphaP07900Details
Protein kinase C alpha typeP17252Details
Microtubule-associated protein 1AP78559Details
14-3-3 protein zeta/deltaP63104Details
Phosphatidylethanolamine-binding protein 1P30086Details
FibronectinP02751Details
Multidrug resistance-associated protein 4O15439Details
Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrialP33316Details
cAMP-specific 3',5'-cyclic phosphodiesterase 4DQ08499Details
Tubulin alpha-1C chainQ9BQE3Details
Fructose-bisphosphate aldolase AP04075Details
Ras-related protein Rab-9AP51151Details
Dual specificity protein kinase CLK1P49759Details
Heat shock protein HSP 90-betaP08238Details
Keratin, type II cytoskeletal 8P05787Details
Synaptotagmin-like protein 4Q96C24Details
Pyridoxal-dependent decarboxylase domain-containing protein 1Q6P996Details
Phospholipase D1Q13393Details
Peptidyl-glycine alpha-amidating monooxygenaseP19021Details
CAD proteinP27708Details
Phosphoribosylformylglycinamidine synthaseO15067Details
Phosphatidylserine synthase 2Q9BVG9Details
Peptidyl-prolyl cis-trans isomerase GQ13427Details
Histone deacetylase 1Q13547Details
Histone deacetylase 2Q92769Details
Histone deacetylase 3O15379Details
Protein farnesyltransferase subunit betaP49356Details
DNA-dependent protein kinase catalytic subunitP78527Details
DNA topoisomerase 2-betaQ02880Details
Keratin, type II cytoskeletal 7P08729Details
Voltage-dependent anion-selective channel protein 1P21796Details
Voltage-dependent anion-selective channel protein 2P45880Details
N-terminal kinase-like proteinQ96KG9Details
Prostaglandin E synthase 3Q15185Details
Focal adhesion kinase 1Q05397Details
Far upstream element-binding protein 1Q96AE4Details
cAMP-dependent protein kinase type II-alpha regulatory subunitP13861Details
cAMP-dependent protein kinase type I-alpha regulatory subunitP10644Details
Heat shock protein beta-1P04792Details
Anthrax toxin receptor 1Q9H6X2Details
Ribosome-binding protein 1Q9P2E9Details
Microtubule-associated protein 4P27816Details
Sarcoplasmic/endoplasmic reticulum calcium ATPase 2P16615Details
Heat shock factor protein 1Q00613Details
Integrin alpha-VP06756Details
Cation-independent mannose-6-phosphate receptorP11717Details
Probable low affinity copper uptake protein 2O15432Details
Disintegrin and metalloproteinase domain-containing protein 17P78536Details
Uracil-DNA glycosylaseP13051Details
Endothelin-converting enzyme 1P42892Details
Inner centromere proteinQ9NQS7Details
60S ribosomal protein L23aP62750Details
Triosephosphate isomeraseP60174Details
Cytochrome b-c1 complex subunit 6, mitochondrialP07919Details
Proteasome subunit alpha type-3P25788Details
Proteasome subunit alpha type-5P28066Details
Casein kinase I isoform gamma-3Q9Y6M4Details
Dual specificity protein kinase CLK3P49761Details
Nuclear receptor coactivator 5Q9HCD5Details
Cyclin-dependent kinase 16Q00536Details
Peroxisomal acyl-coenzyme A oxidase 1Q15067Details
MKL/myocardin-like protein 1Q969V6Details
DestrinP60981Details
Cofilin-1P23528Details
Actin-related protein 2/3 complex subunit 1BO15143Details
Elongation factor 2P13639Details
Mediator of RNA polymerase II transcription subunit 1Q15648Details
Epsin-1Q9Y6I3Details
Phosphoglycerate kinase 1P00558Details
Phosphoglucomutase-1P36871Details
VimentinP08670Details
Inositol 1,4,5-trisphosphate receptor type 1Q14643Details
[3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase, mitochondrialO14874Details
Sorting nexin-3O60493Details
SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5O60264Details
Spectrin beta chain, non-erythrocytic 1Q01082Details
Sodium bicarbonate cotransporter 3Q9Y6M7Details
Myc proto-oncogene proteinP01106Details
Breakpoint cluster region proteinP11274Details
Dual specificity mitogen-activated protein kinase kinase 2P36507Details
Mitogen-activated protein kinase kinase kinase 2Q9Y2U5Details
RalA-binding protein 1Q15311Details
Membrane-associated progesterone receptor component 1O00264Details
Histone H1.4P10412Details
Casein kinase II subunit betaP67870Details
Protein PMLP29590Details
Nucleolar and coiled-body phosphoprotein 1Q14978Details
UtrophinP46939Details
Proprotein convertase subtilisin/kexin type 9Q8NBP7Details
Heterogeneous nuclear ribonucleoprotein HP31943Details
Heterogeneous nuclear ribonucleoprotein H3P31942Details
Hepatoma-derived growth factorP51858Details
Cap-specific mRNA (nucleoside-2'-O-)-methyltransferase 1Q8N1G2Details
Neural cell adhesion molecule L1P32004Details
Heterogeneous nuclear ribonucleoprotein KP61978Details
Heat shock protein 105 kDaQ92598Details
Nuclear migration protein nudCQ9Y266Details
Tumor protein D54O43399Details
14-3-3 protein thetaP27348Details
Chromobox protein homolog 5P45973Details
Junction plakoglobinP14923Details
Far upstream element-binding protein 2Q92945Details
Cysteine and glycine-rich protein 1P21291Details
Filamin-AP21333Details
Heterogeneous nuclear ribonucleoprotein D0Q14103Details
Heterochromatin protein 1-binding protein 3Q5SSJ5Details
Ras GTPase-activating-like protein IQGAP1P46940Details
NucleophosminP06748Details
60S ribosomal protein L14P50914Details
40S ribosomal protein S6P62753Details
Splicing factor 1Q15637Details
Serine/arginine-rich splicing factor 4Q08170Details
ZyxinQ15942Details
Serine/arginine-rich splicing factor 1Q07955Details
Survival motor neuron proteinB4DP61Details
Myosin-9P35579Details
Splicing factor 3B subunit 1O75533Details
Serine/threonine-protein kinase 24Q9Y6E0Details
Non-receptor tyrosine-protein kinase TNK1Q13470Details
AP2-associated protein kinase 1Q2M2I8Details
BMP-2-inducible protein kinaseQ9NSY1Details
Dual specificity protein kinase CLK4Q9HAZ1Details
eIF-2-alpha kinase GCN2Q9P2K8Details
Serine/threonine-protein kinase MARK2Q7KZI7Details
Maternal embryonic leucine zipper kinaseQ14680Details
Misshapen-like kinase 1Q8N4C8Details
Serine/threonine-protein kinase OSR1O95747Details
Serine/threonine-protein kinase PAK 2Q13177Details
Serine/threonine-protein kinase PAK 4O96013Details
Phosphatidylinositol 4-kinase betaQ9UBF8Details
Serine/threonine-protein kinase N2Q16513Details
Serine/threonine-protein kinase PRP4 homologQ13523Details
Serine/threonine-protein kinase RIO2Q9BVS4Details
Histone-lysine N-methyltransferase EZH2Q15910Details
NAD-dependent protein deacetylase sirtuin-2Q8IXJ6Details
DystrophinP11532Details
Cytochrome b reductase 1Q53TN4Details
ATP-citrate synthaseP53396Details
Sodium-coupled neutral amino acid transporter 1Q9H2H9Details
DNA (cytosine-5)-methyltransferase 3AQ9Y6K1Details
Zinc transporter 1Q9Y6M5Details
Plasma membrane calcium-transporting ATPase 1P20020Details
Interleukin-6 receptor subunit betaP40189Details
Receptor protein-tyrosine kinaseQ504U8Details
Eukaryotic translation initiation factor 4E-binding protein 1Q13541Details
Lysine-specific histone demethylase 1AO60341Details
Proliferation marker protein Ki-67P46013Details
ELAV-like protein 1Q15717Details