Prideapplication/xmlftp://ftp.pride.ebi.ac.uk/pride/data/archive/2018/07/PXD009662/QuantpYfiles.xlsxftp://ftp.pride.ebi.ac.uk/pride/data/archive/2018/07/PXD009662/Q741XRAWDATA.zipftp://ftp.pride.ebi.ac.uk/pride/data/archive/2018/07/PXD009662/SearchEngineOutput.zipftp://ftp.pride.ebi.ac.uk/pride/data/archive/2018/07/PXD009662/T618IRAWDATA.zipftp://ftp.pride.ebi.ac.uk/pride/data/archive/2018/07/PXD009662/WTRAWDATA.zipprimaryOK200004360greiskd@ucmail.uc.eduPankaj DwivediMass SpectrometryShotgun proteomicsAcute LeukemiaNot availableCnlAmlRuxolitinibPhosphoproteomicsLc-ms/msSilacIbrutinibhttp://www.ebi.ac.uk/pride/archive/projects/PXD009662B CellCell Suspension Culture. In summary, a retroviral transduction approach was used with BaF3 cells to set-up an in vitro model system expressing WT, T618I, and Q741x G-CSFRs expressing cells. SILAC labelling was used to culture the transduced BaF3 cells in ‘light’ SILAC medium (containing C-12, N-14 Lysine and Arginine) and ‘heavy’ SILAC medium (containing C-13, N-15 Lysine and Arginine). After mixing the comparative samples and digesting them with trypsin, the SILAC-labelled peptides were further enriched for phospho-tyrosine using immobilized pY-1000 phosphotyrosine antibodies peptides as previously described (15-17). Enriched phospho-peptides were analyzed on a TripleTOF 5600+ MS (Sciex, Concord, ON, Canada) coupled to an Eksigent (Dublin, CA) nanoLC Ultra nanoflow system.PrideSILACphosphorylated residue. In summary, a retroviral transduction approach was used with BaF3 cells to set-up an in vitro model system expressing WT, T618I, and Q741x G-CSFRs expressing cells. SILAC labelling was used to culture the transduced BaF3 cells in ‘light’ SILAC medium (containing C-12, N-14 Lysine and Arginine) and ‘heavy’ SILAC medium (containing C-13, N-15 Lysine and Arginine). After mixing the comparative samples and digesting them with trypsin, the SILAC-labelled peptides were further enriched for phospho-tyrosine using immobilized pY-1000 phosphotyrosine antibodies peptides as previously described (15-17). Enriched phospho-peptides were analyzed on a TripleTOF 5600+ MS (Sciex, Concord, ON, Canada) coupled to an Eksigent (Dublin, CA) nanoLC Ultra nanoflow system.ProteomicsKenneth GreisTripleTOF 5600PARTIALDepartment of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45267Mus Musculus (mouse)30967555 Dwivedi P, Muench DE, Wagner M, Azam M, Grimes HL, Greis KD. Phospho serine and threonine analysis of normal and mutated granulocyte colony stimulating factor receptors. Sci Data. 2019 6(1):21 10.1038/s41597-019-0015-829977015 Dwivedi P, Muench DE, Wagner M, Azam M, Grimes HL, Greis KD. Time resolved quantitative phospho-tyrosine analysis reveals Bruton's Tyrosine kinase mediated signaling downstream of the mutated granulocyte-colony stimulating factor receptors. Leukemia. 2018 10.1038/s41375-018-0188-8dwivedpj@mail.uc.eduBiologicalUniversity of CincinnatiUnited StatesGranulocyte-colony stimulating factor receptor (G-CSFR) controls myeloid progenitor proliferation and differentiation to neutrophils. Mutations in CSF3R (encoding G-CSFR) have been reported in patients with chronic neutrophilic leukemia (CNL) and acute myeloid leukemia (AML); however, despite years of research, the malignant downstream signaling of the mutated G-CSFRs is not well understood. Here, we used a quantitative phospho-tyrosine analysis to generate a comprehensive signaling map of G-CSF induced tyrosine phosphorylation in the normal versus mutated (proximal: T618I and truncated: Q741x) G-CSFRs. Unbiased clustering and kinase enrichment analysis identified rapid induction of phospho-proteins associated with endocytosis by the wild type G-CSFR only; while G-CSFR mutants showed abnormal kinetics of canonical Stat3, Stat5, and Mapk phosphorylation, and aberrant activation of Bruton's Tyrosine Kinase (Btk). Mutant-G-CSFR-expressing cells displayed enhanced sensitivity (3-5-fold lower IC50) for ibrutinib-based chemical inhibition of Btk. Primary murine progenitor cells from G-CSFR-Q741x knock-in mice validated activation of Btk by the mutant receptor and retrovirally transduced human CD34<sup>+</sup> umbilical cord blood cells expressing mutant receptors displayed enhanced sensitivity to Ibrutinib. A significantly lower clonogenic potential was displayed by both murine and human primary cells expressing mutated receptors upon ibrutinib treatment. Finally, a dramatic synergy was observed between ibrutinib and ruxolinitib at lower dose of the individual drug. Altogether, these data demonstrate the strength of unsupervised proteomics analyses in dissecting oncogenic pathways, and suggest repositioning Ibrutinib for therapy of myeloid leukemia bearing CSF3R mutations. Phospho-tyrosine data are available via ProteomeXchange with identifier PXD009662.Granulocyte colony stimulating factor receptor (G-CSFR) plays an important role in the production of neutrophil granulocytes. Mutated G-CSFRs have been directly associated with two distinct malignant phenotypes in patients, e.g. acute myeloid leukemia (AML) and chronic neutrophilic leukemia (CNL). However, the signaling mechanism of the mutated G-CSFRs is not well understood. Here, we present a comprehensive SILAC-based quantitative phosphoserine and phosphothreonine dataset of the normal and mutated G-CSFRs signaling using the BaF3 cell-line-based in vitro model system. High pH reversed phase concatenation and Titanium Dioxide Spin Tip column were utilized to increase the dynamic range and detection of the phosphoproteome of G-CSFRs. The dataset was further analyzed using several computational tools to validate the quality of the dataset. Overall, this dataset is the first global phosphoproteomics analysis of both normal and disease-associated-mutant G-CSFRs. We anticipate that this dataset will have a strong potential to decipher the phospho-signaling differences between the normal and malignant G-CSFR biology with therapeutic implications. The phosphoproteomic dataset is available via the PRIDE partner repository.Phospho serine and threonine analysis of normal and mutated granulocyte colony stimulating factor receptors.Time resolved quantitative phospho-tyrosine analysis reveals Bruton's Tyrosine kinase mediated signaling downstream of the mutated granulocyte-colony stimulating factor receptors.Dwivedi Pankaj P, Muench David E DE, Wagner Michael M, Azam Mohammad M, Grimes H Leighton HL, Greis Kenneth D KDIPP2A2, para Tyrosine, d230, Beliefs, Lysine Hydrochloride, L-arginine, DL-Arginine Acetate, L Isomer, Monohydrate, dTAFII250, EfW1, body system, PHAPII, L-(+)-arginine, 5730420M11Rik, dmTAF[[II]]230, peptide, Polypeptides, Background, Lysine Acetate, peptido, template-activating factor I, (2S)-2-amino-5-(carbamimidamido)pentanoic acid, dmTAF1, Taf230, MOD_RES Phosphotyrosine, Cultural, 2, system, Lysine, Arg, NICR95, Backgrounds, L Lysine, TAF250, SET, Taf200, ethnicity, (S)-2-amino-5-guanidinopentanoic acid, anatomical systems, dTAF[[II]]250, TFIID TAF250, peptides, cel, TAF-I, K, cell, phosphatase 2A inhibitor I2PP2A, 2-amino-3-(4-hydroxyphenyl)propanoic acid, 3-(p-Hydroxyphenyl)alanine, ipp2a2, (S)-2-Amino-5-guanidinovaleric acid, beta-Trypsin, R, BaF3, epsilon-diaminocaproic acid, 2pp2a, Arginine, BaF3 cell, Taf1p, Cultural Relativisms, labeling, Monohydrate DL-Arginine Acetate, Y, CG10574, DmelCG4299, dTAF250, set, IGAAD, 2PP2A, LYS, DmelCG10574, L Tyrosine, taf-ibeta, Lysin, Tyr, dSET, dSet, Customs, L-Arg, peptidos, culture, Tyrosin, TAF, L-Arginin, phapii, dTAF[[II]]230, TAF[[II]]250, Phosphotyrosine, igaad, Arginine Hydrochloride, 2-Amino-3-(p-hydroxyphenyl)propionic acid, TAF200, StF-IT-1, arginine, l(3)84Ab, BG:DS00004.13, para-Tyrosine, TAFII-250, Cultural Backgrounds, TAF250/230, L-Isomer, antibodies, DL Arginine Acetate, Cell, Peptide, dTAF230, Belief, Tyrosine, polypeptide, TAFII250, Cultural Background, Cultures, I-2PP2A, L-Isomer Arginine, tirosina, Acetate, body system., p230, Tyrosine O phosphate, Dm I-2, I2PP2A, lysine, Hydrochloride, TAF[[II]]250/230, TFIID, L Arginine, connected anatomical system, L-Lysine, tyrosine, L-Arginine, Taf[[II]]250, TAF[[II]]230, HLA-DR-associated protein II, DI-2, I-2Dm, BaF3 细胞, (2S)-2-amino-5-guanidinopentanoic acid, L-isomer, Tripcellim, TAF[II]250, CG4299, alpha, inhibitor of granzyme A-activated DNase, CG17603, TAF[[II]], beta Trypsin, L isomer, I-2PP1, organ system, Trypure, dSET/TAF-Ibeta, 2610030F17Rik, DmelCG17603, TAF-IBETA, Taf250, SR3-5, dihydrogen phosphate (ester), Relativisms, Tyrosine-O-phosphate, Peptid, TAF-Ibeta, L-Tyrosine, Polypeptide, Relativism, AA407739, Cultural Relativism, 6-diaminohexanoic acid, L-tyrosine, i2pp2a, Enisyl, TAF230, TAF1Normalities, serine, average, Individual Health, Serine, Granulocyte, determination, granular leukocyte, Normality, typical plasmatocyte., L-Threonine, L Threonine, Normalcy, Normalcies, Pl, 2-Amino-3-hydroxypropionic acid, Serin, Health, 2-amino-3-hydroxypropanoic acid, 3-Hydroxyalanine, granular leucocyte, lamellocyte, macrophage, polymorphonuclear leukocyte, chemical analysis, granulocyte, L Serine, assay, threonine, Individual, podocyte, L-Serine, agranular plasmatocyte, ThreoninIPP2A2, para Tyrosine, d230, Beliefs, Lysine Hydrochloride, L-arginine, DL-Arginine Acetate, L Isomer, Monohydrate, dTAFII250, EfW1, body system, PHAPII, L-(+)-arginine, 5730420M11Rik, dmTAF[[II]]230, peptide, Polypeptides, Background, Lysine Acetate, peptido, template-activating factor I, (2S)-2-amino-5-(carbamimidamido)pentanoic acid, dmTAF1, Taf230, MOD_RES Phosphotyrosine, Cultural, 2, system, Lysine, Arg, NICR95, Backgrounds, L Lysine, TAF250, SET, Taf200, ethnicity, (S)-2-amino-5-guanidinopentanoic acid, anatomical systems, dTAF[[II]]250, TFIID TAF250, peptides, cel, TAF-I, K, cell, phosphatase 2A inhibitor I2PP2A, 2-amino-3-(4-hydroxyphenyl)propanoic acid, 3-(p-Hydroxyphenyl)alanine, ipp2a2, (S)-2-Amino-5-guanidinovaleric acid, beta-Trypsin, R, BaF3, epsilon-diaminocaproic acid, 2pp2a, Arginine, BaF3 cell, Taf1p, Cultural Relativisms, labeling, Monohydrate DL-Arginine Acetate, Y, CG10574, DmelCG4299, dTAF250, set, IGAAD, 2PP2A, LYS, DmelCG10574, L Tyrosine, taf-ibeta, Lysin, Tyr, dSET, dSet, Customs, L-Arg, peptidos, culture, Tyrosin, TAF, L-Arginin, phapii, dTAF[[II]]230, TAF[[II]]250, Phosphotyrosine, igaad, Arginine Hydrochloride, 2-Amino-3-(p-hydroxyphenyl)propionic acid, TAF200, StF-IT-1, arginine, l(3)84Ab, BG:DS00004.13, para-Tyrosine, TAFII-250, Cultural Backgrounds, TAF250/230, L-Isomer, antibodies, DL Arginine Acetate, Cell, Peptide, dTAF230, Belief, Tyrosine, polypeptide, TAFII250, Cultural Background, Cultures, I-2PP2A, L-Isomer Arginine, tirosina, Acetate, body system., p230, Tyrosine O phosphate, Dm I-2, I2PP2A, lysine, Hydrochloride, TAF[[II]]250/230, TFIID, L Arginine, connected anatomical system, L-Lysine, tyrosine, L-Arginine, Taf[[II]]250, TAF[[II]]230, HLA-DR-associated protein II, DI-2, I-2Dm, BaF3 细胞, (2S)-2-amino-5-guanidinopentanoic acid, L-isomer, Tripcellim, TAF[II]250, CG4299, alpha, inhibitor of granzyme A-activated DNase, CG17603, TAF[[II]], beta Trypsin, L isomer, I-2PP1, organ system, Trypure, dSET/TAF-Ibeta, 2610030F17Rik, DmelCG17603, TAF-IBETA, Taf250, SR3-5, dihydrogen phosphate (ester), Relativisms, Tyrosine-O-phosphate, Peptid, TAF-Ibeta, L-Tyrosine, Polypeptide, Relativism, AA407739, Cultural Relativism, 6-diaminohexanoic acid, L-tyrosine, i2pp2a, Enisyl, TAF230, TAF1fic, src-4, type 2, para Tyrosine, DmErk, extracellular signal-regulated kinase activity, pp44mapk, leukemia granulocytic, Granulocyte, acute non lymphoblastic leukemia, Laboratory, Ass-1, acute myelogenous leukaemia, GCSF, G-CSF receptor activity, A4, nonselective vesicle endocytosis, House Mouse, phosphorylation, Polymorphonuclear, Prp4 protein kinase activity, Mutations, dmTAF[[II]]230, endocytic import into cell, C-FMS, LeMPK3, macrophage, ATP-protein transphosphorylase activity, p44mpk, SRC 29A, neutrophilic leukemia, ATP:protein phosphotransferase (non-specific) activity, btk29A, Dp38, fold, 2, LE Cell, AT, Mutations., Kinase, Research Activity, SAPK2, Laboratory Research, SEM, Sem, Neutrophil Band Cells, Priorities, adenomas, average, MAP-k, treatment, Dsrc28C, L-methionine aminopeptidase activity, TFIID TAF250, pp42, cel, leukaemia granulocytic, 2-amino-3-(4-hydroxyphenyl)propanoic acid, 3-(p-Hydroxyphenyl)alanine, Dsor2, C17orf33, proteins, acute granulocytic leukaemia, Y, sem, allergic reaction, Dsrc29A, polymorphonuclear leukocyte, FMS, podocyte, ATP Phosphotransferases, single organism signaling, acute myelogenous, p82 kinase activity, ERK-A, ADMIO, dTAF[[II]]230, Stat5, dpERK, dpErk, typical plasmatocyte, MYH-associated polyposis, betaIIPKC, TAF200, Research Priorities, DmMAPK, para-Tyrosine, Normalcy, PMK-2, dp-ERK, PMK-1, chronic neutrophilic leukemia, CG18355, PMK-3, Wee-kinase activity, Neutrophil Band Cell, G-CSF, pMAPK, pMapK, IMD1, activation, Tec29A, Research and Development, MUTYH-associated polyposis, MUTYH-related AFAP, RUTBC3, DmERKA, granulocyte colony stimulating factor receptor activity, rl/MAPK, Caspase-14 subunit p10, PSCTK1, Swiss Mouse, non-specific serine/threonine protein kinase activity, l(2)41Ac, Caspase-14 subunit p19, lenograstim, STAT5, AML - acute myeloid leukemia, CT2415, L isomer, AW109958, Activities, CT34260, dpERk, src28C, Taf250, Proliferation, serine-specific protein kinase activity, multiple colorectal, HIPK2, SAPK, Polymorphonuclear Leukocytes, cytidine 3', Pluripoietin, MUTYH-related attenuated familial polyposis coli, L-Tyrosine, Mouse, Wee 1-like kinase activity, TAF230, CSF3, 3.4.22.-, CSF3R, atypia, acute myeloblastic leukemia, Band Cell, glycogen synthase A kinase activity, Peptidomics, glycogen synthase kinase 3 activity, number, 12559, Dm SRC2, mini-ICE, Normalcies, phosphorylase b kinase kinase activity, EK2-1, CSFR, sensitive, Gene Products, Mus musculus domesticus, atypical, MAM, ribosomal protein S6 kinase II activity, agranular plasmatocyte, MAP, Erk, ERK, CNL, acute myeloid leukaemia (AML), Normalities, protein-serine kinase activity, dTAF[[II]]250, myeloid leukaemia, cell, proliferating, familial adenomatous polyposis 2, HIES, STK32, granulocytic, leukaemia myelogenous, hies, erk, dTAF250, protein-cysteine kinase activity, leukaemia myeloid, G-CSF-R, Hpr kinase activity, AML - acute myeloid leukaemia, Csfg, rll, Development and Research, myelogenous leukemia, Tyrosin, STK26, Tec29, p38-2, LE, M-CSF-R, myelin basic protein kinase activity, leukemia, Individual Health, acute myelogenous leukemia, Polymorphonuclear Neutrophils, granular leukocyte, plasma membrane invagination, Leukocytes, Proteins, stress-activated kinase activity, Phosphorylations, MAP-2 kinase activity, DSrc28, defective, BG:DS00004.13, protein serine kinase activity, Cell, Polymorphonuclear Leukocyte, protein phosphokinase activity, AML, dTAF230, PKA, FIM2, PKC, tirosina, MUTYH-related attenuated FAP, stress-activated protein kinase activity, chemical analysis, mapk2, leukemia myeloid, mapk1, TAF[[II]]250/230, S13, AGMX1, protein kinase p58 activity, BPK, CT41718, non-lymphoblastic leukemia, serine/threonine protein kinase activity, Taf[[II]]250, hypersensitivity, CG12559, DMDA1, dpERK1, acute myeloid leukemia, House Mice, dsk1, CD115, CD114, 5'-cyclic monophosphate-responsive protein kinase activity, atypical PKC activity, signalling, Gene Proteins, hematopoeitic - acute Myleogenous leukemia (AML), 1110034C02Rik, signalling process, dpMAPK, non-lymphocytic leukaemia, MGF, granulocyte, AA959963, MAP syndrome, quantitative, myelocytic, filgrastim, protein serine-threonine kinase activity, SAP kinase activity, glycogen synthase kinase activity, acute myelocytic leukemia, acute Nonlymphocytic leukemia, protein kinase A activity, Activity, determination, methionine aminopeptidase activity, GCSFR, Mpk2, Mus domesticus, p42mapk, CASP-14, Pl, SR2-1, AA408052, kinase-related transforming protein, mitogen-activated protein kinase activity, mpk1, peptidase M activity, myeloid leukemia, rabGAPLP, Erk/Map kinase, DERK-A, RabGAP-5, Swiss Mice, E(sina)7, btk, acute myelocytic leukaemia, Rl, Raf kinase activity, c-src/fps, ASS, serine kinase activity, MP kinase activity, DERK, atypical protein kinase C activity, acute Nonlymphocytic leukaemia, RUSC3, signaling process, Tyr, disease management, MBP kinase II activity, mitogen-activated S6 kinase activity, protein-aspartyl kinase activity, ANLL, dERK, Research Priority, associated, ATK, acute nonlymphocytic leukaemia, somatic mutation, ATP, Src29A, MAP kinase 2 activity, aberrant, Mapk, aprf, 2-Amino-3-(p-hydroxyphenyl)propionic acid, mouse, autosomal recessive familial adenomatous polyposis, Erk1, Maps, ERK1, mapk1a, ERK2, TAFII-250, somatic, TAF250/230, CSF-1R, Tyrosine, M phase-specific cdc2 kinase activity, vesicle endocytosis, Csfgr, TAFII250, LE Cells, MapK, mapk1b, MAPK, G-CSF receptor, Mini-ICE, Individual, serine protein kinase activity, tyrosine, erk2, mapk, APRF, myeloid granulocytic leukemia, autosomal recessive, Mus musculus, Polymorphonuclear Neutrophil, Transphosphorylases, phosphorylase B kinase kinase activity, ERKa, BcDNA:RE08694, protein glutamyl kinase activity, Src2, l(2R)EMS45-39, mice, Filgrastim, susceptibility to, L-isomer, DmelCG12559, MGI-IG, p38, stat3, pluripoietin, CG17603, MICE, TAF[[II]], Aprf, RABGAP5, domesticus, DpErk, DpERK, ErkA, ERKA, hydroxyalkyl-protein kinase activity, Health, WEE1Hu, src4, DMDA, Patient, acute myeloid leukemia (AML), stat5, SR3-5, epsilon PKC, hypersensitivity reaction disease, reduced survival in, src2, pERK, Proliferating, ribosomal S6 protein kinase activity, biological signaling, calcium/phospholipid-dependent protein kinase activity, DmelCG8049, d230, GroupII, acute myeloblastic leukaemia, myelocytic leukaemia, truncate, Gene, dTAFII250, Endocytoses, EfW1, autosomal dominant, acute myelogenous leukemias, presence, C-src2, TYPE, C-src4, DAGA4, acute granulocytic leukemia, non-lymphocytic leukemia, acute non lymphoblastic leukaemia, granular leucocyte, dmTAF1, House, Taf230, DTec29, serine(threonine) protein kinase activity, acute myeloid, M4/M4Eo subtype, SCG3, Mice, Phosphotransferase, sensitivity, familial adenomatous polyposis, T-antigen kinase activity, TAF250, galactosyltransferase-associated kinase activity, Taf200, hematopoeitic - acute Myleogenous leukaemia (AML), Research, tec29, Swiss, xp42, non-lymphoblastic leukaemia, Taf1p, Transphosphorylase, p42 mitogen-activated protein kinase activity, CG18732, ATP:protein phosphotransferase (MAPKK-activated) activity, autosomal recessive multiple colorectal adenomas, Lenograstim, protein kinase (phosphorylating) activity, lamellocyte, L Tyrosine, Raf-1, Clients, DmERK-A, hypersensitivity reaction, TAF, casein kinase (phosphorylating) activity, dsrc29A, Neutrophil, MUTYH-related attenuated familial adenomatous polyposis, data, Leukocyte, ert1, TAF[[II]]250, MUTYH-Associated Polyposis, leukemia myelogenous, malignant, prkm2, prkm1, CT39192, xid, l(3)84Ab, Client, Phosphotransferases, LGMD2C, HDLS, p38delta, count in organism, twitchin kinase activity, Priority, Mus, p230, Protein, AP50 kinase activity, Research Activities, MBP kinase I activity, Xstat3, TFIID, CG8049, AI528679, Xp42, acute, threonine-specific protein kinase activity, myelogenous leukaemia, hypersensitive, TAF[[II]]230, neutrophilic leukaemia, Normality, Kinases, mitogen activated kinase activity, XLA, Su(Raf)2B, btk29a, EY2-2, TAF[II]250, MYH-Associated Polyposis, myeloid granulocytic leukaemia, Laboratory Mice, Protein Gene Products, myelocytic leukemia, D-ERK, DmelCG17603, SCARMD2, acute nonlymphocytic leukemia, Tec, assay, Non-Lymphocytic Leukemia, Laboratory Mouse, FAP2, A-kinase activity, MAP kinase 1 activity, presence or absence in organism, colorectal adenomatous polyposis, TAF1fic, src-4, type 2, para Tyrosine, DmErk, extracellular signal-regulated kinase activity, pp44mapk, leukemia granulocytic, Granulocyte, PCI-32765, acute non lymphoblastic leukemia, Laboratory, Ass-1, FON1, acute myelogenous leukaemia, GCSF, G-CSF receptor activity, A4, nonselective vesicle endocytosis, FLORAL ORGAN NUMBER 1, House Mouse, phosphorylation, Polymorphonuclear, Prp4 protein kinase activity, Mutations, dmTAF[[II]]230, endocytic import into cell, C-FMS, LeMPK3, macrophage, ATP-protein transphosphorylase activity, p44mpk, SRC 29A, ATP:protein phosphotransferase (non-specific) activity, btk29A, Dp38, fold, 2, LE Cell, AT, Research Activity, SAPK2, Laboratory Research, SEM, Sem, Neutrophil Band Cells, Priorities, adenomas, average, MAP-k, treatment, Dsrc28C, L-methionine aminopeptidase activity, TFIID TAF250, pp42, cel, leukaemia granulocytic, 2-amino-3-(4-hydroxyphenyl)propanoic acid, 3-(p-Hydroxyphenyl)alanine, Bdr, Leucocythemias, Dsor2, C17orf33, proteins, acute granulocytic leukaemia, Y, sem, childhood leukemia, SNAP-25, allergic reaction, Dsrc29A, medicine, data., polymorphonuclear leukocyte, FMS, podocyte, single organism signaling, acute myelogenous, p82 kinase activity, ERK-A, cord blood, ADMIO, dTAF[[II]]230, Stat5, dpERK, dpErk, typical plasmatocyte, MYH-associated polyposis, betaIIPKC, TAF200, Research Priorities, DmMAPK, para-Tyrosine, Normalcy, PMK-2, dp-ERK, PMK-1, fetal blood, CG18355, PMK-3, Wee-kinase activity, Neutrophil Band Cell, increased period, G-CSF, pMAPK, pMapK, GENA70, IMD1, activation, Tec29A, Research and Development, MUTYH-associated polyposis, MUTYH-related AFAP, RUTBC3, Leucocythemia, DmERKA, granulocyte colony stimulating factor receptor activity, rl/MAPK, Caspase-14 subunit p10, PSCTK1, Swiss Mouse, non-specific serine/threonine protein kinase activity, l(2)41Ac, Caspase-14 subunit p19, lenograstim, STAT5, AML - acute myeloid leukemia, CT2415, human, L isomer, AW109958, Activities, CT34260, dpERk, src28C, Taf250, serine-specific protein kinase activity, multiple colorectal, HIPK2, SAPK, Polymorphonuclear Leukocytes, cytidine 3', Pluripoietin, MUTYH-related attenuated familial polyposis coli, L-Tyrosine, Mouse, Wee 1-like kinase activity, TAF230, FLORAL DEFECTIVE 10, CSF3, 3.4.22.-, CSF3R, atypia, acute myeloblastic leukemia, Band Cell, glycogen synthase A kinase activity, Peptidomics, childhood leukaemia (disease), glycogen synthase kinase 3 activity, number, 12559, Dm SRC2, mini-ICE, SUPERMAN, Normalcies, phosphorylase b kinase kinase activity, EK2-1, CSFR, sensitive, 1-((3R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo(3, Gene Products, Mus musculus domesticus, leukaemia (disease) of childhood, atypical, Leucocythaemia, MAM, leukaemia, ribosomal protein S6 kinase II activity, agranular plasmatocyte, MAP, Erk, ERK, acute myeloid leukaemia (AML), Normalities, protein-serine kinase activity, dTAF[[II]]250, myeloid leukaemia, cell, familial adenomatous polyposis 2, HIES, STK32, granulocytic, man, leukaemia myelogenous, hies, erk, dTAF250, drugs, protein-cysteine kinase activity, leukaemia myeloid, G-CSF-R, Hpr kinase activity, AML - acute myeloid leukaemia, Csfg, Chronic, rll, Development and Research, myelogenous leukemia, Tyrosin, STK26, Tec29, p38-2, LE, M-CSF-R, myelin basic protein kinase activity, leukemia, Individual Health, acute myelogenous leukemia, Polymorphonuclear Neutrophils, granular leukocyte, plasma membrane invagination, Leukocytes, Proteins, stress-activated kinase activity, Phosphorylations, MAP-2 kinase activity, DSrc28, PCI32765, defective, BG:DS00004.13, Synaptosomal-associated 25 kDa protein, protein serine kinase activity, increased time, Cell, Polymorphonuclear Leukocyte, chronic, Leukemias, protein phosphokinase activity, AML, dTAF230, PKA, FIM2, PKC, tirosina, MUTYH-related attenuated FAP, stress-activated protein kinase activity, chemical analysis, mapk2, leukemia myeloid, mapk1, high time, TAF[[II]]250/230, S13, childhood leukemia (disease), AGMX1, protein kinase p58 activity, BPK, CT41718, non-lymphoblastic leukemia, serine/threonine protein kinase activity, Taf[[II]]250, hypersensitivity, CG12559, DMDA1, dpERK1, acute myeloid leukemia, House Mice, dsk1, CD115, CD114, 5'-cyclic monophosphate-responsive protein kinase activity, atypical PKC activity, signalling, Gene Proteins, hematopoeitic - acute Myleogenous leukemia (AML), 1110034C02Rik, signalling process, dpMAPK, non-lymphocytic leukaemia, MGF, granulocyte, AA959963, MAP syndrome, quantitative, myelocytic, filgrastim, protein serine-threonine kinase activity, SAP kinase activity, glycogen synthase kinase activity, leukemias, acute myelocytic leukemia, acute Nonlymphocytic leukemia, protein kinase A activity, Activity, determination, methionine aminopeptidase activity, GCSFR, Mpk2, Mus domesticus, p42mapk, CASP-14, Pl, SR2-1, AA408052, kinase-related transforming protein, SUP, mitogen-activated protein kinase activity, mpk1, peptidase M activity, myeloid leukemia, rabGAPLP, Erk/Map kinase, DERK-A, RabGAP-5, Swiss Mice, E(sina)7, btk, acute myelocytic leukaemia, Super protein, Rl, sp, Raf kinase activity, c-src/fps, ASS, serine kinase activity, MP kinase activity, DERK, atypical protein kinase C activity, acute Nonlymphocytic leukaemia, RUSC3, signaling process, Tyr, disease management, MBP kinase II activity, mitogen-activated S6 kinase activity, protein-aspartyl kinase activity, ANLL, dERK, Research Priority, associated, leukemia (disease), ATK, acute nonlymphocytic leukaemia, somatic mutation, Src29A, MAP kinase 2 activity, aberrant, Mapk, aprf, 2-Amino-3-(p-hydroxyphenyl)propionic acid, mouse, autosomal recessive familial adenomatous polyposis, Erk1, Maps, ERK1, mapk1a, ERK2, TAFII-250, somatic, TAF250/230, CD34, CSF-1R, Tyrosine, M phase-specific cdc2 kinase activity, vesicle endocytosis, Csfgr, TAFII250, blood (leukemia), LE Cells, MapK, mapk1b, MAPK, G-CSF receptor, Mini-ICE, Individual, serine protein kinase activity, tyrosine, erk2, mapk, APRF, myeloid granulocytic leukemia, autosomal recessive, AU040960, Mus musculus, Polymorphonuclear Neutrophil, phosphorylase B kinase kinase activity, ERKa, BcDNA:RE08694, protein glutamyl kinase activity, Src2, l(2R)EMS45-39, mice, Filgrastim, susceptibility to, L-isomer, DmelCG12559, MGI-IG, p38, stat3, pluripoietin, CG17603, MICE, umbilical cord blood, TAF[[II]], Aprf, leukaemia (disease), RABGAP5, domesticus, DpErk, DpERK, ErkA, disease, ERKA, paediatric leukaemia (disease), hydroxyalkyl-protein kinase activity, Health, WEE1Hu, src4, DMDA, Patient, acute myeloid leukemia (AML), stat5, SR3-5, epsilon PKC, hypersensitivity reaction disease, reduced survival in, PCI 32765, src2, pERK, ribosomal S6 protein kinase activity, biological signaling, calcium/phospholipid-dependent protein kinase activity, DmelCG8049, d230, human being, GroupII, acute myeloblastic leukaemia, myelocytic leukaemia, truncate, Gene, dTAFII250, hematopoietic progenitor cell antigen CD34, slow time, Endocytoses, EfW1, autosomal dominant, acute myelogenous leukemias, presence, C-src2, TYPE, pediatric leukemia (disease), C-src4, DAGA4, acute granulocytic leukemia, non-lymphocytic leukemia, acute non lymphoblastic leukaemia, granular leucocyte, dmTAF1, House, Taf230, DTec29, leukaemia NOS, serine(threonine) protein kinase activity, acute myeloid, leukemia (disease) of childhood, M4/M4Eo subtype, SCG3, Mice, sensitivity, familial adenomatous polyposis, T-antigen kinase activity, TAF250, galactosyltransferase-associated kinase activity, Taf200, hematopoeitic - acute Myleogenous leukaemia (AML), Research, tec29, Swiss, xp42, non-lymphoblastic leukaemia, Taf1p, p42 mitogen-activated protein kinase activity, CG18732, ATP:protein phosphotransferase (MAPKK-activated) activity, autosomal recessive multiple colorectal adenomas, Lenograstim, protein kinase (phosphorylating) activity, Mif1, 4-d)pyrimidin-1-yl)piperidin-1- yl)prop-2-en-1-one, lamellocyte, L Tyrosine, Raf-1, Clients, DmERK-A, hypersensitivity reaction, TAF, casein kinase (phosphorylating) activity, dsrc29A, Neutrophil, MUTYH-related attenuated familial adenomatous polyposis, Imbruvica, data, Leukocyte, ert1, TAF[[II]]250, MUTYH-Associated Polyposis, leukemia myelogenous, malignant, drug, prkm2, prkm1, CT39192, xid, l(3)84Ab, Client, LGMD2C, HDLS, p38delta, count in organism, twitchin kinase activity, Priority, Mus, p230, Protein, AP50 kinase activity, Research Activities, MBP kinase I activity, Xstat3, TFIID, prolonged period, CG8049, AI528679, Leucocythaemias, Xp42, acute, threonine-specific protein kinase activity, myelogenous leukaemia, hypersensitive, TAF[[II]]230, Normality, mitogen activated kinase activity, XLA, Su(Raf)2B, btk29a, general, EY2-2, TAF[II]250, FLO10, MYH-Associated Polyposis, myeloid granulocytic leukaemia, HERP, Laboratory Mice, Protein Gene Products, myelocytic leukemia, D-ERK, DmelCG17603, SCARMD2, acute nonlymphocytic leukemia, Tec, assay, Non-Lymphocytic Leukemia, Laboratory Mouse, FAP2, A-kinase activity, MAP kinase 1 activity, presence or absence in organism, colorectal adenomatous polyposis, TAF1para Tyrosine, biological signaling, Granulocyte, determination, granular leukocyte, Effects, typical plasmatocyte., number, 2-Amino-3-(p-hydroxyphenyl)propionic acid, Longterm Effect, para-Tyrosine, presence, Pl, Phosphotransferases, Long Term, Tyrosine, period, count in organism, granular leucocyte, macrophage, tirosina, Long Term Effects, chemical analysis, Kinase, Effect, agranular plasmatocyte, tyrosine, Phosphotransferase, Transphosphorylases, Longterm, Kinases, 2-amino-3-(4-hydroxyphenyl)propanoic acid, 3-(p-Hydroxyphenyl)alanine, L-isomer, Long-Term, Transphosphorylase, Y, Longterm Effects, signalling, L isomer, signalling process, L Tyrosine, lamellocyte, Tyr, signaling process, polymorphonuclear leukocyte, granulocyte, Long-Term Effect, L-Tyrosine, assay, quantitative, Tyrosin, podocyte, ATP Phosphotransferases, time, Long-Term Effects, ATP, single organism signaling, presence or absence in organism436trueTime resolved quantitative phospho-tyrosine analysis reveals Bruton’s Tyrosine kinase mediated signaling downstream of the mutated granulocyte-colony stimulating factor receptorsGranulocyte-colony stimulating factor receptor (G-CSFR) controls myeloid progenitor proliferation and differentiation to neutrophils. Mutations in CSF3R (encoding G-CSFR) have been reported in patients with chronic neutrophilic leukemia (CNL) and acute myeloid leukemia (AML); however, despite years of research, the malignant downstream signaling of the mutated G-CSFRs is not well understood. Here, we utilized a quantitative phospho-tyrosine analysis to generate a comprehensive signaling map of G-CSF induced tyrosine phosphorylation in the normal versus mutated (proximal: T618I and truncated: Q741x) G-CSFRs. Unbiased clustering and kinase enrichment analysis identified rapid induction of phospho-proteins associated with endocytosis by the wild-type G-CSFR only; while G-CSFR mutants showed abnormal kinetics of canonical STAT3, STAT5 and MAPK phosphorylation, and aberrant activation of Bruton’s Tyrosine Kinase (Btk). Mutant-G-CSFR-expressing cells displayed enhanced sensitivity (5-fold lower IC50) for Ibrutinib-based chemical inhibition of Btk. Finally, primary murine progenitor cells from G-CSFR-d715x knock-in mice validate activation of Btk by the mutant receptor, and display enhanced sensitivity to Ibrutinib. Together, these data demonstrate the strength of unsupervised proteomics analyses in dissecting oncogenic pathways, and suggest repositioning Ibrutinib for therapy of myeloid leukemia bearing CSF3R mutations.2018-07-112018-05-03PXD0096622806551646099180498511145422492156843544071284218327042363336351198343006636362758385696363121766668888111430155571145263145262364934613126957366649239161936413645106656889511363647627236611123294422295558326813042323122586365434607925193659106321432059712938655819125023254537111957748186619682158672256807617554373592536685862740816918045427877512010892250583674147956410039236942049433445974142001258641935293NCBITaxon:77643671567593643867716054048313152826930456271639162429204277944762376369612181003296292211376394863948840479NCBITaxon:215713152731051067125027820596875497792016516368407173630969893610478214836432042929410106132049138169374327732046640707453511110310780621745921612928867128867641006945694101676341021076127735113165821358430141729817463367541287356756840301350621813019411192943936711041136445913949843202530127032022149875110475941204788613474951537211097165299827905135551398031758543980126086639808137575551832019644719821118503114155421932555211383439119318198139818102697026635311069955529NCBITaxon:47518502983354764146547798251021691572739823897648407413735186287054824153NCBITaxon:505579844675251000364334147548021035974137081154665478983532215998381067710348198523487804225314884142228632266347946157187125939915991915729529292117527198601488406334249518691234235238152335985898598865597464998703920211107263990363527215987419082874394232418235024145113969293190259390719017463601237474636172262536001319722119158531058859698951105198997237989772000263419610264266722758858156899628737562690724420237172019998570724074767927459615333554319311671833554184005136861505968666211961748666134751536329NCBITaxon:17632862871103411033348837670580271848186536859598607575527472036105135294296110098402321000734882412336363071047005187878945556449447NCBITaxon:13356262664955419591399878168119011478281055524NCBITaxon:96063181781358584690081366848197915351930728593008526411409005118499526225412133759139014381113944235084370416744312044143708351581990119519532590841370137023943222774862615835583715371633376057267998086371137121906503714759172073127262981274575727090309031637910372814243371421044792491108239412NCBITaxon:9615658858147802692661006581373527504541356638164752037506442236695021293497905463224555253651997649908143899237453747264732376026473128870559553614169152527403271602938511497864794363755293824794372251177529912044741673872175091938441376593934347393271591002263767423444234546700128768959119846704146479293652803428038280351080348330779179392112621229502711311803738681911265269971028622527391076015973611432425071140981087135547743658142450722953379698204232124223321803369822130080347081645733185889716546759928777020382931412529550811481744888643745264999728303571830855071762997076789268370415156288765138856392456115293202086595551655181135491432137159749535026143213858781707683194963401614280053164686275110466038151845474485009747697477118051240174841855601555479204274381513201488711053253297261005941289093164351211604990013894382835423242331082934122058560416299131122731701879915429131267818187104931640729946714423683033373304852646383011306413992530642369923121162065261610337286129940207340115357652611114716133865431201725323712552329935316317NCBITaxon:11084993841063267872862321933486208621160791392227681196125522814953932132232334774121827532917573129948861814084341033519963139248913924881153381153393304393755699286265599339112094886241571839975864442374864353324442606653324134390976821271786371979856863999839986865535291486541042986357358257632884019864982380111911028688999586652203411508599632138119380625631886571303443112130886581144889198466645463NCBITaxon:11072NCBITaxon:11071142800628835374375116597145943116598854331116781077854314408043933434NCBITaxon:11082693977381382189931824431935128387145953116885311213278695berry8694100333586972443664701501114286921504751499105484204714722354025120847014649744497431170089306218644193061107632330805660396016217974825853946055396513212790568813377512981766378876017112147861050236694657349632051124501897441739412450128853183889198679488531911137910371647351660152943631631198573896939343237956026087121346334323223544314275241433611334565560291699636436802790105603140818838185733703401881274414936530437552196969716203871398558408172405598609183827275921274423408170275981274420127442623545513656531762793821176275943286303902474801199150956481882291690255120455148167238473848190695148498101510693731263753405203860186497405224052141856451804NCBITaxon:81347800915227548479387033384938719172261756109461614351203258120550523525944732054938641125722651216512538803766861206781122022307432201186705118670573873348691219387918680239800718680121545146835140818615084712067776918388516086113888691521677867212790100870435123171969281239294867713315484542261262198131882682411229265716329576938124712461485451328388348392949113903631204162665890771514880036942694169436945187901015080817053942065421055687317447127015329242814111946691169601454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