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Protein tyrosine kinases (PTKs) play key roles in cellular signal transduction, cell cycle regulation, cell division, and cell differentiation. Dysregulation of PTK-activated pathways, often by receptor overexpression, gene amplification, or genetic mutation, is a causal factor underlying numerous cancers. In this study, we have developed a parallel reaction monitoring-based assay for quantitative profiling of 83 PTKs. The assay detects 308 proteotypic peptides from 54 receptor tyrosine kinases and 29 nonreceptor tyrosine kinases in a single run. Quantitative comparisons were based on the labeled reference peptide method. We implemented the assay in four cell models: 1) a comparison of proliferating versus epidermal growth factor-stimulated A431 cells, 2) a comparison of SW480Null (mutant APC) and SW480APC (APC restored) colon tumor cell lines, and 3) a comparison of 10 colorectal cancer cell lines with different genomic abnormalities, and 4) lung cancer cell lines with either susceptibility (11.Picotti P. Bodenmiller B. Mueller L.N. Domon B. Aebersold R. Full dynamic range proteome analysis of S. cerevisiae by targeted proteomics.Cell. 2009; 138: 795-806Abstract Full Text Full Text PDF PubMed Scopus (647) Google Scholar, 12.Gallien S. Duriez E. Demeure K. Domon B. Selectivity of LC-MS/MS analysis: implication for proteomics experiments.J. Proteomics. 2013; 81: 148-158Crossref PubMed Scopus (104) Google Scholar, 13.Karlsson C. Malmstrom L. Aebersold R. Malmstrom J. Proteome-wide selected reaction monitoring assays for the human pathogen Streptococcus pyogenes.Nat. Commun. 2012; 3: 1301Crossref PubMed Scopus (62) Google Scholar, 14.Gallien S. Duriez E. Crone C. Kellmann M. Moehring T. Domon B. Targeted proteomic quantification on quadrupole-orbitrap mass spectrometer.Mol. Cell. Proteomics. 2012; 11: 1709-1723Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar, 15.Peterson A.C. Russell J.D. Bailey D.J. Westphall M.S. Coon J.J. Parallel reaction monitoring for high resolution and high mass accuracy quantitative, targeted proteomics.Mol. Cell. Proteomics. 2012; 11: 1475-1488Abstract Full Text Full Text PDF PubMed Scopus (819) Google Scholar, 16.Chen Y. Gruidl M. Remily-Wood E. Liu R.Z. Eschrich S. Lloyd M. Nasir A. Bui M.M. Huang E. Shibata D. Yeatman T. Koomen J.M. Quantification of beta-catenin signaling components in colon cancer cell lines, tissue sections, and microdissected tumor cells using reaction monitoring mass spectrometry.J. Proteome Res. 2010; 9: 4215-4227Crossref PubMed Scopus (44) Google Scholar, 17.Rebecca V.W. Wood E. Fedorenko I.V. Paraiso K.H. Haarberg H.E. Chen Y. Xiang Y. Sarnaik A. Gibney G.T. Sondak V.K. Koomen J.M. Smalley K.S. Evaluating melanoma drug response and therapeutic escape with quantitative proteomics.Mol. Cell. Proteomics. 2014; 13: 1844-1854Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 18.Wolf-Yadlin A. Hautaniemi S. Lauffenburger D.A. White F.M. Multiple reaction monitoring for robust quantitative proteomic analysis of cellular signaling networks.Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 5860-5865Crossref PubMed Scopus (430) Google Scholar) or acquired resistance (11–18R) to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib. We observed distinct PTK expression changes that were induced by stimuli, genomic features or drug resistance, which were consistent with previous reports. However, most of the measured expression differences were novel observations. For example, acquired resistance to erlotinib in the 11–18 cell model was associated not only with previously reported up-regulation of MET, but also with up-regulation of FLK2 and down-regulation of LYN and PTK7. Immunoblot analyses and shotgun proteomics data were highly consistent with parallel reaction monitoring data. Multiplexed parallel reaction monitoring assays provide a targeted, systems-level profiling approach to evaluate cancer-related proteotypes and adaptations. Data are available through Proteome eXchange Accession PXD002706. Protein tyrosine kinases (PTKs) play key roles in cellular signal transduction, cell cycle regulation, cell division, and cell differentiation. Dysregulation of PTK-activated pathways, often by receptor overexpression, gene amplification, or genetic mutation, is a causal factor underlying numerous cancers. In this study, we have developed a parallel reaction monitoring-based assay for quantitative profiling of 83 PTKs. The assay detects 308 proteotypic peptides from 54 receptor tyrosine kinases and 29 nonreceptor tyrosine kinases in a single run. Quantitative comparisons were based on the labeled reference peptide method. We implemented the assay in four cell models: 1) a comparison of proliferating versus epidermal growth factor-stimulated A431 cells, 2) a comparison of SW480Null (mutant APC) and SW480APC (APC restored) colon tumor cell lines, and 3) a comparison of 10 colorectal cancer cell lines with different genomic abnormalities, and 4) lung cancer cell lines with either susceptibility (11.Picotti P. Bodenmiller B. Mueller L.N. Domon B. Aebersold R. Full dynamic range proteome analysis of S. cerevisiae by targeted proteomics.Cell. 2009; 138: 795-806Abstract Full Text Full Text PDF PubMed Scopus (647) Google Scholar, 12.Gallien S. Duriez E. Demeure K. Domon B. Selectivity of LC-MS/MS analysis: implication for proteomics experiments.J. Proteomics. 2013; 81: 148-158Crossref PubMed Scopus (104) Google Scholar, 13.Karlsson C. Malmstrom L. Aebersold R. Malmstrom J. Proteome-wide selected reaction monitoring assays for the human pathogen Streptococcus pyogenes.Nat. Commun. 2012; 3: 1301Crossref PubMed Scopus (62) Google Scholar, 14.Gallien S. Duriez E. Crone C. Kellmann M. Moehring T. Domon B. Targeted proteomic quantification on quadrupole-orbitrap mass spectrometer.Mol. Cell. Proteomics. 2012; 11: 1709-1723Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar, 15.Peterson A.C. Russell J.D. Bailey D.J. Westphall M.S. Coon J.J. Parallel reaction monitoring for high resolution and high mass accuracy quantitative, targeted proteomics.Mol. Cell. Proteomics. 2012; 11: 1475-1488Abstract Full Text Full Text PDF PubMed Scopus (819) Google Scholar, 16.Chen Y. Gruidl M. Remily-Wood E. Liu R.Z. Eschrich S. Lloyd M. Nasir A. Bui M.M. Huang E. Shibata D. Yeatman T. Koomen J.M. Quantification of beta-catenin signaling components in colon cancer cell lines, tissue sections, and microdissected tumor cells using reaction monitoring mass spectrometry.J. Proteome Res. 2010; 9: 4215-4227Crossref PubMed Scopus (44) Google Scholar, 17.Rebecca V.W. Wood E. Fedorenko I.V. Paraiso K.H. Haarberg H.E. Chen Y. Xiang Y. Sarnaik A. Gibney G.T. Sondak V.K. Koomen J.M. Smalley K.S. Evaluating melanoma drug response and therapeutic escape with quantitative proteomics.Mol. Cell. Proteomics. 2014; 13: 1844-1854Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 18.Wolf-Yadlin A. Hautaniemi S. Lauffenburger D.A. White F.M. Multiple reaction monitoring for robust quantitative proteomic analysis of cellular signaling networks.Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 5860-5865Crossref PubMed Scopus (430) Google Scholar) or acquired resistance (11–18R) to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib. We observed distinct PTK expression changes that were induced by stimuli, genomic features or drug resistance, which were consistent with previous reports. However, most of the measured expression differences were novel observations. For example, acquired resistance to erlotinib in the 11–18 cell model was associated not only with previously reported up-regulation of MET, but also with up-regulation of FLK2 and down-regulation of LYN and PTK7. Immunoblot analyses and shotgun proteomics data were highly consistent with parallel reaction monitoring data. Multiplexed parallel reaction monitoring assays provide a targeted, systems-level profiling approach to evaluate cancer-related proteotypes and adaptations. Data are available through Proteome eXchange Accession PXD002706. Protein tyrosine kinases (PTKs) 1The abbreviations used are:PTKprotein tyrosine kinasebRPLCbasic reverse phase liquid chromatographyCRCcolorectal cancerCVcoefficient of variationEGFepidermal growth factorFDRfalse discovery rateLCliquid chromatographyLRPlabeled reference peptideMRMmultiple reaction monitoringMSmass spectrometryMS/MStandem mass spectrometryMSImicrosatellite instabilityPRMparallel reaction monitoringRTKreceptor tyrosine kinaseSCXstrong cation exchange chromatographyTEABtriethylamine bicarbonate. are critical effectors of cell fate and are expressed ubiquitously during development and throughout the adult body. Ninety PTKs are encoded in the human genome and among them 58 are receptor type and 32 are nonreceptor tyrosine kinases (1.Lemmon M.A. Schlessinger J. Cell signaling by receptor tyrosine kinases.Cell. 2010; 141: 1117-1134Abstract Full Text Full Text PDF PubMed Scopus (3105) Google Scholar, 2.Robinson D.R. Wu Y.M. Lin S.F. The protein tyrosine kinase family of the human genome.Oncogene. 2000; 19: 5548-5557Crossref PubMed Scopus (839) Google Scholar). PTKs initiate intracellular signaling events that elicit diverse cellular responses such as survival, proliferation, differentiation, and motility (3.Hubbard S.R. Till J.H. Protein tyrosine kinase structure and function.Annu. Rev. Biochem. 2000; 69: 373-398Crossref PubMed Scopus (884) Google Scholar). PTK are some of the most frequently altered genes in cancer, either via mutation, overexpression, or amplification. The resultant deregulated cellular signaling contributes to disease progression and drug resistance. Regulation of PTKs is controlled both by extensive post-translational modifications, particularly protein phosphorylation and by changes in PTK abundance (4.Blume-Jensen P. Hunter T. Oncogenic kinase PubMed Scopus Google Scholar, R. Hunter T. S. The protein kinase of the human PubMed Scopus Google Scholar, J. cancer with kinase Rev. 2009; 9: PubMed Scopus Google Scholar). is in the expression of PTKs to drug response and protein tyrosine kinase reverse phase liquid colorectal cancer of epidermal growth factor discovery liquid labeled reference peptide reaction monitoring mass mass parallel reaction monitoring receptor tyrosine kinase cation exchange bicarbonate. expression of PTKs is measured by cell and which provide for a of in a single Multiplexed targeted proteomic on the of protein expression in PTK used targeted proteomics approach for quantification is reaction monitoring also selected reaction which is on a or mass Targeted of by mass 2013; PubMed Scopus Google Scholar). In with by of protein four to of in B. D.R. S. C. J.M. T. A. J. M. D. D. A. S. M. L. P. of the and of reaction monitoring-based of in 2009; PubMed Scopus Google Scholar, quantification of model with Scholar, M.A. D. J. Multiple reaction of in human Cell. Proteomics. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). single cell (11.Picotti P. Bodenmiller B. Mueller L.N. Domon B. Aebersold R. Full dynamic range proteome analysis of S. cerevisiae by targeted proteomics.Cell. 2009; 138: 795-806Abstract Full Text Full Text PDF PubMed Scopus (647) Google Scholar). the high and of the mass using a not which and protein quantification S. Duriez E. Demeure K. Domon B. Selectivity of LC-MS/MS analysis: implication for proteomics experiments.J. Proteomics. 2013; 81: 148-158Crossref PubMed Scopus (104) Google Scholar). In on a and of peptides and peptide that to C. Malmstrom L. Aebersold R. Malmstrom J. Proteome-wide selected reaction monitoring assays for the human pathogen Streptococcus pyogenes.Nat. Commun. 2012; 3: 1301Crossref PubMed Scopus (62) Google Scholar). resolution and mass peptide analysis with mass such as the the with the high resolution and high accuracy of mass of for targeted peptide the most of which is parallel reaction monitoring which both high resolution and from which S. Duriez E. Crone C. Kellmann M. Moehring T. Domon B. Targeted proteomic quantification on quadrupole-orbitrap mass spectrometer.Mol. Cell. Proteomics. 2012; 11: 1709-1723Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar, 15.Peterson A.C. Russell J.D. Bailey D.J. Westphall M.S. Coon J.J. Parallel reaction monitoring for high resolution and high mass accuracy quantitative, targeted proteomics.Mol. Cell. Proteomics. 2012; 11: 1475-1488Abstract Full Text Full Text PDF PubMed Scopus (819) Google Scholar). key of this approach is the highly of for peptides of from particularly approach to targeted proteome analysis is to assay for and in or Koomen and this approach with analyses of components of the signaling Y. Gruidl M. Remily-Wood E. Liu R.Z. Eschrich S. Lloyd M. Nasir A. Bui M.M. Huang E. Shibata D. Yeatman T. Koomen J.M. Quantification of beta-catenin signaling components in colon cancer cell lines, tissue sections, and microdissected tumor cells using reaction monitoring mass spectrometry.J. Proteome Res. 2010; 9: 4215-4227Crossref PubMed Scopus (44) Google Scholar) and to signaling V.W. Wood E. Fedorenko I.V. Paraiso K.H. Haarberg H.E. Chen Y. Xiang Y. Sarnaik A. Gibney G.T. Sondak V.K. Koomen J.M. Smalley K.S. Evaluating melanoma drug response and therapeutic escape with quantitative proteomics.Mol. Cell. Proteomics. 2014; 13: 1844-1854Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Multiplexed assay have used to in tyrosine kinase signaling A. Hautaniemi S. Lauffenburger D.A. White F.M. Multiple reaction monitoring for robust quantitative proteomic analysis of cellular signaling networks.Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 5860-5865Crossref PubMed Scopus (430) Google Scholar) and to the protein expression of cellular A. Quantitative analysis of in cancer cells by selected reaction monitoring Cell. Proteomics. 2012; 11: Full Text Full Text PDF PubMed Scopus Google Scholar). In this study, we a assay for of 83 which detects 308 proteotypic peptides from 54 receptor tyrosine kinases and 29 nonreceptor tyrosine kinases in a single run. We analysis of PTK expression changes by genomic or drug resistance in tumor cell PTK expression changes are and distinct for the The profiling of PTK expression changes in cell of for of the approach to systems-level analysis of PTK signaling and in cancer cell lines were from the SW480APC (APC restored) and SW480Null (APC cells were a from and 11–18 and lung tumor cell lines K. T. J. Lin Y. L. E. K. K. S. K. L. P. D. M. with acquired resistance to gene but in or Natl. Acad. Sci. U.S.A. 2012; PubMed Scopus Google Scholar) were by of cell lines were in and The and SW480APC cells were in The and cells were in and cells were in and cells were in J. P. M. 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We the model to PTK expression PTKs were in this study, of which differences a in protein is Y. underlying and of receptor tyrosine PubMed Scopus Google changes we observed to and down-regulation of most and up-regulation of and shotgun LC-MS/MS and data for PTKs in the A431 with LC-MS/MS shotgun proteomics and in protein expression were observed the analyses of PTKs not by shotgun most which was most by the data that for a of expressed shotgun proteomics data and data are We also with for selected PTK with phosphorylation which signaling and LYN for which were were for The were consistent with shotgun and data. are a of most colon and with or in of and of colorectal Rev. PubMed Scopus Google Scholar). We previously proteomic of in colon cells B. of a single gene in a colorectal cancer Proteome Res. 2012; 11: PubMed Scopus Google Scholar). 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H.E. and resistance of lung to or PubMed Scopus Google Scholar). of the lines and both a type and a abundance in and was expressed in type cells, the cell lines and expressed However, the cell lines and expressed to type Immunoblot analysis differences in expression of the cell lines and have four and of PTK for cells in expression of the PTK and that LYN which was expressed in cell lines, but high in the cell lines and Immunoblot analysis of LYN were consistent with the We PTK for the 10 cell lines based on as and and and and expression in in cells However, protein of PTKs were highly and cell lines and have We that cells on and and in type cells expression of PTKs and type of the cell lines and have and and of the cell lines and and and and with type cells protein abundance of PTK was highly cell of PTK profiling is to of drug resistance in PTK signaling We this in a lung tumor cell model of acquired resistance to the PTK inhibitor erlotinib K. T. J. Lin Y. L. E. K. K. S. K. L. P. D. M. with acquired resistance to gene but in or Natl. Acad. Sci. U.S.A. 2012; PubMed Scopus Google Scholar). The cell 11–18 to which of cells in the of which to K. T. J. Lin Y. L. E. K. K. S. K. L. P. D. M. with acquired resistance to gene but in or Natl. Acad. Sci. U.S.A. 2012; PubMed Scopus Google Scholar). with the PTK in both cell lines, of which differences and were in cells, and were analyses also were consistent with for of the PTKs that were in shotgun proteomic analyses and also were by analysis analyses also abundance in not reported as a of this cell K. T. J. Lin Y. L. E. K. K. S. K. L. P. D. M. with acquired resistance to gene but in or Natl. Acad. Sci. U.S.A. 2012; PubMed Scopus Google have that in lung cells, by signaling through growth factor and K. T. Y. C. J. T. T. C. to resistance in lung cancer by 2007; PubMed Scopus Google Scholar, D. the of the inhibitor 2012; PubMed Scopus Google Scholar). is associated with acquired resistance to in A. S. A. S. E. A. E. A. D. 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S. of the receptor resistance to in colorectal 2013; 3: PubMed Scopus Google Scholar). the of PTK abundance changes versus PTK we a profiling analysis of the 11–18 and cells with a analysis tyrosine phosphorylation on with phosphorylation differences in tyrosine phosphorylation 11–18 and cells of are in Data on the PTKs targeted by are in resistance in cells in phosphorylation with MET, and phosphorylation and phosphorylation of is consistent with of as associated with resistance to on PTKs. not in a PTK assay was developed from a of human some not have either of protein abundance or of of of the We analyses of the cell lines in and In PTK were in the A431 cell PTKs were as the In PTK were in the SW480APC PTKs were as the In PTK were in the PTKs were as the analyses a high and for of the in were not as either protein abundance or of PTKs are among the most of as for PTK expression different and of cancer and in PTK expression are of resistance to targeted cancer that targeted analysis of PTK expression in of drug susceptibility and resistance. we provide of for this approach with a assay to to 83 PTKs in PTK assay detects in PTK expression in cellular model and the data are highly consistent with data from and shotgun LC-MS/MS we the labeled reference peptide as a to such as the of using labeled peptide for S. Domon B. Targeted Cell. Proteomics. Full Text Full Text PDF PubMed Scopus Google Scholar). We observed distinct PTK expression changes in of the cell model we analyses of colon tumor cell lines the of with PTK as and distinct in different analyses previously reported PTK expression changes induced by or acquired resistance to but also adaptations. PTK analyses to PTKs for which of expression was the analysis approach by targeted to PTK peptides of T. R. M. Wu S. L. J. Liu T. K. targeted approach for quantification of in human Natl. Acad. Sci. U.S.A. 2012; PubMed Scopus Google Scholar). were to cell PTK assay to of through of but that phosphorylation in is highly to tissue K. K. D.A. White F.M. C. signaling analysis in human is by and Res. PubMed Scopus Google Scholar, P. Liu T. D.R. M.A. M.A. D.A. R. P. S.R. D. S. D. White M. in and phosphorylation changes in kinase but not protein Cell. Proteomics. 2014; 13: Full Text Full Text PDF PubMed Scopus Google protein abundance PTK profiling the protein expression provide a robust to of signaling in human with
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