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available"],"repository":["GPMDB"],"pubmed_abstract":["Mutations in the epidermal growth factor receptor (EGFR) kinase domain occur in 10-30% of lung adenocarcinoma and are associated with tyrosine kinase inhibitor (TKI) sensitivity. We sought to identify the immediate direct and indirect phosphorylation targets of mutant EGFRs in lung adenocarcinoma. We undertook SILAC strategy, phosphopeptide enrichment, and quantitative MS to identify dynamic changes of phosphorylation downstream of mutant EGFRs in lung adenocarcinoma cells harboring EGFR(L858R) and EGFR(L858R/T790M) , the TKI-sensitive, and TKI-resistant mutations, respectively. Top canonical pathways that were inhibited upon erlotinib treatment in sensitive cells, but not in the resistant cells include EGFR, insulin receptor, hepatocyte growth factor, mitogen-activated protein kinase, mechanistic target of rapamycin, ribosomal protein S6 kinase beta 1, and Janus kinase/signal transducer and activator of transcription signaling. We identified phosphosites in proteins of the autophagy network, such as ULK1 (S623) that is constitutively phosphorylated in these lung adenocarcinoma cells; phosphorylation is inhibited upon erlotinib treatment in sensitive cells, but not in resistant cells. Finally, kinase-substrate prediction analysis from our data indicated that substrates of basophilic kinases from, AGC and Calcium and calmodulin-dependent kinase groups, as well as STE group kinases were significantly enriched and those of proline-directed kinases from, CMGC and Casein kinase groups were significantly depleted among substrates that exhibited increased phosphorylation upon EGF stimulation and reduced phosphorylation upon TKI inhibition. This is the first study to date to examine global phosphorylation changes upon erlotinib treatment of lung adenocarcinoma cells and results from this study provide new insights into signaling downstream of mutant EGFRs in lung adenocarcinoma. All MS data have been deposited in the ProteomeXchange with identifier PXD001101 (http://proteomecentral.proteomexchange.org/dataset/PXD001101)."],"pubmed_title":["Identifying novel targets of oncogenic EGF receptor signaling in lung cancer through global phosphoproteomics."],"pubmed_authors":["Zhang Xu X,Belkina Natalya N,Jacob Harrys Kishore Charles HK,Maity Tapan T,Biswas Romi R,Venugopalan Abhilash A,Shaw Patrick G PG,Kim Min-Sik MS,Chaerkady Raghothama R,Pandey Akhilesh A,Guha Udayan U,","Zhang Xu X, Belkina Natalya N, Jacob Harrys Kishore Charles HK, Maity Tapan T, Biswas Romi R, Venugopalan Abhilash A, Shaw Patrick G PG, Kim Min-Sik MS, Chaerkady Raghothama R, Pandey Akhilesh A, Guha Udayan U"],"name_synonyms":["Lung Cancer, EGF receptor binding, transforming growth factor alpha receptor ligand, biological signaling, Pulmonary Neoplasms, Lung, epidermal growth factor receptor ligand, URG, Lung Neoplasms, Pulmonary Neoplasm, Neoplasms, EGFR binding, LNCR, Epidermal growth factor, TGF-alpha receptor binding, LUNG NEOPL, PULM NEOPL, Lung Cancers, Cancers, Carcinoma of the Lung, signalling, transforming growth factor alpha receptor binding, EGF, transforming growth factor alpha, HOMG4, signalling process, Lung Neoplasm, NEOPL PULM, cancer of lung, AI790464, signaling process, Pulmonary., EGF receptor ligand, Neoplasm, carcinoma OF LUNG, Pulmonary Cancers, Cancer of the Lung, NEOPL LUNG, Pulmonary Cancer, TGFalpha receptor binding, Urogastrone, epidermal growth factor, single organism signaling, Pulmonary, Cancer"],"description_synonyms":["4-nitrocatechol sulfokinase activity, receptor tyrosine-protein kinase erbB-1, data, ritodrine sulfotransferase activity, insensitive, H3255, proto-oncogene c-ErbB-1, Wa5, Lung adenocarcinoma, TGF-alpha receptor activity, phenol sulfotransferase activity, ERBB, Stp, number, Phosphorylations, Errb1, aryl sulphotransferase activity, arylsulfotransferase, mENA, presence, sulfokinase activity, phosphorylation, Cell, PIG61, count in organism, Stp1, Experiment, p-nitrophenol sulfotransferase activity, count, epidermal growth factor receptor activity, wa2, sensitive, adenocarcinoma of lung (disorder), AI552599, Adenocarcinoma of the Lung, PST, EGF receptor activity, Mutations., ST1A1, 1-naphthol phenol sulfotransferase activity, Adenocarcinoma of Lung, resistant, EGFR, dopamine sulfotransferase activity, 3'-phosphoadenylyl-sulfate:phenol sulfotransferase activity, ERBB1, wa-2, Lung Adenocarcinoma, Errp, Erbb, 2-naphtholsulfotransferase activity, phenol sulfokinase activity, AI266890, 9030024J15Rik, transforming growth factor-alpha receptor activity, quantitative, HER1, NISBD2, presence or absence in organism"],"pubmed_title_synonyms":["Lung Cancer, EGF receptor binding, transforming growth factor alpha receptor ligand, biological signaling, Pulmonary Neoplasms, Lung, epidermal growth factor receptor ligand, URG, Lung Neoplasms, Pulmonary Neoplasm, Neoplasms, EGFR binding, LNCR, Epidermal growth factor, TGF-alpha receptor binding, LUNG NEOPL, PULM NEOPL, Lung Cancers, Cancers, Carcinoma of the Lung, signalling, transforming growth factor alpha receptor binding, EGF, transforming growth factor alpha, HOMG4, signalling process, Lung Neoplasm, NEOPL PULM, cancer of lung, AI790464, signaling process, Pulmonary., EGF receptor ligand, Neoplasm, carcinoma OF LUNG, Pulmonary Cancers, Cancer of the Lung, NEOPL LUNG, Pulmonary Cancer, TGFalpha receptor binding, Urogastrone, epidermal growth factor, single organism signaling, Pulmonary, Cancer"],"pubmed_abstract_synonyms":["InChI=1S/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1, STE, insensitive, Phosphodiesterase Activator, CALML2, determination, Calcium Dependent, FKBP12-rapamycin complex-associated protein, Calcium 40, Receptors, Calcium-Dependent Activator Protein, TGF-alpha receptor binding, Hepatocyte, Errb1, Cyclic AMP-Phosphodiesterase Activator, Hepatopoietin A, phosphorylation, ATG1A, PIG61, CD220, Mutations, autophagy, ATG1, ste, Autophagic Cell Deaths, C5H9NO2, AI552599, Cellular Autophagies, kinase-related transforming protein, L-Proline, UNC51, Kinase, Mammalian target of rapamycin, Gpi-1, present in fewer numbers in organism, Insulin Receptor beta Subunit, CALM, 23, treatment, 24, calcio, Ribosomal, 25), Autophagies, Nlk, Macro autophagy, tyrosine kinase inhibitors, P, Cyclic AMP-Phosphodiesterase, Macro-autophagies, hypoplasia, SF, proteins, (2S)-pyrrolidine-2-carboxylic acid, PROLINE, DNA-dependent, transforming growth factor alpha receptor binding, INSR, decreased, CAMC, signaling process, disease management, Calcium-Dependent Activator, 9030024J15Rik, associated, ATP Phosphotransferases, EST-1, CAM3, NISBD2, ATP, FK506-binding protein 12-rapamycin complex-associated protein 1, single organism signaling, Blood Coagulation Factor IV, Ca, Data Set., Gpi, Mechanistic target of rapamycin, Coagulation, Autophagic, Wa5, DNA-dependent transcription, Lung adenocarcinoma, 12-15H, R75000, N-(3-ethynylphenyl)-6, Calcium-Dependent Regulator, Protein S6, 2-3H3, Unc51.1, results, Autophagic Cell, 5-7, mste, mKIAA0722, count, mOC-X, wa2, adenocarcinoma of lung (disorder), MAPK, Autophagic Programmed Cell Death, Autophagocytosis, Activator Protein, Cellular, Autophagic Cell Death, Mtap7, NK|GPI, Bovine Activator, Phosphodiesterase Activating, Urogastrone, RAPT1, Transphosphorylases, Insulin Receptor alpha Chain, ST1E1, Org, ORG, resistant, prolinum, Autophagy, EGFR, Rapamycin and FKBP12 target 1, Epidermal growth factor, Gpi1-r, Gpi1-s, scatter factor, Cell Death, (-)-proline, (S)-pyrrolidine-2-carboxylic acid, Gpi1-t, Scatter Factor, Lung Adenocarcinoma, Insulin Receptors, Specificity and Sensitivity, InChIKey=AAKJLRGGTJKAMG-UHFFFAOYSA-N, Phosphodiesterase Protein Activator, AMP-Phosphodiesterase Activator, TGFalpha receptor binding, L-pyrrolidine-2-carboxylic acid, Bglap-rs1, hyperphosphorylated, Gpi1s, receptor tyrosine-protein kinase erbB-1, transcription, biological signaling, EGF receptor binding, proto-oncogene c-ErbB-1, (-)-(S)-proline, AI461847, Macroautophagy, L-alpha-pyrrolidinecarboxylic acid, number, Gene, mshi, CAMIII, Phosphodiesterase Activating Factor, Calcium Dependent Regulator, mENA, Insulin Receptor, presence, (H, Insulin Receptor Protein-Tyrosine Kinase, Calcium Dependent Activator Protein, HGF, IR, reduced, sensitive, 20Ca, AI790464, subnumerary, Insulin, Factor IV, Adenocarcinoma of the Lung, Gene Products, Cellular Autophagy, EGF receptor activity, Pgi, Growth Factor, transcription regulator activity, Protein Activator, tiny, Macro-autophagy, sensitivity, epidermal growth factor, Bovine Activator Protein, Cyclic AMP Phosphodiesterase Activator, study, Calcium-40, Adenocarcinoma of Lung, HGF receptor binding, transforming growth factor alpha receptor ligand, epidermal growth factor receptor ligand, URG, Gpi-1r, Gpi-1s, Transducer, Phi, EGFR binding, Gpi-1t, 2-Pyrrolidinecarboxylic acid, HPTA, Activator, Insulin Receptor Protein Tyrosine Kinase, Deaths, decreased number, Activating Factor, 8-11H2, Lymphokines and Cytokines, Phosphodiesterase Protein, (S)-2-pyrrolidinecarboxylic acid, Bovine, EST, HOMG4, hepatopoeitin-A, L Proline, EGF receptor ligand, Sensitivity, Insulin-Dependent Tyrosine Protein Kinase, (S)-2-carboxypyrrolidine, Hepatocyte Growth, hATG1, Insulin Receptor beta Chain, small, Macroautophagies, cellular transcription, data, AU041434, hepatocyte growth factor receptor ligand, TGF-alpha receptor activity, prolina, ERBB, CaM, Proteins, Phosphorylations, Factor, mTOR, Kalzium, MF, Amf, Phosphotransferases, Cell, polypeptide, count in organism, 2.7.11.1, transforming growth factor alpha, epidermal growth factor receptor activity, Programmed Cell Death, Protein, chemical analysis, protein tyrosine kinase inhibitor, proline, Death, 7-bis(2-methoxyethoxy)quinazolin-4-amine, Scatter, Cell Deaths, MAP-7, NK, Calcium, (-)-2-pyrrolidinecarboxylic acid, L-Prolin, 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Experiment: pST_SILAC_R1a, file: H3255_pST_SILAC_R1_F4_a.mzml. Published as part of Proteomics. 2015 Jan;15(2-3):340-55  . From the Abstract: {{i}} . We sought to identify the immediate direct and indirect phosphorylation targets of mutant EGFRs in lung adenocarcinoma. We undertook SILAC strategy, phosphopeptide enrichment, and quantitative MS to identify dynamic changes of phosphorylation downstream of mutant EGFRs in lung adenocarcinoma cells harboring EGFR(L858R) and EGFR(L858R/T790M) , the TKI-sensitive, and TKI-resistant mutations, respectively. {{/i}}","dates":{"submission":"2015-02-08"},"accession":"GPM32320007613","cross_references":{"pubmed":["25404012"],"Pride":["PXD001101"],"pride":[],"Pride Archive":["PXD001101"]}}