Prideapplication/xmlftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Des-Ksites.txtftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/TotalProteome_Proteingroup.txtftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_Proteome_Lean6.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_ActiveKinome_Peptide_OIR5.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_Proteome_Lean2.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_ActiveKinome_Peptide_Lean8.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_ActiveKinome_Peptide_OIR1.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_Proteome_OIR2.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_ActiveKinome_Peptide_Lean4.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_ActiveKinome_Peptide_Lean3.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_ActiveKinome_Peptide_OIR2.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_Proteome_OIR3.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_Proteome_Lean5.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_ActiveKinome_Peptide_OIR6.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_ActiveKinome_Peptide_Lean7.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_Proteome_Lean4.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_ActiveKinome_Peptide_OIR3.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_ActiveKinome_Peptide_Lean2.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_ActiveKinome_Peptide_Lean6.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_Proteome_Lean8.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_Proteome_OIR4.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_ActiveKinome_Peptide_OIR7.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_Proteome_OIR8.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_ActiveKinome_Peptide_OIR8.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_Proteome_Lean3.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_Proteome_OIR5.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_Proteome_OIR1.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_Proteome_Lean7.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_ActiveKinome_Peptide_Lean5.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_Proteome_OIR7.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_ActiveKinome_Peptide_Lean1.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_Proteome_Lean1.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_Proteome_OIR6.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD011909/Andy_ActiveKinome_Peptide_OIR4.rawprimaryOK200Zhengping.yi@wayne.eduYue Andy QiAffinity purification coupled with mass spectrometry proteomicsMass SpectrometryType 2 Diabetes MellitusNot availableActive kinomeQuantitative proteomicsProtein kinaseInsulin resistanceHuman skeletal musclehttp://www.ebi.ac.uk/pride/archive/projects/PXD011909The approach we used included extensive clinical and proteomics data acquisition and bioinformatic analysis. The clinical studies started with participant recruitment and were followed by comprehensive screening tests, and hyperinsulinemic-euglycemic clamp and muscle biopsies. The proteomics studies were conducted as follows: biopsy homogenization; spike-in standards, stable isotope labeled protein lysates from primary human skeletal muscle cells obtained by stable isotope labeling with amino acids in cell culture (SILAC) to minimize experimental variation; activity-based profiling probes (ABPP) with beads to enrich active kinases; in-solution trypsin digestion to generate tryptic peptides; and HPLC-ESI-MS/MS analysis to identify/quantify enriched active kinases. Multiple biological comparisons were used to minimize false positives. Extensive bioinformatics and literature search were used to integrate clinical and proteomics data and to identify pathways/functional categories, in which identified active kinases were involved, that were impacted by OIR.PrideSILACNo PTMs are included in the datasetDatabase search of the MS raw files was conducted by MaxQuant software package (version 1.5.4.7) 32 against UniProt human reference proteome database (version April, 2016) , where SILAC quantification (Arg10 and Lys4) and desthiobiotin modified lysine residue (des-K) were applied with a false discovery rate (FDR) for protein and peptide identification at 0.01.ProteomicsZhengping YiLTQ Orbitrap ElitePARTIALDepartment of Pharmaceutical Sciences - Room 3146, Eugene Applebaum College of Pharmacy/Health Sciences, Wayne State University, 6135 Woodward Ave., Detroit, MI 48202Homo Sapiens (human)31652310 Qi Y, Zhang X, Seyoum B, Msallaty Z, Mallisho A, Caruso M, Damacharla D, Ma D, Al-Janabi W, Tagett R, Alharbi M, Calme G, Mestareehi A, Draghici S, Abou-Samra A, Kowluru A, Yi Z. Kinome profiling reveals abnormal activity of kinases in skeletal muscle from adults with obesity and insulin resistance. J Clin Endocrinol Metab. 2019 10.1210/clinem/dgz115andy.qi@nih.govNational Cancer Institute/NIHUnited States<h4>Context</h4>Obesity-related insulin resistance (OIR) is one of the main contributors to type 2 diabetes and other metabolic diseases. Protein kinases are implicated in insulin signaling and glucose metabolism. Molecular mechanisms underlying OIR involving global kinase activities remain incompletely understood.<h4>Objective</h4>To investigate abnormal kinase activity associated with OIR in human skeletal muscle.<h4>Design</h4>Utilization of stable isotopic labeling-based quantitative proteomics combined with affinity-based active enzyme probes to profile in vivo kinase activity in skeletal muscle from lean control (Lean) and OIR participants.<h4>Participants</h4>A total of 16 nondiabetic adults, 8 Lean and 8 with OIR, underwent hyperinsulinemic-euglycemic clamp with muscle biopsy.<h4>Results</h4>We identified the first active kinome, comprising 54 active protein kinases, in human skeletal muscle. The activities of 23 kinases were different in OIR muscle compared with Lean muscle (11 hyper- and 12 hypo-active), while their protein abundance was the same between the 2 groups. The activities of multiple kinases involved in adenosine monophosphate-activated protein kinase (AMPK) and p38 signaling were lower in OIR compared with Lean. On the contrary, multiple kinases in the c-Jun N-terminal kinase (JNK) signaling pathway exhibited higher activity in OIR vs Lean. The kinase-substrate-prediction based on experimental data further confirmed a potential downregulation of insulin signaling (eg, inhibited phosphorylation of insulin receptor substrate-1 and AKT1/2).<h4>Conclusions</h4>These findings provide a global view of the kinome activity in OIR and Lean muscle, pinpoint novel specific impairment in kinase activities in signaling pathways important for skeletal muscle insulin resistance, and may provide potential drug targets (ie, abnormal kinase activities) to prevent and/or reverse skeletal muscle insulin resistance in humans.Kinome Profiling Reveals Abnormal Activity of Kinases in Skeletal Muscle From Adults With Obesity and Insulin Resistance.Qi Yue Y, Zhang Xiangmin X, Seyoum Berhane B, Msallaty Zaher Z, Mallisho Abdullah A, Caruso Michael M, Damacharla Divyasri D, Ma Danjun D, Al-Janabi Wissam W, Tagett Rebecca R, Alharbi Majed M, Calme Griffin G, Mestareehi Aktham A, Draghici Sorin S, Abou-Samra Abdul A, Kowluru Anjaneyulu A, Yi Zhengping ZAmyloid intracellular domain 57, APP, ABETA, Amyloid intracellular domain 59, criteria, Activity, amyloid-beta A4 protein, determination, experimental, Peptidomics, False, P3(40), Aminosaeure, Aminocarbonsaeure, Amino acid, A4, CTFgamma, amyloid beta A4 protein, protein, alpha-amino acid, spef1a, guidelines, protein-containing complex, Isotope-Coded Affinity, betaApp, Amyloid intracellular domain 50, Abpp, AAA, AID(59), Cvap, peptide, Polypeptides, protein polypeptide chains, AG, peptido, polypeptide chain, Beta-amyloid protein 42, cerebral vascular amyloid peptide, APP-C57, APP-C59, Human Skeletal Muscle Cells, Beta-amyloid protein 40, alzheimer disease amyloid protein, protease nexin-II, Isotopically-Coded Affinity, protein aggregate, amyloidogenic glycoprotein, AID(50), Isotopically-Coded Affinity Tagging, methods, Ag, F, SPEF1A, amino acids, CLAMP, Biopsies, peptides, PreA4, experimental section, beta-Trypsin, PDZD1, S-APP-beta, proteins, Gamma-CTF(59), ESI, Solution, HPLC, Alzheimer disease amyloid A4 protein homolog, N-APP, AID(57), Gamma-secretase C-terminal fragment 50, C20orf28, Stable, Gamma-secretase C-terminal fragment 57, data., Gamma-secretase C-terminal fragment 59, musculus, AD1, Isotope-Coded Affinity Tagging, Abeta, peptidos, APPI, Tagging, Clamp, C80, 4931426K16Rik, Stable Isotope Labeling, C83, data, Amyloidogenic glycoprotein, AICD-50, S-APP-alpha, protein complex, E030013M08Rik, Aminokarbonsaeure, alpha-amino acids, Gamma-CTF(57), Labeling, alpha-amino carboxylic acids, Peptide, Gamma-CTF(50), Literatures, C99, APP-C99, polypeptide, Isotope, native protein, natural protein, Stable Isotope, Adap, chemical analysis, Protein, AICD-57, Isotope Coded Affinity Tagging, AICD-59, Cerebral vascular amyloid peptide, Amino Acid, Acid, P3(42), PN-II, CAP70, Screening Tests, Amino acids, NHERF-3, Tripcellim, amyloid precursor protein, Soluble APP-beta, muscle, alzheimer disease amyloid A4 protein homolog, Isotope Labeling, Alzheimer disease amyloid protein, Amino, Protease nexin-II, Affinity Tagging, beta Trypsin, Isotopically-Coded, muscle element, experimental procedures, C31, Trypure, NHERF3, Soluble APP-alpha, Isotope-Coded, Peptid, Acids, assay, PN2, Beta-APP42, Polypeptide, Beta-APP40, General activity, amyloid-beta (A4) precursor protein, CVAP, ABPPInsulin Sensitivity., atypia, adults, Activity, aberrant, Obesity NOS, obesity disease, Adiposity, OBESITY NOS, defective, Overweight and obesity, skeletal muscle, Adiposis, obesity, Obesity, Obese, somatic muscle, Drug resistance to insulin (disorder), unspecified, IR, Insulin, Obesity [Ambiguous], Obese (finding), Resistance, OBESITY, Sensitivity, atypical, Adults, General activity, adult, obesity disorder, Obesity (disorder), striated muscle, skeletal muscle system(E)-4, (E)-3, 4-bis(4-hydroxyphenyl)-3-hexene, Bru, human being, Raw, False, mental retardation and dysequlibrium syndrome, mental retardation, homoaconitase activity, des, protein, Computer, Diethylstilbestrol, protein-containing complex, ZTNF2, 2-hydroxybutane-1, TALL-2, 4-diyldiphenol, peptide, Polypeptides, protein polypeptide chains, ClvPrd, peptido, polypeptide chain, trans-4, 2, 4, Del(8)44H, Software Engineering, protein aggregate, Computer Program, Application, Svc, Open Source Softwares, cerebellar ataxia, proportion, desthiobiotin, F, dialysis dysequilibrium syndrome, A proliferation-inducing ligand, peptides, 4'-(1, Software Application, Open, TRDL-1, TNF-related death ligand 1, Open Source Software, Computer Programs and Programming, VLDLRCH, proteins, cis-homoaconitase activity, DmelCG9078, man, Computer Software Application, Tools, (1R, dysequilibrium syndrome, des1, cerebellar hypoplasia, peptidos, 2-diethyl-1, alpha'-diethyl-(E)-4, Distilbene, nonprogressive, ratio, Applications Software, HACN activity, trans-Diethylstilbesterol, Open Source, LysF, 4-tricarboxylate hydro-lyase [(Z)-but-1-ene-1, des-1, Computer Software, (4R-cis)-isomer, protein complex, LGMD2R, SSP29, total expressed protein, 2-ethenediyl)bisphenol, TALL2, (cis)-(+-)-isomer, Source Softwares, CD256, Trdl1, Software Tools, Tool, Programs, polypeptide, Program, Computer Applications, Software Tool, TNF- and APOL-related leukocyte expressed ligand 2, native protein, dietilestilbestrol, natural protein, Lys4, l(2)gdh-2, 4'-dihydroxy-alpha, Computer Applications Software, April, Protein, Computer Applications Softwares, VLDLR associated, Softwares, Software, Data Base, cerebellar disorder, non-progressive cerebellar ataxia-intellectual disability syndrome, beta-diethylstilbene, Software Applications, with mental retardation, and dysequilibrium, Col4a-1, Ifc, Tall2, DES-1, CG9078, 2S)-1-hydroxybutane-1, Source Software, 4-tricarboxylate-forming], Engineering, 2310026N09Rik, 5-methyl-2-oxo-4-imidazolidinehexanoic acid, cerebellar ataxia-intellectual disability-dysequilibrium syndrome syndrome, proportionality, CAMRQ syndrome, rate, alpha, l(2)26Ab, human, APRIL, CAMRQ, Computer Programs, Applications, ms(2)04875, Applications Softwares, PHAPI2, CSM2, CSM1, quotient, 4'-stilbenediol, DES, Peptid, dethiobiotin, diethylstilbestrol, trans-Diethylstilbestrol, Polypeptide, 4-tricarboxylate hydro-lyase activity, 4'-(3E)-hex-3-ene-3, diethylstilbestrolum, trans-Diethylstilboesterol, Proteomes, Peptide., Computer Software ApplicationsSoluble, type 2, extracellular signal-regulated kinase activity, GrpL, PRKBA, pp44mapk, GRPL, Akt/PKB, SAPK signalling pathway, Growth factor receptor-binding protein, CRKII, noninsulin-dependent diabetes mellitus, beta-hydroxy-beta-methylglutaryl-CoA reductase kinase activity, NURF38, DAKT1/PKB, insuline humaine, AKT1, p38-alpha, Downregulation, phosphorylation, p38MAPK, p38a, Hog, p38ALPHA, I-peptide kinase activity, protein polypeptide chains, unspecified, LeMPK3, cAMP-dependent protein kinase, p44mpk, hnRNP A2/B1, symptoms, Non-Insulin Dependent Diabetes Mellitus, Dp38, 2, Kinase, SAPK2, Mpk34C, p38B, p38A, Thesaurismosis, HAMPKb, mapk14a, pp42, hrp40, ATP:acetyl-CoA carboxylase phosphotransferase activity, hnRNP36, proteins, Dm p38b, Hrb87Fa, Hrb85CD, RacPK, NIDDM, ampk2, hrp36, 5' cAMP-dependent protein kinase activity, Ampka2, Grf40, medicine, metabolic process disease, dMKK3, Disorder of metabolism NOS (disorder), severe, ATP Phosphotransferases, HMG-CoA reductase kinase activity, GRBLG, ESTS:186F5S, single organism signaling, DmMPK2, insulinum humanum, screening, Regular, 6.3.2.-, csbp, ERK-2, CG4634, Modern., PMK-2, RAC-PK-alpha, PMK-1, disorder of metabolic process, PMK-3, Hrb87f, Regular Insulin, CSBP, insulin (recombinant), AKT/PKB, Double ring-finger protein, Obesity [Ambiguous], OBESITY, p-Akt, D-MPK2, GRAP-2, Soluble Insulin, glucose metabolism, DmelCG5475, PKA C, Mek3, MEK3, DMEK3, EG:132E8.2, xAct, Type II Diabetes, insulina humana, signs, Adiposity, OBESITY NOS, c-Crk, dAKT/dPKB, PKB/dAKT, human, DmelCG3051, experimental procedures, NURF-38, CSBP2, PRKAA, CSBP1, stress-activated protein kinase signaling 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defective, 3-hydroxy-3-methylglutaryl coenzyme A reductase kinase activity, Down Regulation, acetyl coenzyme A carboxylase kinase (phosphorylating) activity, hydroxymethylglutaryl-CoA reductase (NADPH) kinase activity, DmMKK3, Drug resistance to insulin (disorder), PDIP38, stress-activated protein kinase signalling pathway, acetyl-coenzyme A carboxylase kinase activity, cyclic AMP-dependent protein kinase activity, Down-Regulation, PKB, PKA, native protein, CWS6, p38MAPKK, disorder of metabolism NOS, Down-Regulation (Physiology), Gprk-4, Insulin A Chain, PKB-ALPHA, Resistance, F18A8_2, CG4006, Sodium, Novolin, intrinsic catalyst activity, p38 beta, Obesity (disorder), Metabolic disorders, Nurf38, Dakt1, Metabolic disease (disorder), pkb, metabolic disease, P42MAPK, Obesity NOS, Crk1, muscle, Crk3, CSPB1, 5'-cAMP-dependent protein kinase activity, hydroxymethylglutaryl-CoA reductase kinase activity, hydroxymethylglutaryl coenzyme A reductase kinase activity, signalling, diabetes mellitis type 2, reductase kinase activity, 38 kDa DNA polymerase delta interaction protein, dAkt/PKB, Metabolic Diseases, signalling process, D-MKK3, CRK1, protection against, digenic, Receptor, General activity, thymoma viral proto-oncogene, Insulin B Chain, adult onset diabetes, protein kinase A activity, Nurf 38, Activity, sapk2, Mpk2, Mpk3, Crko, p42mapk, AMPKa2, protein, D-p38, AMPKa1, ATP:hydroxymethylglutaryl-CoA reductase (NADPH) phosphotransferase activity, Crk-II, p38 alpha, Adiposis, NURF, CD220, Obese, DmelCG4634, p38/NURF-38, human insulin, mitogen-activated protein kinase activity, Q14, Q16, protein aggregate, RK, mpk2, Adapter protein GRID, type II diabetes mellitus, insulin, CG3051, DMKK3, Man (Taxonomy), non-insulin dependent diabetes, reference sample, MEK3/MKK3, Metabolic disease, AMPK2, 3', non-insulin dependent diabetes mellitus, metabolic disorder, type 2 diabetes mellitus, acetyl-CoA carboxylase bound kinase activity, PKB|Akt, MP kinase activity, insulin human, 38, type 2 diabetes mellitus non-insulin dependent, INSR, Dmp38a, AHA1, dAMPKa, Hematopoietic cell-associated adapter protein GrpL, Dmp38b, signaling process, MBP kinase II activity, DmelCG12749, P11, type 2 diabetes, snf1a, METABOLISM DISORDER NOS, CG5475, MD - Metabolic disorders, Insulin Sensitivity, ATP, PKB alpha, diabetes mellitis type II, 3-hydroxy-3-methylglutaryl-CoA reductase kinase activity, MAP kinase 2 activity, dakt, aberrant, T2DM - type 2 diabetes mellitus, ERK1, ERK2, Erk2, A230093K24Rik, Hrb2, l(3)89Bq, late onset, D-P38a, GRBX, GrbX, AKT1 kinase, D-p38b, D-p38a, PKB/Akt, PKB/AKT, protein kinase B alpha, p41mapk, dAkt, dAKT, Syn, Receptor Down-Regulation, MAPK, Obese (finding), Diseases, JNK signaling pathway, NOS, P38, C14orf3, DAkt, acetyl-CoA carboxylase kinase (AMP-activated) activity, CG12244, HRB87F/hrp36, l(3)04226, Transphosphorylases, DPKB, METAB DIS, SH3-SH2-SH3 adapter Mona, GADS, pAkt, JTV-1, susceptibility to, HRB87F, Mona, p38alpha, p38, Prkm15, prkaa, acetyl-CoA carboxylase kinase-3 (AMP-activated) activity, proto-oncogene c-Akt, Prkm14, insulin resistance, insulin resistance-related, v-akt1, muscle element, protein kinase B, Proto-oncogene c-Crk, type II, Dakt, ATP:protein phosphotransferase (cAMP-dependent) activity, p41, type II diabetes, ampka1, p40, dPKB, DmelCG12304, acetyl-CoA carboxylase kinase activity, Unspecified disorder of metabolism, 186F5S, Protein Kinase, DRAC-PK85, biological signaling, AMPKalpha, l(1)G0252, human being, Metabolic Disease, ampk, experimental, CG7393, Insulin B, skeletal muscle, Obesity, CrkIII, p38Hog, Dpkb, dp38a, JNK signalling pathway, dp38b, Generalized metabolic disorder, Gads, polypeptide chain, Homo sapiens, N38, non-insulin-dependent diabetes mellitus, p42-MAPK, AMPK, SAPK signaling pathway, Phosphotransferase, acetyl-CoA carboxylase kinase (cAMP-independent) activity, ampkalpha, acetyl-CoA carboxylase kinase-2 activity, Generalized metabolic disorder (disorder), study, Mkk3, MKK3, methods, DmelCG12244, STK5, experimental section, F18A8.2, Grf-40, Overweight and obesity, Transphosphorylase, Ampk, p42 mitogen-activated protein kinase activity, Crk-III, ATP-protein phosphotransferase, ATP:protein phosphotransferase (MAPKK-activated) activity, adult-onset diabetes, Iletin, GRID, musculus, Gprk4, DRAC-PK, Sensitivity, Metabolic disorder, Metabolic Disorder, K+ transporter 1, association with, diabetes, Controlled, Disease, Controlling, data, protein complex, DMPK2, drug, anon-sts23, P11/Hrb87F, disorder of metabolism NOS (disorder), Phosphotransferases, Crk-I, DMKK3/lic, obesity, DmelCG7393, p38delta, somatic muscle, Sodium Insulin, natural protein, DIS METAB, group 2, Protein, Generalised metabolic disorder, MBP kinase I activity, D-Akt, obesity disorder, l(2)k16102, Type 2 Diabetes, Exubera, diabetes mellitus, Thesaurismoses, Metabolic, akt1, hydroxymethylglutaryl-CoA reductase (NADPH2) kinase activity, dAkt1, Kinases, mitogen activated kinase activity, INS, DRAC-PK66, Mxi2, POLD4, cellular glucose metabolic process, Sapk2A, MAPK2, hydroxymethylglutaryl coenzyme A reductase kinase (phosphorylating) activity, dp38, Dorfin, dakt1, mxi2, ERT1, PKBalpha, Modern Man, BG:DS00797.3, dAKT1, RAC, Rac, POTASSIUM TRANSPORTER, MAP kinase 1 activity, skeletal muscle systemSoluble, type 2, extracellular signal-regulated kinase activity, GrpL, PRKBA, pp44mapk, GRPL, Akt/PKB, Growth factor receptor-binding protein, SAPKa, CRKII, noninsulin-dependent diabetes mellitus, beta-hydroxy-beta-methylglutaryl-CoA reductase kinase activity, Adenylic Acid, NURF38, DAKT1/PKB, insuline humaine, 5'-Adenosine monophosphate, jra, spef1a, AKT1, p38-alpha, 5'-adenylic acid, phosphorylation, p38MAPK, p38a, Hog, p38ALPHA, I-peptide kinase activity, protein polypeptide chains, unspecified, LeMPK3, cAMP-dependent protein kinase, p44mpk, hnRNP A2/B1, Adenosine-5'-monophosphoric acid, symptoms, Non-Insulin Dependent Diabetes Mellitus, Dp38, 2, Kinase, SAPK1, phosphokinase activity, SAPK2, Mpk34C, adult, JNK-46, p38B, p38A, Junc, Thesaurismosis, HAMPKb, SPEF1A, mapk14a, Biopsies, pp42, DBSK/JNK, Junk, hrp40, ATP:acetyl-CoA carboxylase phosphotransferase activity, hnRNP36, proteins, V, adenosine phosphate, Dm p38b, Hrb87Fa, 5'-Adenylic acid, Hrb85CD, RacPK, NIDDM, ampk2, Jun, JUN, hrp36, 5' cAMP-dependent protein kinase activity, Ampka2, Grf40, medicine, metabolic process disease, dMKK3, Disorder of metabolism NOS (disorder), severe, ATP Phosphotransferases, HMG-CoA reductase kinase activity, GRBLG, ESTS:186F5S, single organism signaling, DmMPK2, insulinum humanum, jun, screening, Regular, 2'-Adenosine Monophosphate, D-Jun, Adenosine Phosphate Dipotassium, 6.3.2.-, dJNK, csbp, ERK-2, CG4634, Modern., PMK-2, RAC-PK-alpha, PMK-1, disorder of metabolic process, 2'-Adenylic Acid, signal transduction by trans-phosphorylation, PMK-3, Hrb87f, Regular Insulin, CSBP, insulin (recombinant), AKT/PKB, Double ring-finger protein, D-jun, Obesity [Ambiguous], OBESITY, p-Akt, D-MPK2, GRAP-2, Soluble Insulin, glucose metabolism, Acid, DmelCG5475, PKA C, Mek3, MEK3, DMEK3, EG:132E8.2, xAct, Type II Diabetes, insulina humana, Adenosine 5'-Phosphate, signs, Adiposity, OBESITY NOS, c-Crk, dAKT/dPKB, PKB/dAKT, human, DmelCG3051, NURF-38, Adenosine, CSBP2, DJNK, PRKAA, CSBP1, non-insulin-dependent, signaling pathway, SNF1-related protein kinase 2.2, acetyl-CoA carboxylase kinase 2 activity, dAMPKalpha, Csbp2, ACK3, Csbp1, ACK2, Monophosphate, adenosine 3', hypertension, humans, RAC-ALPHA, D-p38 MAPK, atypia, Grf40 adapter protein, DmelCG4006, maturity-onset diabetes, Peptidomics, cJun, number, obesity disease, ATAKT1, protein-containing complex, GRB-2-like protein, Exip, noninsulin dependent diabetes, Human, PRKM15, v-akt, akt-1, Prkm8, IR, dMPK2, Insulin, p38 MAPK, PRKM14, sapk2a, metabolism disorder, atypical, 5'-Adenylic, dNURF, EXIP, noninsulin-dependent, dJRA, dJra, Man, DmelCG5680, ERK, PRKM1, DJNK/bsk, Chain, p38beta, PRKM2, Hrp36, disease of metabolism, JTV1, p38Ka, p38Kb, DmAMPK alpha, dJun, dJUN, JNK21B1|2, AI848995, PRKM8, Disorder of metabolism NOS, BC023857, man, prkaa1, GRB2L, DmelCG2275, 5'-cyclophosphate-dependent protein kinase activity, CG12749, drugs, Insulin recombinant, STK29, AKT, Akt, STK22, 5'-Phosphate, HRP36, l(2R)IA109, STK26, p38-2, myelin basic protein kinase activity, FBgn0023169, striated muscle, Dp38b, SAPK1c, 2'-AMP, Dp38a, RING finger protein 19A, SAPK2A, findings, JNK3alpha1, akt, c-jun, Phosphorylations, MAP-2 kinase activity, Protein GADS, DAkt1, defective, DAKT1, 3-hydroxy-3-methylglutaryl coenzyme A reductase kinase activity, acetyl coenzyme A carboxylase kinase (phosphorylating) activity, Djun, hydroxymethylglutaryl-CoA reductase (NADPH) kinase activity, DmMKK3, Drug resistance to insulin (disorder), AMP, PDIP38, JNK/SAPK, acetyl-coenzyme A carboxylase kinase activity, dm-Jun, SRK2D, cyclic AMP-dependent protein kinase activity, PKB, PKA, native protein, JNK1, CWS6, p38MAPKK, disorder of metabolism NOS, D-JNK, Gprk-4, Insulin A Chain, 5'-Adenylic Acid, JNK1A2, PKB-ALPHA, Resistance, djun, F18A8_2, CG4006, Sodium, Adenosine Phosphate, Novolin, signalling cascade, intrinsic catalyst activity, p38 beta, Obesity (disorder), Adenosine 5'-phosphate, Metabolic disorders, DJUN, DJun, Nurf38, Dakt1, Metabolic disease (disorder), CAP70, pkb, metabolic disease, P42MAPK, Obesity NOS, adenosine-5'P, pA, Crk1, CG2275, muscle, Crk3, CSPB1, 5'-cAMP-dependent protein kinase activity, Adenosine 2'-Phosphate, hydroxymethylglutaryl-CoA reductase kinase activity, hydroxymethylglutaryl coenzyme A reductase kinase activity, signalling, diabetes mellitis type 2, reductase kinase activity, AP1, 38 kDa DNA polymerase delta interaction protein, dAkt/PKB, Dipotassium, Metabolic Diseases, signalling process, D-MKK3, dAP-1, CRK1, CG5680, protection against, digenic, 2' Adenylic Acid, quantitative, PROTEIN KINASE, General activity, Adenylic acid, thymoma viral proto-oncogene, Insulin B Chain, Adenosine 5' Phosphate, D-jun/Jra, adult onset diabetes, protein kinase A activity, Nurf 38, Activity, sapk2, AP-1, d-jun, Mpk2, Mpk3, Crko, p42mapk, AMPKa2, protein, D-p38, PAdo, AMPKa1, ATP:hydroxymethylglutaryl-CoA reductase (NADPH) phosphotransferase activity, BSK, Bsk, Crk-II, p38 alpha, Adiposis, NURF, CD220, Obese, DmelCG4634, p38/NURF-38, human insulin, mitogen-activated protein kinase activity, Q14, Q16, protein aggregate, RK, mpk2, Adapter protein GRID, signal transduction by protein phosphorylation, type II diabetes mellitus, insulin, CG3051, DMKK3, Man (Taxonomy), non-insulin dependent diabetes, reference sample, MEK3/MKK3, Metabolic disease, l(2)IA109, AMPK2, 3', non-insulin dependent diabetes mellitus, metabolic disorder, type 2 diabetes mellitus, acetyl-CoA carboxylase bound kinase activity, AI849689, PKB|Akt, phosphate d'adenosine, MP kinase activity, insulin human, 38, type 2 diabetes mellitus non-insulin dependent, INSR, C20orf28, Dmp38a, AHA1, dAMPKa, Hematopoietic cell-associated adapter protein GrpL, Dmp38b, signaling process, MBP kinase II activity, DmelCG12749, P11, c-Jun, type 2 diabetes, snf1a, METABOLISM DISORDER NOS, associated, CG5475, MD - Metabolic disorders, 4931426K16Rik, Insulin Sensitivity, ATP, PKB alpha, diabetes mellitis type II, 3-hydroxy-3-methylglutaryl-CoA reductase kinase activity, D-junk, MAP kinase 2 activity, d-JRA, Adenosine 3'-Phosphate, dakt, aberrant, signal transduction by conformational transition, T2DM - type 2 diabetes mellitus, ERK1, ERK2, Erk2, A230093K24Rik, Hrb2, l(3)89Bq, late onset, results, D-P38a, Adenosine 3' Phosphate, GRBX, GrbX, AKT1 kinase, D-p38b, D-p38a, JNK21B1/2, signaling cascade, PKB/Akt, PKB/AKT, protein kinase B alpha, p41mapk, dAkt, dAKT, Syn, MAPK, Obese (finding), Diseases, 2'-Adenylic, fosfato de adenosina, NOS, P38, C14orf3, DAkt, Adults, acetyl-CoA carboxylase kinase (AMP-activated) activity, CG12244, HRB87F/hrp36, l(3)04226, Transphosphorylases, DPKB, METAB DIS, SH3-SH2-SH3 adapter Mona, adults, GADS, pAkt, JTV-1, susceptibility to, HRB87F, Mona, p38alpha, p38, Prkm15, Phosphaden, prkaa, acetyl-CoA carboxylase kinase-3 (AMP-activated) activity, proto-oncogene c-Akt, 5'-O-phosphonoadenosine, Prkm14, insulin resistance, insulin resistance-related, v-akt1, muscle element, protein kinase B, Proto-oncogene c-Crk, type II, SNF1-RELATED PROTEIN KINASE 2-2, Dakt, ATP:protein phosphotransferase (cAMP-dependent) activity, p41, d-Jun, type II diabetes, ampka1, p40, dPKB, DmelCG12304, acetyl-CoA carboxylase kinase activity, Unspecified disorder of metabolism, 186F5S, Protein Kinase, adenosini phosphas, BSK/DJNK, DRAC-PK85, biological signaling, AMPKalpha, l(1)G0252, human being, Metabolic Disease, Phosphate Disodium, ampk, CG7393, Adenosine 2' Phosphate, l(2)46Ef, Insulin B, adenosine 5'-(dihydrogen phosphate), skeletal muscle, presence, Obesity, CrkIII, p38Hog, Dpkb, dp38a, dp38b, Generalized metabolic disorder, Gads, polypeptide chain, Homo sapiens, N38, non-insulin-dependent diabetes mellitus, p42-MAPK, AMPK, Phosphotransferase, acetyl-CoA carboxylase kinase (cAMP-independent) activity, ampkalpha, acetyl-CoA carboxylase kinase-2 activity, Generalized metabolic disorder (disorder), 5'-AMP, Mkk3, MKK3, 2' Adenosine Monophosphate, CLAMP, Adenylate, DmelCG12244, STK5, F18A8.2, Grf-40, PDZD1, labeling, Overweight and obesity, c-Jun N-terminal kinase activity, Transphosphorylase, Ampk, p42 mitogen-activated protein kinase activity, Crk-III, ATP-protein phosphotransferase, ATP:protein phosphotransferase (MAPKK-activated) activity, adult-onset diabetes, Iletin, signalling pathway, SNRK2-2, GRID, musculus, Ado5'P, Gprk4, DRAC-PK, Sensitivity, Metabolic disorder, signal transduction by cis-phosphorylation, Metabolic Disorder, K+ transporter 1, association with, Clamp, diabetes, Adenosine 5'-monophosphate, Controlled, ADENOSINE MONOPHOSPHATE, Disease, Controlling, data, Jnk, JNK, protein complex, DMPK2, drug, anon-sts23, 5' Adenylic Acid, P11/Hrb87F, disorder of metabolism NOS (disorder), 2'-Adenosine, Phosphotransferases, Crk-I, DMKK3/lic, obesity, DmelCG7393, p38delta, somatic muscle, count in organism, jnk, Sodium Insulin, natural protein, DIS METAB, group 2, Protein, Generalised metabolic disorder, MBP kinase I activity, D-Akt, obesity disorder, l(2)k16102, Type 2 Diabetes, Exubera, SPK-2-2, Phosphate Dipotassium, diabetes mellitus, Thesaurismoses, Metabolic, akt1, hydroxymethylglutaryl-CoA reductase (NADPH2) kinase activity, dAkt1, Kinases, mitogen activated kinase activity, INS, DRAC-PK66, NHERF-3, Mxi2, POLD4, cellular glucose metabolic process, Sapk2A, Disodium, MAPK2, hydroxymethylglutaryl coenzyme A reductase kinase (phosphorylating) activity, dp38, Dorfin, Adenosine Phosphate Disodium, NHERF3, dakt1, mxi2, ERT1, PKBalpha, Modern Man, BG:DS00797.3, dAKT1, RAC, Rac, JRA, POTASSIUM TRANSPORTER, MAP kinase 1 activity, skeletal muscle system, presence or absence in organismInsulin Sensitivity., somatic muscle, Drug resistance to insulin (disorder), human being, IR, Insulin, Resistance, Sensitivity, man, skeletal muscle, human, striated muscle, skeletal muscle systemfalseActive kinome in human skeletal muscle insulin resistanceObesity-related insulin resistance (OIR) is one of the main contributors to type 2 diabetes and other metabolic diseases. Protein kinases are implicated in key signaling steps including insulin signaling and glucose metabolism. Molecular mechanisms underlying OIR involving global active kinases remain less understood. Herein, we report findings from an in vivo active kinase profiling study in skeletal muscle from lean control (Lean) and OIR human participants, which identified the 1st active kinome comprised of 54 active protein kinases in human skeletal muscle. The activities of 23 kinases were different in OIR compared to Lean muscle (11 hyper- and 12 hypo-active), while their protein abundance was the same between the two groups. The activities of multiple kinases involved in AMPK and p38 signaling were lower in OIR compared to Lean. On the contrary, multiple kinases in JNK signaling pathway exhibited higher activity in OIR vs. Lean muscle. The kinase-substrate-prediction based on experimental data further confirmed a potential down-regulation of insulin signaling (e.g., inhibited phosphorylation of insulin receptor substrate-1 and AKT1/2). These findings provide a global view of the active kinome in OIR and Lean muscle, pinpoint novel specific impairment in kinase activities in multiple signaling pathways important for skeletal muscle insulin resistance, and provide potential drug targets (i.e., abnormal active kinase) to prevent and/or reverse skeletal muscle insulin resistance in humans.2020-01-232018-11-30PXD0119092806551646099180498295358511145284218809058113633363515242602758385NCBITaxon:128068888561896111430118726355557114526236493461327467073853883641135461582158236889547627211232944222911809923233654583334607925193659143205971293865581914932637371250232NCBITaxon:12721119577481866584345135867221755437408169180454266834453058612668351498225058149636745855452811320810039237514636942049433208964208963445974137979128384400667935293671521659940483216597216595455013152826930421659156271616968332183217292042779447623764543172030949801975255569781439843948840479NCBITaxon:21575253385515343989903712285775951520596876234555588845587077918178081736309431794571698936160488409859NCBITaxon:3716210478267940150590714836432042106132049138169363035554320466326334565453511025411103217459216129410026420369456941016763410210761277351131658239254727933428146135843017463345774449167547604893267568403019172651813019411192943936711041131023932025559863258278839659104759347495165299835525663175854310243260866310245980875741755518320196447145268045796190832331156114155421932555217634123598755529NCBITaxon:47518502547611361574146547718006655648433767729976798251021699823897641373511557444474153NCBITaxon:5055789969844100036465349334147548019467512991143597412764731370863265478765698353221599838192011985247946409860995867668599191572951372211711011076878349741986014884063342492359859886559746499870392021110729433117113972159874190850371170828418235024145113919021978224746360461471237437593925325664890507945265919722119151774208588596NCBITaxon:61575052102830798951105198997237505957613172000263419610264940772275689964975157244NCBITaxon:22023717NCBITaxon:1703612857050617476792745062724915961538400524643213686150596866629417347515363291018194301086731018557303963558633149286287132161865368595105135260710185687294110091416333NCBITaxon:619184023210007348824187878645159812863577553470951451225786260704260705260707658457405416561007133705654195NCBITaxon:3055504457913998781681928752829126806315327341478281055524NCBITaxon:9606469008150251930283672859300852NCBITaxon:56938268830640179469915101515482428381113704759272370828167728503515819901195195326738637024924053608862248881756261583558371533376057267119350199808611935021678793711371272407371457125627457903113335503728142433747924910078711082NCBITaxon:961559463318586260799141262200298492670NCBITaxon:12637192812492125283038568385695911100658123756127504542666255151978837503600941293497905435247214012576499085151514389923745374744544641524323592887051580595536157932716029385114978633892894535936479437NCBITaxon:6854412754225117159010901341673871589552101296610306129671585158451584937659393432715910022637673388942345128768914647929365761642803421641331599280382803536909108917689462181214108034817939228788929502711311749346819227321890382107601247190400727114311402064119810871355477436581424507229533796982042321291632180334708714537209164573315754699287770202060328114319338293550833291292211487252649997283035727550717629970767892683704152140532941281607839563924227377596207325516936053307972551811354915974953502611595561432138406072414473349194963401614334731646104660381518454744850035670974775124017484182042746076994688103762014887289093164358500713894649408941442423277422140921157781154756929793244704749906604162103591905158749907312989913112273170187103589915NCBITaxon:37296103609833411307981336795316407103401578630333733063830113064139925306423636505954788343171033729940445862073401153571119529652611114716133865413131663430552132312017993512993850573163176426197940115134584457726787286232193348621160791392227983516811961255228116761757312108077213487999948861814084341033519963218496139248820963304393758626NCBITaxon:2697049339862436941103121958832050920290610997586448643249952529724634389427863789426256737863912334355141998349317998686554055343529148654514712454661042986357124679151641358884019373345087718238039129529719748693102868899951337310548771251632138985076255470119380625631886571303443516558658862238NCBITaxon:44664946454636493NCBITaxon:110711428006288356491845881087439145943854331116781077854314408043933495346939773821899318226900351281459533996686959541869420030895448697244366206656395453005586233551804264308692200302284812426428150475149910510299386262903512089557117008930621864419306157558413101653823525577223994636010636010439947544404237610212790568813377518236116229629817677187093128110502382451855796694654318632051824097441739412450128853183889198853191113782559103716473516601261557NCBITaxon:101142845031631198573859523343237956026087121346395984275295952664373343232235443142752422430814336195931334565943274169963112223360520121697952528386972864368012187073347472790104081882976038181249885340188439733127441416395888587252029554648038343691224326408172124193559552128161405592042546551945822886091838271274423408170193329829721274420127442694328413996166018762548296471876247480119915095648188229725431480154120455138473848188294519069511663360364849850569310151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