CPLM 1.0 - Compendium of Protein Lysine Modification
TagContent
CPLM ID CPLM-004302
UniProt Accession
Genbank Protein ID
Genbank Nucleotide ID
Protein Name
 Insulin receptor 
Protein Synonyms/Alias
 IR; CD220; Insulin receptor subunit alpha; Insulin receptor subunit beta 
Gene Name
 Insr 
Gene Synonyms/Alias
  
Created Date
 July 27, 2013 
Organism
 Rattus norvegicus (Rat) 
NCBI Taxa ID
 10116 
Lysine Modification
Position
Peptide
Type
References
1058VETRVAVKTVNESASubiquitination[1]
1196DYYRKGGKGLLPVRWubiquitination[2]
Reference
 [1] Synaptic protein ubiquitination in rat brain revealed by antibody-based ubiquitome analysis.
 Na CH, Jones DR, Yang Y, Wang X, Xu Y, Peng J.
 J Proteome Res. 2012 Sep 7;11(9):4722-32. [PMID: 22871113]
 [2] Proteomic analyses reveal divergent ubiquitylation site patterns in murine tissues.
 Wagner SA, Beli P, Weinert BT, Schölz C, Kelstrup CD, Young C, Nielsen ML, Olsen JV, Brakebusch C, Choudhary C.
 Mol Cell Proteomics. 2012 Dec;11(12):1578-85. [PMID: 22790023] 
Functional Description
 Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src- homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti- apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K- AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). When present in a hybrid receptor with IGF1R, binds IGF1 (By similarity). 
Sequence Annotation
 DOMAIN 623 696 Fibronectin type-III 1.
 DOMAIN 758 845 Fibronectin type-III 2.
 DOMAIN 851 947 Fibronectin type-III 3.
 DOMAIN 1024 1299 Protein kinase.
 NP_BIND 1105 1111 ATP (By similarity).
 NP_BIND 1164 1165 ATP (By similarity).
 REGION 734 742 Insulin-binding (By similarity).
 REGION 997 1000 Important for interaction with IRS1, SHC1
 REGION 1362 1365 PIK3R1 binding (By similarity).
 ACT_SITE 1160 1160 Proton donor/acceptor (By similarity).
 BINDING 1034 1034 ATP (By similarity).
 BINDING 1058 1058 ATP (By similarity).
 BINDING 1178 1178 ATP (By similarity).
 MOD_RES 399 399 Phosphoserine (By similarity).
 MOD_RES 400 400 Phosphotyrosine (By similarity).
 MOD_RES 406 406 Phosphoserine (By similarity).
 MOD_RES 1000 1000 Phosphotyrosine; by autocatalysis (By
 MOD_RES 1186 1186 Phosphotyrosine; by autocatalysis (By
 MOD_RES 1190 1190 Phosphotyrosine; by autocatalysis (By
 MOD_RES 1191 1191 Phosphotyrosine; by autocatalysis (By
 MOD_RES 1356 1356 Phosphotyrosine; by autocatalysis (By
 MOD_RES 1362 1362 Phosphotyrosine; by autocatalysis (By
 CARBOHYD 42 42 N-linked (GlcNAc...) (Potential).
 CARBOHYD 51 51 N-linked (GlcNAc...) (Potential).
 CARBOHYD 104 104 N-linked (GlcNAc...) (Potential).
 CARBOHYD 137 137 N-linked (GlcNAc...) (Potential).
 CARBOHYD 241 241 N-linked (GlcNAc...) (Potential).
 CARBOHYD 281 281 N-linked (GlcNAc...) (Potential).
 CARBOHYD 321 321 N-linked (GlcNAc...) (Potential).
 CARBOHYD 363 363 N-linked (GlcNAc...) (Potential).
 CARBOHYD 423 423 N-linked (GlcNAc...) (Potential).
 CARBOHYD 444 444 N-linked (GlcNAc...) (Potential).
 CARBOHYD 540 540 N-linked (GlcNAc...) (Potential).
 CARBOHYD 634 634 N-linked (GlcNAc...) (Potential).
 CARBOHYD 652 652 N-linked (GlcNAc...) (Potential).
 CARBOHYD 699 699 N-linked (GlcNAc...) (Potential).
 CARBOHYD 770 770 N-linked (GlcNAc...) (Potential).
 CARBOHYD 783 783 N-linked (GlcNAc...) (Potential).
 CARBOHYD 921 921 N-linked (GlcNAc...) (Potential).
 CARBOHYD 934 934 N-linked (GlcNAc...) (Potential).
 DISULFID 34 52 By similarity.
 DISULFID 152 181 By similarity.
 DISULFID 185 208 By similarity.
 DISULFID 195 214 By similarity.
 DISULFID 218 227 By similarity.
 DISULFID 222 233 By similarity.
 DISULFID 234 242 By similarity.
 DISULFID 238 251 By similarity.
 DISULFID 254 263 By similarity.
 DISULFID 267 279 By similarity.
 DISULFID 285 310 By similarity.
 DISULFID 292 300 By similarity.
 DISULFID 314 327 By similarity.
 DISULFID 330 334 By similarity.
 DISULFID 338 359 By similarity.
 DISULFID 461 494 By similarity.
 DISULFID 550 550 Interchain (By similarity).
 DISULFID 675 900 By similarity.  
Keyword
 Alternative splicing; ATP-binding; Cell membrane; Cleavage on pair of basic residues; Complete proteome; Disulfide bond; Glycoprotein; Kinase; Membrane; Nucleotide-binding; Phosphoprotein; Receptor; Reference proteome; Repeat; Signal; Transferase; Transmembrane; Transmembrane helix; Tyrosine-protein kinase. 
Sequence Source
 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 
Protein Length
 1383 AA 
Protein Sequence
MGSGRGCETT AVPLLMAVAV AGGTAGHLYP GEVCPGMDIR NNLTRLHELE NCSVIEGHLQ 60
ILLMFKTRPE DFRDLSFPKL IMITDYLLLF RVYGLESLKD LFPNLTVIRG SRLFFNYALV 120
IFEMVHLKEL GLYNLMNITR GSVRIEKNNE LCYLATIDWS RILDYVEDNY IVLNKDDNEE 180
CGDVCPGTAK GKTNCPATVI NGQFVERCWT HSHCQKVCPT ICKSHGCTAE GLCCHKECLG 240
NCSEPDDPTK CVACRNFYLD GQCVETCPPP YYHFQDWRCV NFSFCQDLHY KCRNSRKPGC 300
HQYVIHNNKC IPECPSGYTM NSSNLMCTPC LGPCPKVCQI LEGEKTIDSV TSAQELRGCT 360
VINGSLIINI RGGNNLAAEL EANLGLIEEI SGFLKIRRSY ALVSLSFFRK LHLIRGETLE 420
IGNYSFYALD NQNLRQLWDW NKHNLTITQG KLFFHYNPKL CLSEIHKMEE VSGTKGRQER 480
NDIALKTNGD QASCENELLK FSFIRTSFDK ILLRWEPYWP PDFRDLLGFM LFYKEAPYQN 540
VTEFDGQDAC GSNSWTVVDI DPPQRSNDPK SQTPSHPGWL MRGLKPWTQY AIFVKTLVTF 600
SDERRTYGAK SDIIYVQTDA TNPSVPLDPI SVSNSSSQII LKWKPPSDPN GNITHYLVYW 660
ERQAEDSELF ELDYCLKGLK LPSRTWSPPF ESDDSQKHNQ SEYDDSASEC CSCPKTDSQI 720
LKELEESSFR KTFEDYLHNV VFVPRKTSSG NGAEDTRPSR KRRSLEEVGN VTATTPTLPD 780
FPNISSTIAP TSHEEHRPFE KVVNKESLVI SGLRHFTGYR IELQACNQDS PEERSGVAAY 840
VSARTMPEAK ADDIVGPVTH EIFENNVVHL MWQEPKEPNG LIVLYEVSYR RYGDEELHLC 900
VSRKHFALER GCRLRGLSPG NYSVRVRATS LAGNGSWTEP TYFYVTDYLD VPSNIAKIII 960
GPLIFVFLFS VVIGSIYLFL RKRQPDGPMG PLYASSNPEY LSASDVFPSS VYVPDEWEVP 1020
REKITLLREL GQGSFGMVYE GNAKDIIKGE VETRVAVKTV NESASLRERI EFLNEASVMK 1080
GFTCHHVVRL LGVVSKGQPT LVVMELMAHG DLKSHLRSLR PDAENNPGRP PPTLQEMIQM 1140
TAEIADGMAY LNAKKFVHRD LAARNCMVAH DFTVKIGDFG MTRDIYETDY YRKGGKGLLP 1200
VRWMSPESLK DGVFTASSDM WSFGVVLWEI TSLAEQPYQG LSNEQVLKFV MDGGYLDPPD 1260
NCPERLTDLM RMCWQFNPKM RPTFLEIVNL LKDDLHPSFP EVSFFYSEEN KAPESEELEM 1320
EFEDMENVPL DRSSHCQREE AGCREGGSSL SIKRTYDEHI PYTHMNGGKK NGRVLTLPRS 1380
NPS 1383 
Gene Ontology
 GO:0005829; C:cytosol; IDA:RGD.
 GO:0005768; C:endosome; IDA:RGD.
 GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
 GO:0005634; C:nucleus; IDA:RGD.
 GO:0005886; C:plasma membrane; IDA:RGD.
 GO:0045202; C:synapse; IDA:RGD.
 GO:0043423; F:3-phosphoinositide-dependent protein kinase binding; IDA:RGD.
 GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 GO:0043559; F:insulin binding; IDA:RGD.
 GO:0043560; F:insulin receptor substrate binding; IMP:RGD.
 GO:0005009; F:insulin-activated receptor activity; IDA:RGD.
 GO:0031405; F:lipoic acid binding; IPI:RGD.
 GO:0032403; F:protein complex binding; IDA:RGD.
 GO:0019903; F:protein phosphatase binding; IMP:RGD.
 GO:0045444; P:fat cell differentiation; IEP:RGD.
 GO:0042593; P:glucose homeostasis; IDA:RGD.
 GO:0010629; P:negative regulation of gene expression; IMP:RGD.
 GO:0001933; P:negative regulation of protein phosphorylation; IMP:RGD.
 GO:0032410; P:negative regulation of transporter activity; IMP:RGD.
 GO:0018108; P:peptidyl-tyrosine phosphorylation; IMP:RGD.
 GO:0010560; P:positive regulation of glycoprotein biosynthetic process; IMP:RGD.
 GO:0042327; P:positive regulation of phosphorylation; IDA:BHF-UCL.
 GO:0046777; P:protein autophosphorylation; IDA:RGD.
 GO:0051290; P:protein heterotetramerization; IDA:RGD.
 GO:0010310; P:regulation of hydrogen peroxide metabolic process; IDA:RGD.
 GO:0014823; P:response to activity; IEP:RGD.
 GO:0032355; P:response to estradiol stimulus; IEP:RGD.
 GO:0045471; P:response to ethanol; IEP:RGD.
 GO:0051384; P:response to glucocorticoid stimulus; IEP:RGD.
 GO:0009749; P:response to glucose stimulus; IEP:BHF-UCL.
 GO:0010042; P:response to manganese ion; IEP:RGD.
 GO:0033574; P:response to testosterone stimulus; IEP:RGD.
 GO:0034612; P:response to tumor necrosis factor; IMP:RGD.
 GO:0033280; P:response to vitamin D; IEP:RGD. 
Interpro
 IPR000494; EGF_rcpt_L.
 IPR003961; Fibronectin_type3.
 IPR006211; Furin-like_Cys-rich_dom.
 IPR006212; Furin_repeat.
 IPR009030; Growth_fac_rcpt_N_dom.
 IPR013783; Ig-like_fold.
 IPR011009; Kinase-like_dom.
 IPR000719; Prot_kinase_cat_dom.
 IPR017441; Protein_kinase_ATP_BS.
 IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
 IPR008266; Tyr_kinase_AS.
 IPR020635; Tyr_kinase_cat_dom.
 IPR016246; Tyr_kinase_insulin-like_rcpt.
 IPR002011; Tyr_kinase_rcpt_2_CS. 
Pfam
 PF00041; fn3
 PF00757; Furin-like
 PF07714; Pkinase_Tyr
 PF01030; Recep_L_domain 
SMART
 SM00060; FN3
 SM00261; FU
 SM00219; TyrKc 
PROSITE
 PS50853; FN3
 PS00107; PROTEIN_KINASE_ATP
 PS50011; PROTEIN_KINASE_DOM
 PS00109; PROTEIN_KINASE_TYR
 PS00239; RECEPTOR_TYR_KIN_II 
PRINTS
 PR00109; TYRKINASE.