CPLM 1.0 - Compendium of Protein Lysine Modification
TagContent
CPLM ID CPLM-004313
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
 Mus musculus (Mouse) 
NCBI Taxa ID
 10090 
Lysine Modification
Position
Peptide
Type
References
1012EWEVPREKITLLRELubiquitination[1]
1037GNAKDIIKGEAETRVubiquitination[1]
1047AETRVAVKTVNESASubiquitination[1]
Reference
 [1] 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 624 697 Fibronectin type-III 1.
 DOMAIN 747 832 Fibronectin type-III 2.
 DOMAIN 840 936 Fibronectin type-III 3.
 DOMAIN 1013 1288 Protein kinase.
 NP_BIND 1094 1100 ATP (By similarity).
 NP_BIND 1153 1154 ATP (By similarity).
 REGION 735 743 Insulin-binding (By similarity).
 REGION 986 989 Important for interaction with IRS1, SHC1
 REGION 1351 1354 PIK3R1 binding (By similarity).
 ACT_SITE 1149 1149 Proton donor/acceptor (By similarity).
 BINDING 1023 1023 ATP (By similarity).
 BINDING 1047 1047 ATP.
 BINDING 1167 1167 ATP (By similarity).
 MOD_RES 400 400 Phosphoserine (By similarity).
 MOD_RES 401 401 Phosphotyrosine (By similarity).
 MOD_RES 407 407 Phosphoserine (By similarity).
 MOD_RES 989 989 Phosphotyrosine; by autocatalysis (By
 MOD_RES 1175 1175 Phosphotyrosine; by autocatalysis (By
 MOD_RES 1179 1179 Phosphotyrosine; by autocatalysis (By
 MOD_RES 1180 1180 Phosphotyrosine; by autocatalysis (By
 MOD_RES 1345 1345 Phosphotyrosine; by autocatalysis (By
 MOD_RES 1351 1351 Phosphotyrosine; by autocatalysis (By
 CARBOHYD 43 43 N-linked (GlcNAc...) (Potential).
 CARBOHYD 52 52 N-linked (GlcNAc...) (Potential).
 CARBOHYD 105 105 N-linked (GlcNAc...) (Potential).
 CARBOHYD 138 138 N-linked (GlcNAc...) (Potential).
 CARBOHYD 242 242 N-linked (GlcNAc...) (Potential).
 CARBOHYD 282 282 N-linked (GlcNAc...) (Potential).
 CARBOHYD 322 322 N-linked (GlcNAc...) (Potential).
 CARBOHYD 364 364 N-linked (GlcNAc...) (Potential).
 CARBOHYD 424 424 N-linked (GlcNAc...) (Potential).
 CARBOHYD 445 445 N-linked (GlcNAc...).
 CARBOHYD 541 541 N-linked (GlcNAc...) (Potential).
 CARBOHYD 635 635 N-linked (GlcNAc...) (Potential).
 CARBOHYD 653 653 N-linked (GlcNAc...) (Potential).
 CARBOHYD 700 700 N-linked (GlcNAc...) (Potential).
 CARBOHYD 759 759 N-linked (GlcNAc...) (Potential).
 CARBOHYD 772 772 N-linked (GlcNAc...) (Potential).
 CARBOHYD 910 910 N-linked (GlcNAc...) (Potential).
 CARBOHYD 923 923 N-linked (GlcNAc...) (Potential).
 DISULFID 35 53 By similarity.
 DISULFID 153 182 By similarity.
 DISULFID 186 209 By similarity.
 DISULFID 196 215 By similarity.
 DISULFID 219 228 By similarity.
 DISULFID 223 234 By similarity.
 DISULFID 235 243 By similarity.
 DISULFID 239 252 By similarity.
 DISULFID 255 264 By similarity.
 DISULFID 268 280 By similarity.
 DISULFID 286 311 By similarity.
 DISULFID 293 301 By similarity.
 DISULFID 315 328 By similarity.
 DISULFID 331 335 By similarity.
 DISULFID 339 360 By similarity.
 DISULFID 462 495 By similarity.
 DISULFID 551 551 Interchain (By similarity).
 DISULFID 676 889 By similarity.
 DISULFID 815 824 By similarity.  
Keyword
 3D-structure; 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
 1372 AA 
Protein Sequence
MGFGRGCETT AVPLLVAVAA LLVGTAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL 60
QILLMFKTRP EDFRDLSFPK LIMITDYLLL FRVYGLESLK DLFPNLTVIR GSRLFFNYAL 120
VIFEMVHLKE LGLYNLMNIT RGSVRIEKNN ELCYLATIDW SRILDSVEDN YIVLNKDDNE 180
ECGDVCPGTA KGKTNCPATV INGQFVERCW THSHCQKVCP TICKSHGCTA EGLCCHKECL 240
GNCSEPDDPT KCVACRNFYL DGQCVETCPP PYYHFQDWRC VNFSFCQDLH FKCRNSRKPG 300
CHQYVIHNNK CIPECPSGYT MNSSNLMCTP CLGPCPKVCQ ILEGEKTIDS VTSAQELRGC 360
TVINGSLIIN IRGGNNLAAE LEANLGLIEE ISGFLKIRRS YALVSLSFFR KLHLIRGETL 420
EIGNYSFYAL DNQNLRQLWD WSKHNLTITQ GKLFFHYNPK LCLSEIHKME EVSGTKGRQE 480
RNDIALKTNG DQASCENELL KFSFIRTSFD KILLRWEPYW PPDFRDLLGF MLFYKEAPYQ 540
NVTEFDGQDA CGSNSWTVVD IDPPQRSNDP KSQTPSHPGW LMRGLKPWTQ YAIFVKTLVT 600
FSDERRTYGA KSDIIYVQTD ATNPSVPLDP ISVSNSSSQI ILKWKPPSDP NGNITHYLVY 660
WERQAEDSEL FELDYCLKGL KLPSRTWSPP FESDDSQKHN QSEYDDSASE CCSCPKTDSQ 720
ILKELEESSF RKTFEDYLHN VVFVPRPSRK RRSLEEVGNV TATTLTLPDF PNVSSTIVPT 780
SQEEHRPFEK VVNKESLVIS GLRHFTGYRI ELQACNQDSP DERCSVAAYV SARTMPEAKA 840
DDIVGPVTHE IFENNVVHLM WQEPKEPNGL IVLYEVSYRR YGDEELHLCV SRKHFALERG 900
CRLRGLSPGN YSVRVRATSL AGNGSWTEPT YFYVTDYLDV PSNIAKIIIG PLIFVFLFSV 960
VIGSIYLFLR KRQPDGPMGP LYASSNPEYL SASDVFPSSV YVPDEWEVPR EKITLLRELG 1020
QGSFGMVYEG NAKDIIKGEA ETRVAVKTVN ESASLRERIE FLNEASVMKG FTCHHVVRLL 1080
GVVSKGQPTL VVMELMAHGD LKSHLRSLRP DAENNPGRPP PTLQEMIQMT AEIADGMAYL 1140
NAKKFVHRDL AARNCMVAHD FTVKIGDFGM TRDIYETDYY RKGGKGLLPV RWMSPESLKD 1200
GVFTASSDMW SFGVVLWEIT SLAEQPYQGL SNEQVLKFVM DGGYLDPPDN CPERLTDLMR 1260
MCWQFNPKMR PTFLEIVNLL KDDLHPSFPE VSFFYSEENK APESEELEME FEDMENVPLD 1320
RSSHCQREEA GGREGGSSLS IKRTYDEHIP YTHMNGGKKN GRVLTLPRSN PS 1372 
Gene Ontology
 GO:0005901; C:caveola; IDA:MGI.
 GO:0005899; C:insulin receptor complex; IEA:Compara.
 GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 GO:0005525; F:GTP binding; IEA:Compara.
 GO:0043559; F:insulin binding; ISS:UniProtKB.
 GO:0043560; F:insulin receptor substrate binding; ISS:UniProtKB.
 GO:0005009; F:insulin-activated receptor activity; ISS:UniProtKB.
 GO:0043548; F:phosphatidylinositol 3-kinase binding; ISS:UniProtKB.
 GO:0051425; F:PTB domain binding; ISS:UniProtKB.
 GO:0004716; F:receptor signaling protein tyrosine kinase activity; IEA:Compara.
 GO:0042169; F:SH2 domain binding; ISS:UniProtKB.
 GO:0000187; P:activation of MAPK activity; IEA:Compara.
 GO:0032148; P:activation of protein kinase B activity; IEA:Compara.
 GO:0071363; P:cellular response to growth factor stimulus; IDA:MGI.
 GO:0031017; P:exocrine pancreas development; IMP:MGI.
 GO:0007186; P:G-protein coupled receptor signaling pathway; IEA:Compara.
 GO:0042593; P:glucose homeostasis; IEA:Compara.
 GO:0003007; P:heart morphogenesis; IEA:Compara.
 GO:0030238; P:male sex determination; IMP:MGI.
 GO:0009887; P:organ morphogenesis; IMP:MGI.
 GO:0018108; P:peptidyl-tyrosine phosphorylation; IEA:Compara.
 GO:0030335; P:positive regulation of cell migration; IEA:Compara.
 GO:0048639; P:positive regulation of developmental growth; IEA:Compara.
 GO:0045740; P:positive regulation of DNA replication; IEA:Compara.
 GO:0045725; P:positive regulation of glycogen biosynthetic process; IMP:BHF-UCL.
 GO:0045821; P:positive regulation of glycolysis; IEA:Compara.
 GO:0045840; P:positive regulation of mitosis; IEA:Compara.
 GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IEA:Compara.
 GO:0051897; P:positive regulation of protein kinase B signaling cascade; IEA:Compara.
 GO:0060267; P:positive regulation of respiratory burst; IEA:Compara.
 GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
 GO:0051290; P:protein heterotetramerization; ISS:UniProtKB.
 GO:0045995; P:regulation of embryonic development; IEA:Compara.
 GO:0006355; P:regulation of transcription, DNA-dependent; IEA:Compara.
 GO:0019087; P:transformation of host cell by virus; IEA:Compara. 
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.