P06213

※ Protein Information

Tag	Content
UniProt Accession	INSR_HUMAN; P06213;
Entrez ID	3643
GenBank Protein ID	NM_000208.3; NM_001079817.2;
GenBank Nucleotide ID	NP_000199.2; NP_001073285.1;
Protein Name	Insulin receptor (IR) (EC 2.7.10.1) (CD antigen CD220) [Cleaved into: Insulin receptor subunit alpha; Insulin receptor subunit beta]
Gene Name	INSR
Organism	Homo sapiens
NCBI Taxa ID	9606
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 phosphotyrosine residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs pr(view all) 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 phosphotyrosine 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). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.
Sequence (Fasta)	MATGGRRGAA AAPLLVAVAA LLLGAAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL 60 QILLMFKTRP EDFRDLSFPK LIMITDYLLL FRVYGLESLK DLFPNLTVIR GSRLFFNYAL 120 VIFEMVHLKE LGLYNLMNIT RGSVRIEKNN ELCYLATIDW SRILDSVEDN YIVLNKDDNE 180 ECGDICPGTA KGKTNCPATV INGQFVERCW THSHCQKVCP TICKSHGCTA EGLCCHSECL 240 GNCSQPDDPT KCVACRNFYL DGRCVETCPP PYYHFQDWRC VNFSFCQDLH HKCKNSRRQG 300 CHQYVIHNNK CIPECPSGYT MNSSNLLCTP CLGPCPKVCH LLEGEKTIDS VTSAQELRGC 360 TVINGSLIIN IRGGNNLAAE LEANLGLIEE ISGYLKIRRS YALVSLSFFR KLRLIRGETL 420 EIGNYSFYAL DNQNLRQLWD WSKHNLTITQ GKLFFHYNPK LCLSEIHKME EVSGTKGRQE 480 RNDIALKTNG DQASCENELL KFSYIRTSFD KILLRWEPYW PPDFRDLLGF MLFYKEAPYQ 540 NVTEFDGQDA CGSNSWTVVD IDPPLRSNDP KSQNHPGWLM RGLKPWTQYA IFVKTLVTFS 600 DERRTYGAKS DIIYVQTDAT NPSVPLDPIS VSNSSSQIIL KWKPPSDPNG NITHYLVFWE 660 RQAEDSELFE LDYCLKGLKL PSRTWSPPFE SEDSQKHNQS EYEDSAGECC SCPKTDSQIL 720 KELEESSFRK TFEDYLHNVV FVPRKTSSGT GAEDPRPSRK RRSLGDVGNV TVAVPTVAAF 780 PNTSSTSVPT SPEEHRPFEK VVNKESLVIS GLRHFTGYRI ELQACNQDTP EERCSVAAYV 840 SARTMPEAKA DDIVGPVTHE IFENNVVHLM WQEPKEPNGL IVLYEVSYRR YGDEELHLCV 900 SRKHFALERG CRLRGLSPGN YSVRIRATSL AGNGSWTEPT YFYVTDYLDV PSNIAKIIIG 960 PLIFVFLFSV VIGSIYLFLR KRQPDGPLGP LYASSNPEYL SASDVFPCSV YVPDEWEVSR 1020 EKITLLRELG QGSFGMVYEG NARDIIKGEA ETRVAVKTVN ESASLRERIE FLNEASVMKG 1080 FTCHHVVRLL GVVSKGQPTL VVMELMAHGD LKSYLRSLRP EAENNPGRPP PTLQEMIQMA 1140 AEIADGMAYL NAKKFVHRDL AARNCMVAHD FTVKIGDFGM TRDIYETDYY RKGGKGLLPV 1200 RWMAPESLKD GVFTTSSDMW SFGVVLWEIT SLAEQPYQGL SNEQVLKFVM DGGYLDQPDN 1260 CPERVTDLMR MCWQFNPKMR PTFLEIVNLL KDDLHPSFPE VSFFHSEENK APESEELEME 1320 FEDMENVPLD RSSHCQREEA GGRDGGSSLG FKRSYEEHIP YTHMNGGKKN GRILTLPRSN 1380 PS 1383 Fasta Sequence >P06213\|INSR\|Homo sapiens (Human) MATGGRRGAAAAPLLVAVAALLLGAAGHLYPGEVCPGMDIRNNLTRLHELENCSVIEGHLQILLMFKTRPEDFRDLSFPKLIMITDYLLLFRVYGLESLKDLFPNLTVIRGSRLFFNYALVIFEMVHLKELGLYNLMNITRGSVRIEKNNELCYLATIDWSRILDSVEDNYIVLNKDDNEECGDICPGTAKGKTNCPATVINGQFVERCWTHSHCQKVCPTICKSHGCTAEGLCCHSECLGNCSQPDDPTKCVACRNFYLDGRCVETCPPPYYHFQDWRCVNFSFCQDLHHKCKNSRRQGCHQYVIHNNKCIPECPSGYTMNSSNLLCTPCLGPCPKVCHLLEGEKTIDSVTSAQELRGCTVINGSLIINIRGGNNLAAELEANLGLIEEISGYLKIRRSYALVSLSFFRKLRLIRGETLEIGNYSFYALDNQNLRQLWDWSKHNLTITQGKLFFHYNPKLCLSEIHKMEEVSGTKGRQERNDIALKTNGDQASCENELLKFSYIRTSFDKILLRWEPYWPPDFRDLLGFMLFYKEAPYQNVTEFDGQDACGSNSWTVVDIDPPLRSNDPKSQNHPGWLMRGLKPWTQYAIFVKTLVTFSDERRTYGAKSDIIYVQTDATNPSVPLDPISVSNSSSQIILKWKPPSDPNGNITHYLVFWERQAEDSELFELDYCLKGLKLPSRTWSPPFESEDSQKHNQSEYEDSAGECCSCPKTDSQILKELEESSFRKTFEDYLHNVVFVPRKTSSGTGAEDPRPSRKRRSLGDVGNVTVAVPTVAAFPNTSSTSVPTSPEEHRPFEKVVNKESLVISGLRHFTGYRIELQACNQDTPEERCSVAAYVSARTMPEAKADDIVGPVTHEIFENNVVHLMWQEPKEPNGLIVLYEVSYRRYGDEELHLCVSRKHFALERGCRLRGLSPGNYSVRIRATSLAGNGSWTEPTYFYVTDYLDVPSNIAKIIIGPLIFVFLFSVVIGSIYLFLRKRQPDGPLGPLYASSNPEYLSASDVFPCSVYVPDEWEVSREKITLLRELGQGSFGMVYEGNARDIIKGEAETRVAVKTVNESASLRERIEFLNEASVMKGFTCHHVVRLLGVVSKGQPTLVVMELMAHGDLKSYLRSLRPEAENNPGRPPPTLQEMIQMAAEIADGMAYLNAKKFVHRDLAARNCMVAHDFTVKIGDFGMTRDIYETDYYRKGGKGLLPVRWMAPESLKDGVFTTSSDMWSFGVVLWEITSLAEQPYQGLSNEQVLKFVMDGGYLDQPDNCPERVTDLMRMCWQFNPKMRPTFLEIVNLLKDDLHPSFPEVSFFHSEENKAPESEELEMEFEDMENVPLDRSSHCQREEAGGRDGGSSLGFKRSYEEHIPYTHMNGGKKNGRILTLPRSNPS

※ PTM-Disease Association

Num	PTM	Disease	Type	PTM Site	PMID
1	Tyrosine Phosphorylation	Diabetes mellitus	D	Y1149	17272402
1	[Reference]: Tissue kallikrein reverses insulin resistance and attenuates nephropathy in diabetic rats by activation of phosphatidylinositol 3-kinase/protein kinase B and adenosine 5'-monophosphate-activated protein kinase signaling pathways.
2	Tyrosine Phosphorylation	Neuroblastoma	U	Y1185	24349301
2	[Reference]: Increased in NB10 cells (MYCN amplified neuroblastoma line) compared to NPC cells (normal neural crest line)
3	Tyrosine Phosphorylation	Neuroblastoma	U	Y1189	24349301
3	[Reference]: Increased in NB10 cells (MYCN amplified neuroblastoma line) compared to NPC cells (normal neural crest line)

※ Disease Cross-ref Annotation

Database	Annotation
CTD (Curated) (count: 16) (view all)	MESH:D000544 ; Alzheimer Disease MESH:D003921 ; Diabetes Mellitus, Experimental MESH:C562710 ; Diabetes Mellitus, Insulin-Resistant, with Acanthosis Nigricans MESH:D003929 ; Diabetic Neuropathies MESH:D056731 ; Donohue Syndrome MESH:D018149 ; Glucose Intolerance MESH:D065630 ; Hernias, Diaphragmatic, Congenital MESH:D006930 ; Hyperalgesia MESH:D006943 ; Hyperglycemia MESH:C566494 ; Hyperinsulinemic Hypoglycemia, Familial, 5 MESH:D006946 ; Hyperinsulinism MESH:D007333 ; Insulin Resistance MESH:D020961 ; Lewy Body Disease MESH:D008171 ; Lung Diseases MESH:D010300 ; Parkinson Disease MESH:D019966 ; Substance-Related Disorders
DisGeNet (Curated) (count: 138) (view all)	C0000731; Abdomen distended C0000889; Acanthosis Nigricans C0001206; Acromegaly C0002395; Alzheimer's Disease C0006625; Cachexia C0008370; Cholestasis C0011849; Diabetes Mellitus C0011853; Diabetes Mellitus, Experimental C0011860; Diabetes Mellitus, Non-Insulin-Dependent C0011880; Diabetic Ketoacidosis C0011882; Diabetic Neuropathies C0015300; Exophthalmos C0015934; Fetal Growth Retardation C0017566; Gingival Hyperplasia C0017567; Gingival Hypertrophy C0018418; Gynecomastia C0019294; Hernia, Inguinal C0019322; Umbilical hernia C0020429; Hyperalgesia C0020456; Hyperglycemia C0020459; Hyperinsulinism C0020534; Orbital separation excessive C0020555; Hypertrichosis C0020615; Hypoglycemia C0020617; Hypoglycemic coma C0021296; Infant, Small for Gestational Age C0021655; Insulin Resistance C0024032; Low Birth Weights C0024115; Lung diseases C0024433; Macrostomia C0029927; Ovarian Cysts C0030567; Parkinson Disease C0031117; Peripheral Neuropathy C0033687; Proteinuria C0034012; Delayed Puberty C0034013; Precocious Puberty C0040128; Thyroid Diseases C0151811; Subcutaneous nodule C0151908; Dry skin C0152421; Macrotia C0156394; Hypertrophy of clitoris C0221357; Brachydactyly C0234958; muscle degeneration C0235833; Congenital diaphragmatic hernia C0235986; Growth hormone excess C0235991; Small for gestational age (disorder) C0236969; Substance-Related Disorders C0238394; Female Pseudohermaphroditism C0239234; Low set ears C0239946; Fibrosis, Liver C0239998; Recurrent infections C0240635; Byzanthine arch palate C0259817; Xerosis C0263536; Hypertrophy of nail C0263537; Onychogryposis C0265344; Donohue Syndrome C0266054; Premature tooth eruption C0266617; Congenital anomaly of face C0269011; Increased size of penis C0270948; Neurogenic Muscular Atrophy C0271650; Impaired glucose tolerance C0271695; Rabson-Mendenhall Syndrome C0271708; Fasting Hypoglycemia C0277959; Coarse hair C0302501; Mandibular hyperplasia C0332606; Elfin facies C0338656; Impaired cognition C0342278; Diabetes Mellitus, Insulin-Resistant, with Acanthosis Nigricans C0342336; Insulin resistance - type A C0349588; Short stature C0376480; Gingival Overgrowth C0399526; Class III malocclusion C0424503; Dysmorphic facies C0426870; Large hand C0442874; Neuropathy C0541764; Delayed bone age C0541794; Skeletal muscle atrophy C0545053; Advanced bone age C0554972; Large auricle C0557874; Global developmental delay C0576225; Long foot C0597167; Islets of Langerhans hyperplasia C0683322; Mental impairment C0746926; Multiple, subcutaneous nodules C0752347; Lewy Body Disease C0854110; Insulin resistant diabetes C0870082; Hyperkeratosis C0877056; Hypoglycaemic seizure C1280433; Lipoatrophy C1385263; facial deformity C1386048; Intrauterine retardation C1834405; Nail dysplasia C1835581; Large protruding ears C1836542; Depressed nasal bridge C1836940; Excess nuchal skin C1837404; High, narrow palate C1837760; Prominent eyes C1839739; Prominent lower lip C1842774; Hyperpigmented macules C1843479; Neurogenic muscle atrophy, especially in the lower limbs C1844809; Thick nasal alae C1845847; Coarse facial features C1848490; Protruding eyes C1848570; Large, floppy ears C1849211; Generalized hirsutism C1850189; Large pinnae C1855062; Large dysplastic ears C1855513; Prominent nipples C1855514; Severe failure to thrive C1855520; Hyperglycemia, Postprandial C1855538; Small face C1857486; Low-set, posteriorly rotated ears C1857656; Precociously senile appearance C1859778; Postnatal growth retardation C1860838; Large prominent ears C1862425; Prominent globes C1864897; Cognitive delay C1864903; Hyperinsulinaemic hypoglycaemia C1864952; Hyperinsulinemic Hypoglycemia, Familial, 5 C1864954; Hyperinsulinemia, fasting C2053437; Full lower lip C2227134; mandibular excess (physical finding) C2674608; Feeding difficulties in infancy C3550546; Depressed nasal root/bridge C3806482; Recurrent respiratory infections C4020875; Mental and motor retardation C4020899; Autosomal recessive predisposition C4021664; Abnormality of the abdominal wall C4024615; Adipose tissue loss C4024878; Generalized hyperpigmentation C4025860; Hearing abnormality C4072825; Thickened facial skin with coarse facial features C4072832; Distortion of face C4072833; Funny looking face C4072834; Rough hair texture C4280495; Concave bridge of nose C4280644; Increased size of mandible C4280645; Hypertrophy of lower jaw
GWASdb (count: 29) (view all)	rs1864193; Alcohol dependence; alcohol dependence rs1549616; Salmonella-induced pyroptosis; Null rs11667110; Aortic root size; cardiovascular system disease rs16994200; Multiple complex diseases; Null rs2059807; Polycystic ovary syndrome; polycystic ovary syndrome rs3815901; Triglycerides; coronary artery disease\|lipid metabolism disorder\|arteriosclerosis rs2303672; Triglycerides; coronary artery disease\|lipid metabolism disorder\|arteriosclerosis rs8112883; Triglycerides; coronary artery disease\|lipid metabolism disorder\|arteriosclerosis rs8108622; Height; Null rs10500204; Alcohol dependence; alcohol dependence rs891088; Height; Null rs2115386; Amyotrophic Lateral Sclerosis; amyotrophic lateral sclerosis rs2115386; Diabetic retinopathy; diabetic retinopathy rs1035942; Urate levels; gout rs2042902; Diabetic retinopathy; diabetic retinopathy rs12609995; Triglycerides; coronary artery disease\|lipid metabolism disorder\|arteriosclerosis rs7508679; Type 2 diabetes; type 2 diabetes mellitus rs7508679; Hypothyroidism; hypothyroidism rs4804416; Hypothyroidism; hypothyroidism rs4804416; Thyroid hormone levels; hypothyroidism\|hyperthyroidism rs7248104; Type 2 diabetes; type 2 diabetes mellitus rs7248104; Hypothyroidism; hypothyroidism rs7248104; Triglycerides; coronary artery disease\|lipid metabolism disorder\|arteriosclerosis rs4804418; Triglycerides; coronary artery disease\|lipid metabolism disorder\|arteriosclerosis rs4804424; Type 2 diabetes; type 2 diabetes mellitus rs12460755; Fasting insulin-related traits; type 2 diabetes mellitus rs890862; Myocardial infarction; myocardial infarction rs4804103; Schizophrenia; schizophrenia rs11673642; Obesity (extreme); obesity

※ PTM Sites

PTM	Modification Sites
Phosphorylation (count: 40) (view all)	1001 SSNPEYLSASDVFPC dbPAF 1011 DVFPCSVYVPDEWEV dbPAF 1033 LRELGQGSFGMVYEG dbPAF 1038 QGSFGMVYEGNARDI dbPAF 1062 AVKTVNESASLRERI dbPAF 1064 KTVNESASLRERIEF dbPAF 1149 EIADGMAYLNAKKFV dbPAF 1185 FGMTRDIYETDYYRK dbPAF 1187 MTRDIYETDYYRKGG dbPAF 1189 RDIYETDYYRKGGKG dbPAF 1190 DIYETDYYRKGGKGL dbPAF 1216 KDGVFTTSSDMWSFG dbPAF 1217 DGVFTTSSDMWSFGV dbPAF 1221 TTSSDMWSFGVVLWE dbPAF 1314 EENKAPESEELEMEF dbPAF 1332 ENVPLDRSSHCQREE dbPAF 1333 NVPLDRSSHCQREEA dbPAF 1348 GGRDGGSSLGFKRSY dbPAF 1354 SSLGFKRSYEEHIPY dbPAF 1355 SLGFKRSYEEHIPYT dbPAF 1361 SYEEHIPYTHMNGGK dbPAF 1362 YEEHIPYTHMNGGKK dbPAF 1375 KKNGRILTLPRSNPS dbPAF 1379 RILTLPRSNPS**** dbPAF 361 AQELRGCTVINGSLI dbPAF 366 GCTVINGSLIINIRG dbPAF 400 GYLKIRRSYALVSLS dbPAF 401 YLKIRRSYALVSLSF dbPAF 407 SYALVSLSFFRKLRL dbPAF 464 YNPKLCLSEIHKMEE dbPAF 715 ECCSCPKTDSQILKE dbPAF 717 CSCPKTDSQILKELE dbPAF 731 EESSFRKTFEDYLHN dbPAF 818 GLRHFTGYRIELQAC dbPAF 929 SVRIRATSLAGNGSW dbPAF 94 YLLLFRVYGLESLKD dbPAF 940 NGSWTEPTYFYVTDY dbPAF 98 FRVYGLESLKDLFPN dbPAF 992 DGPLGPLYASSNPEY dbPAF 999 YASSNPEYLSASDVF dbPAF
Acetylation (count: 1)	1112 LMAHGDLKSYLRSLR PLMD
Ubiquitination (count: 8) (view all)	1022 EWEVSREKITLLREL PLMD 1047 GNARDIIKGEAETRV PLMD 1057 AETRVAVKTVNESAS PLMD 1095 RLLGVVSKGQPTLVV PLMD 1192 YETDYYRKGGKGLLP PLMD 1195 DYYRKGGKGLLPVRW PLMD 129 IFEMVHLKELGLYNL PLMD 1352 GGSSLGFKRSYEEHI PLMD
Methylation (count: 1)	1352 GGSSLGFKRSYEEHI PLMD

※ Protein-Protein Interaction

Network

Interaction

Source

O14508	P06213	HPRD
O14543	P06213	HPRD
O15524	P06213	HPRD
O60674	P06213	HPRD
P04049	P06213	HPRD
P06213	P08069	HPRD
P06213	P12931	HPRD
P06213	P15498	HPRD
P06213	P17252	HPRD
P06213	P19174	MINT
P06213	P20936	HPRD; MINT
P06213	P22681	HPRD
P06213	P23458	HPRD
P06213	P23470	IntAct
P06213	P27361	HPRD
P06213	P27986	HPRD; DIP; MINT
P06213	P29353	DIP; IntAct; MINT
P06213	P35568	HPRD; DIP; IntAct; MINT
P06213	P42229	HPRD
P06213	P46108	HPRD
P06213	P46109	HPRD; IntAct
P06213	P51692	HPRD
P06213	P62158	HPRD
P06213	Q03135	HPRD
P06213	Q05655	HPRD
P06213	Q06124	MINT
P06213	Q07666	HPRD
P06213	Q15796	HPRD
P06213	Q9Y4H2	HPRD; MINT

PTMD Annotation Information

※ Protein Information

Functional Description

Fasta Sequence

※ PTM-Disease Association

※ Disease Cross-ref Annotation

※ PTM Sites

※ Protein-Protein Interaction