INSR (insulin receptor)

Gene

• Entrez ID: 3643
• Gene name: Insulin receptor
• Gene symbol: INSR
• Synonyms: CD220, HHF5
• Chromosome: 19
• Chromosome location: 19p13.2
• Summary: This gene encodes a member of the receptor tyrosine kinase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form a heterotetrameric receptor. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. Mutations in this gene underlie the inherited severe insulin resistance syndromes including type A insulin resistance syndrome, Donohue syndrome and Rabson-Mendenhall syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs1799816	C>T	Benign, likely-benign, uncertain-significance, conflicting-interpretations-of-pathogenicity, benign-likely-benign	Coding sequence variant, missense variant
rs41304772	C>T	Conflicting-interpretations-of-pathogenicity	Coding sequence variant, synonymous variant
rs52836744	C>T	Pathogenic	Coding sequence variant, missense variant
rs121913135	C>A	Pathogenic	Coding sequence variant, missense variant
rs121913136	T>C	Pathogenic	Coding sequence variant, missense variant
rs121913137	G>A,C	Pathogenic	Coding sequence variant, missense variant, stop gained
rs121913138	C>A	Pathogenic	Coding sequence variant, missense variant
rs121913139	C>T	Pathogenic	Coding sequence variant, missense variant
rs121913140	C>G,T	Pathogenic	Stop gained, coding sequence variant, missense variant
rs121913141	A>C,G	Pathogenic	Coding sequence variant, missense variant
rs121913142	A>C	Pathogenic	Coding sequence variant, missense variant
rs121913143	G>T	Pathogenic	Coding sequence variant, missense variant
rs121913144	G>A	Pathogenic	Coding sequence variant, stop gained
rs121913145	T>C	Pathogenic	Coding sequence variant, missense variant
rs121913146	C>T	Pathogenic	Coding sequence variant, stop gained
rs121913147	T>C	Pathogenic	Coding sequence variant, missense variant
rs121913148	C>T	Pathogenic	Coding sequence variant, missense variant
rs121913150	C>T	Pathogenic	Coding sequence variant, missense variant
rs121913151	G>A	Pathogenic, uncertain-significance	Coding sequence variant, stop gained
rs121913152	A>G	Pathogenic	Coding sequence variant, missense variant
rs121913153	C>A,G,T	Pathogenic	Coding sequence variant, missense variant
rs121913154	G>A,T	Pathogenic	Coding sequence variant, missense variant
rs121913155	T>A	Pathogenic	Coding sequence variant, stop gained
rs121913156	C>T	Pathogenic	Coding sequence variant, missense variant
rs121913157	C>T	Pathogenic	Coding sequence variant, missense variant
rs121913158	C>G	Pathogenic	Coding sequence variant, missense variant
rs121913159	G>C	Pathogenic	Coding sequence variant, missense variant
rs121913160	T>C	Pathogenic	Coding sequence variant, missense variant
rs138528064	G>A	Likely-benign, conflicting-interpretations-of-pathogenicity	Coding sequence variant, missense variant
rs140573575	C>A,G,T	Benign, conflicting-interpretations-of-pathogenicity	Synonymous variant, coding sequence variant
rs140852238	C>T	Uncertain-significance, likely-benign, conflicting-interpretations-of-pathogenicity	Missense variant, coding sequence variant
rs146588336	G>C	Uncertain-significance, likely-benign, conflicting-interpretations-of-pathogenicity	Missense variant, coding sequence variant
rs147125937	C>T	Uncertain-significance, conflicting-interpretations-of-pathogenicity	Synonymous variant, coding sequence variant
rs149795690	A>G	Conflicting-interpretations-of-pathogenicity	Synonymous variant, coding sequence variant
rs201445608	C>G,T	Conflicting-interpretations-of-pathogenicity	Synonymous variant, coding sequence variant
rs267607184	C>T	Pathogenic	Missense variant, coding sequence variant
rs376497490	G>A,C	Conflicting-interpretations-of-pathogenicity	Synonymous variant, coding sequence variant, intron variant
rs387906538	G>A,C	Pathogenic	Stop gained, coding sequence variant, missense variant
rs587776819	T>C	Pathogenic	Splice acceptor variant
rs587776820	GTCCTGGT>-	Pathogenic	Frameshift variant, coding sequence variant
rs752552480	G>A	Likely-pathogenic	Coding sequence variant, missense variant
rs781007453	G>A,C	Pathogenic	Missense variant, coding sequence variant
rs797045624	A>G	Pathogenic	Splice donor variant
rs886037750	C>T	Pathogenic	Missense variant, coding sequence variant
rs1135401737	C>A	Pathogenic	Coding sequence variant, missense variant
rs1135401738	G>A	Pathogenic	Coding sequence variant, missense variant
rs1135401739	C>A	Pathogenic	Coding sequence variant, missense variant
rs1135401740	A>C	Pathogenic	Coding sequence variant, stop gained
rs1135401741	C>T	Pathogenic	Coding sequence variant, missense variant
rs1135401742	T>C	Pathogenic	Coding sequence variant, missense variant
rs1347163319	GTTA>-	Pathogenic	Frameshift variant, coding sequence variant
rs1555689937	A>G	Pathogenic	Coding sequence variant, missense variant
rs1555735951	ATCACTGGCA>CTTCC	Pathogenic	Frameshift variant, coding sequence variant
rs1555736246	GATA>-	Likely-pathogenic	Frameshift variant, coding sequence variant
rs1568426700	G>A	Pathogenic	Coding sequence variant, missense variant
rs1599874183	G>A	Likely-pathogenic	Coding sequence variant, missense variant
rs1599881881	A>G	Likely-pathogenic	Coding sequence variant, missense variant
rs1599937180	G>A	Likely-pathogenic	Stop gained, coding sequence variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT029227	hsa-miR-26b-5p	Microarray	19088304
MIRT438296	hsa-miR-195-5p	Luciferase reporter assay, qRT-PCR, Western blot	25240198
MIRT495786	hsa-miR-7108-3p	PAR-CLIP	22291592
MIRT731383	hsa-miR-15b-5p	Luciferase reporter assay, qRT-PCR, Western blot	26179126

Transcription factors

Transcription factor	Regulation	Reference
CEBPA	Activation	8288055
CEBPB	Activation	8288055
ESR2	Repression	22099628
HMGA1	Activation	16707431
HMGA1	Repression	17434141
SP1	Activation	1311316;16707431
SP1	Unknown	7983788

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000187	Process	Activation of MAPK activity	IMP	17001305
GO:0001540	Function	Amyloid-beta binding	IPI	19406747
GO:0001934	Process	Positive regulation of protein phosphorylation	IDA	7556070
GO:0002092	Process	Positive regulation of receptor internalization	IDA	25401701
GO:0003007	Process	Heart morphogenesis	IMP	7693131
GO:0004713	Function	Protein tyrosine kinase activity	IDA	8496180
GO:0004713	Function	Protein tyrosine kinase activity	IMP	7537849
GO:0004714	Function	Transmembrane receptor protein tyrosine kinase activity	IBA	21873635
GO:0005009	Function	Insulin-activated receptor activity	IBA	21873635
GO:0005009	Function	Insulin-activated receptor activity	IDA	6849137, 8440175
GO:0005159	Function	Insulin-like growth factor receptor binding	IDA	8452530
GO:0005515	Function	Protein binding	IPI	7493946, 7537849, 7935368, 8452530, 8702689, 8999839, 9506989, 9593725, 9742218, 10500481, 10660596, 11136729, 11163213, 11279102, 11289049, 11374898, 11506178, 11579209, 11796522, 12237455, 12634852, 14568990, 14722096, 15588987, 15629149, 16582879, 16926280, 17092689, 17135270, 171
GO:0005524	Function	ATP binding	IDA	6849137
GO:0005525	Function	GTP binding	IDA	9092559
GO:0005635	Component	Nuclear envelope	IDA	19406747
GO:0005764	Component	Lysosome	IEA
GO:0005770	Component	Late endosome	IEA
GO:0005886	Component	Plasma membrane	IC	6849137
GO:0005886	Component	Plasma membrane	IDA	23137377
GO:0005886	Component	Plasma membrane	TAS
GO:0005887	Component	Integral component of plasma membrane	IBA	21873635
GO:0005887	Component	Integral component of plasma membrane	IDA	9092559
GO:0005899	Component	Insulin receptor complex	IBA	21873635
GO:0005899	Component	Insulin receptor complex	IDA	1898103
GO:0005899	Component	Insulin receptor complex	IMP	15069075
GO:0005901	Component	Caveola	IDA	15182363
GO:0005975	Process	Carbohydrate metabolic process	IEA
GO:0006355	Process	Regulation of transcription, DNA-templated	IMP	12881524
GO:0006468	Process	Protein phosphorylation	TAS	19188609
GO:0006898	Process	Receptor-mediated endocytosis	ISS	19406747
GO:0007169	Process	Transmembrane receptor protein tyrosine kinase signaling pathway	IBA	21873635
GO:0007186	Process	G protein-coupled receptor signaling pathway	IDA	9092559
GO:0007275	Process	Multicellular organism development	IBA	21873635
GO:0007612	Process	Learning	TAS	19188609
GO:0007613	Process	Memory	TAS	19188609
GO:0008284	Process	Positive regulation of cell population proliferation	IC	11500939
GO:0008284	Process	Positive regulation of cell population proliferation	IDA	17925406
GO:0008284	Process	Positive regulation of cell population proliferation	IMP	12138094
GO:0008286	Process	Insulin receptor signaling pathway	IDA	6849137, 8440175, 20455999
GO:0008286	Process	Insulin receptor signaling pathway	ISS	19406747
GO:0008286	Process	Insulin receptor signaling pathway	TAS
GO:0009897	Component	External side of plasma membrane	ISS
GO:0010008	Component	Endosome membrane	TAS
GO:0014068	Process	Positive regulation of phosphatidylinositol 3-kinase signaling	IBA	21873635
GO:0016020	Component	Membrane	IDA	8452530
GO:0018108	Process	Peptidyl-tyrosine phosphorylation	IDA	8496180
GO:0019087	Process	Transformation of host cell by virus	IMP	17001305
GO:0019904	Function	Protein domain specific binding	IPI	16246733
GO:0030335	Process	Positive regulation of cell migration	IMP	12138094
GO:0030424	Component	Axon	IBA	21873635
GO:0031981	Component	Nuclear lumen	IDA	19406747
GO:0031994	Function	Insulin-like growth factor I binding	IPI	8452530
GO:0031995	Function	Insulin-like growth factor II binding	IPI	12138094
GO:0032147	Process	Activation of protein kinase activity	IMP	9819385
GO:0032148	Process	Activation of protein kinase B activity	IDA	7556070
GO:0032590	Component	Dendrite membrane	ISS
GO:0032809	Component	Neuronal cell body membrane	ISS
GO:0032869	Process	Cellular response to insulin stimulus	IDA	8440175
GO:0033674	Process	Positive regulation of kinase activity	IBA	21873635
GO:0038024	Function	Cargo receptor activity	ISS	19406747
GO:0042593	Process	Glucose homeostasis	IBA	21873635
GO:0042593	Process	Glucose homeostasis	IMP	7693131
GO:0043235	Component	Receptor complex	IBA	21873635
GO:0043235	Component	Receptor complex	IDA	23382219
GO:0043243	Process	Positive regulation of protein-containing complex disassembly	ISS	19406747
GO:0043410	Process	Positive regulation of MAPK cascade	IBA	21873635
GO:0043410	Process	Positive regulation of MAPK cascade	IDA	20455999
GO:0043410	Process	Positive regulation of MAPK cascade	IMP	11500939
GO:0043548	Function	Phosphatidylinositol 3-kinase binding	IPI	7537849, 8276809
GO:0043559	Function	Insulin binding	IDA	8440175
GO:0043559	Function	Insulin binding	IPI	8452530
GO:0043560	Function	Insulin receptor substrate binding	IBA	21873635
GO:0043560	Function	Insulin receptor substrate binding	IPI	7493946, 7537849, 7559478
GO:0044877	Function	Protein-containing complex binding	IPI	19406747
GO:0045429	Process	Positive regulation of nitric oxide biosynthetic process	IMP	10747347
GO:0045725	Process	Positive regulation of glycogen biosynthetic process	IDA	17925406
GO:0045821	Process	Positive regulation of glycolytic process	IMP	7693131
GO:0045840	Process	Positive regulation of mitotic nuclear division	IMP	11500939
GO:0045995	Process	Regulation of embryonic development	IMP	7693131
GO:0046326	Process	Positive regulation of glucose import	IDA	3518947
GO:0046326	Process	Positive regulation of glucose import	NAS	11001060
GO:0046777	Process	Protein autophosphorylation	IDA	6849137, 8496180
GO:0046777	Process	Protein autophosphorylation	IMP	7537849
GO:0048639	Process	Positive regulation of developmental growth	IMP	7693131
GO:0051425	Function	PTB domain binding	IPI	7559478
GO:0051897	Process	Positive regulation of protein kinase B signaling	IBA	21873635
GO:0051897	Process	Positive regulation of protein kinase B signaling	IMP	11500939
GO:0060267	Process	Positive regulation of respiratory burst	IDA	9092559
GO:0070062	Component	Extracellular exosome	HDA	20458337
GO:0097062	Process	Dendritic spine maintenance	ISS	19406747
GO:0097242	Process	Amyloid-beta clearance	ISS	19406747
GO:0150104	Process	Transport across blood-brain barrier	NAS	26590417, 30280653
GO:1990535	Process	Neuron projection maintenance	ISS

Other IDs

• MIM: 147670
• HGNC: 6091
• e!Ensembl: ENSG00000171105

Protein

• UniProt ID: P06213
• Protein name: Insulin receptor (IR) (EC 2.7.10.1) (CD antigen CD220) [Cleaved into: Insulin receptor subunit alpha; Insulin receptor subunit beta]
• Protein function: 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. In adipocytes, inhibits lipolysis (By similarity).
• PDB: 1GAG, 1I44, 1IR3, 1IRK, 1P14, 1RQQ, 2AUH, 2B4S, 2HR7, 2MFR, 2Z8C, 3BU3, 3BU5, 3BU6, 3EKK, 3EKN, 3ETA, 3W11, 3W12, 3W13, 4IBM, 4OGA, 4XLV, 4XSS, 4XST, 4ZXB, 5E1S, 5HHW, 5J3H, 5KQV, 5U1M, 6HN4, 6HN5, 6PXV, 6PXW, 6SOF, 6VEP, 6VEQ
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF01030	Recep_L_domain	52 → 164	Receptor L domain	Repeat
  PF00757	Furin-like	179 → 340	Furin-like cysteine rich region	Domain
  PF01030	Recep_L_domain	359 → 473	Receptor L domain	Repeat
  PF17870	Insulin_TMD	940 → 987	Insulin receptor trans-membrane segment	Domain
  PF07714	PK_Tyr_Ser-Thr	1023 → 1290	Protein tyrosine and serine/threonine kinase	Domain

• Sequence:

  MATGGRRGAAAAPLLVAVAALLLGAAGHLYPGEVCPGMDIRNNLTRLHELENCSVIEGHL
  QILLMFKTRPEDFRDLSFPKLIMITDYLLLFRVYGLESLKDLFPNLTVIRGSRLFFNYAL
  VIFEMVHLKELGLYNLMNITRGSVRIEKNNELCYLATIDWSRILDSVEDNYIVLNKDDNE
  ECGDICPGTAKGKTNCPATVINGQFVERCWTHSHCQKVCPTICKSHGCTAEGLCCHSECL
  GNCSQPDDPTKCVACRNFYLDGRCVETCPPPYYHFQDWRCVNFSFCQDLHHKCKNSRRQG
  CHQYVIHNNKCIPECPSGYTMNSSNLLCTPCLGPCPKVCHLLEGEKTIDSVTSAQELRGC
  TVINGSLIINIRGGNNLAAELEANLGLIEEISGYLKIRRSYALVSLSFFRKLRLIRGETL
  EIGNYSFYALDNQNLRQLWDWSKHNLTITQGKLFFHYNPKLCLSEIHKMEEVSGTKGRQE
  RNDIALKTNGDQASCENELLKFSYIRTSFDKILLRWEPYWPPDFRDLLGFMLFYKEAPYQ
  NVTEFDGQDACGSNSWTVVDIDPPLRSNDPKSQNHPGWLMRGLKPWTQYAIFVKTLVTFS
  DERRTYGAKSDIIYVQTDATNPSVPLDPISVSNSSSQIILKWKPPSDPNGNITHYLVFWE
  RQAEDSELFELDYCLKGLKLPSRTWSPPFESEDSQKHNQSEYEDSAGECCSCPKTDSQIL
  KELEESSFRKTFEDYLHNVVFVPRKTSSGTGAEDPRPSRKRRSLGDVGNVTVAVPTVAAF
  PNTSSTSVPTSPEEHRPFEKVVNKESLVISGLRHFTGYRIELQACNQDTPEERCSVAAYV
  SARTMPEAKADDIVGPVTHEIFENNVVHLMWQEPKEPNGLIVLYEVSYRRYGDEELHLCV
  SRKHFALERGCRLRGLSPGNYSVRIRATSLAGNGSWTEPTYFYVTDYLDVPSNIAKIIIG
  PLIFVFLFSVVIGSIYLFLRKRQPDGPLGPLYASSNPEYLSASDVFPCSVYVPDEWEVSR
  EKITLLRELGQGSFGMVYEGNARDIIKGEAETRVAVKTVNESASLRERIEFLNEASVMKG
  FTCHHVVRLLGVVSKGQPTLVVMELMAHGDLKSYLRSLRPEAENNPGRPPPTLQEMIQMA
  AEIADGMAYLNAKKFVHRDLAARNCMVAHDFTVKIGDFGMTRDIYETDYYRKGGKGLLPV
  RWMAPESLKDGVFTTSSDMWSFGVVLWEITSLAEQPYQGLSNEQVLKFVMDGGYLDQPDN
  CPERVTDLMRMCWQFNPKMRPTFLEIVNLLKDDLHPSFPEVSFFHSEENKAPESEELEME
  FEDMENVPLDRSSHCQREEAGGRDGGSSLGFKRSYEEHIPYTHMNGGKKNGRILTLPRSN
  PS

• Sequence length: 1382