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Sep. 10, 2014:
A total of 174 experimentally verified S-nitrosylation sites on 94 S-nitrosylated proteins from individualized human colorectal cancer tissues using a label-free quantitation strategy.

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Protein Name: Insulin receptor

UniprotKB/SwissProt ID: INSR_HUMAN (P06213)

Gene Name: INSR

Organism: Homo sapiens (Human).

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 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). 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.

Other Modifications: View all modification sites in dbPTM

Protein Subcellular Localization: Cell membrane; Single-pass type I membrane protein.

PDB :
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Protein disease:
Disease database Database Entry Disease information
KEGGH00719 Leprechaunism; Donohue syndrome
KEGGH00942 Rabson-Mendenhall syndrome
KEGGH01228 Insulin-resistant diabetes mellitus with acanthosis nigricans (IRAN); Type A insulin resistance
KEGGH01267 Familial hyperinsulinemic hypoglycemia (HHF)
OMIM147670INSULIN RECEPTOR; INSR
OMIM246200DONOHUE SYNDROME ;;LEPRECHAUNISM INSULIN RECEPTOR, DEFECT IN, INCLUDED
OMIM262190PINEAL HYPERPLASIA, INSULIN-RESISTANT DIABETES MELLITUS, AND SOMATIC ABNORMALITIES ;;MENDENH
OMIM609968HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 5; HHF5
OMIM610549DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS ;;INSULIN RECEPTOR, DEFECT I
HPRD00975Diabetes mellitus, insulin-resistant
HPRD00975Diabetes mellitus, insulin-resistant, with acanthosis nigricans
HPRD00975Diabetes mellitus, noninsulin-dependent
HPRD00975Hyperinsulinemic hypoglycemia, familial, 5
HPRD00975Insulin resistance
HPRD00975Leprechaunism
HPRD00975Leprechaunism ARK 1, allele 1
HPRD00975Leprechaunism ARK 1, allele 2
HPRD00975Leprechaunism minn 1
HPRD00975Leprechaunism, Atlanta 1 type
HPRD00975Leprechaunism, Geldeimalsen type
HPRD00975Leprechaunism, Helmond type
HPRD00975Leprechaunism, mount sinai type
HPRD00975Leprechaunism, verona 1 type
HPRD00975Leprechaunism, Winnipeg type
HPRD00975Rabson-Mendenhall syndrome
Network with metabolic pathway:
Kegg map ID Pathway Link
map04930Type II diabetes mellitus
map04960Aldosterone-regulated sodium reabsorption
map04066HIF-1 signaling pathway
map04520Adherens junction
map04151PI3K-Akt signaling pathway
map04910Insulin signaling pathway
Graphical Visualization of S-nitrosylation Sites:
Overview of Protein S-nitrosylation Sites with Functional and Structural Information
InterPro ID Domain
IPR000494
IPR000719
IPR001245
IPR002011
IPR003961
IPR006211
IPR006212
IPR008266
IPR008957
IPR009030
IPR011009

3D Structure Databases:
3D structure databases
EntryMethodResolution (A)ChainPositionsView
1GAG X-ray 2.70 A A1005-1310Link
1I44 X-ray 2.40 A A1005-1310Link
1IR3 X-ray 1.90 A A1005-1310Link
1IRK X-ray 2.10 A A1005-1310Link
1P14 X-ray 1.90 A A1005-1298Link
1RQQ X-ray 2.60 A A/B1005-1310Link
2AUH X-ray 3.20 A A1005-1310Link
2B4S X-ray 2.30 A B/D1005-1310Link
2DTG X-ray 3.80 A E28-943Link
2HR7 X-ray 2.32 A A/B28-512Link
2Z8C X-ray 3.25 A A1009-1310Link
3BU3 X-ray 1.65 A A1005-1310Link
3BU5 X-ray 2.10 A A1005-1310Link
3BU6 X-ray 1.95 A A1005-1310Link
3EKK X-ray 2.10 A A1005-1310Link
3EKN X-ray 2.20 A A1005-1310Link
3ETA X-ray 2.60 A A/B1017-1322Link
3LOH X-ray 3.80 A E28-956Link
3W11 X-ray 3.90 A E28-337Link
3W12 X-ray 4.30 A E28-337Link
F731-746
3W13 X-ray 4.30 A E28-337Link
3W14 X-ray 4.40 A E28-620Link
F731-746
4IBM X-ray 1.80 A A/B1005-1310Link

The S-nitrosylation sites of INSR_HUMAN

No. Position S-nitrosylated Peptide Secondary Structure of S-nitrosylated Peptide Solvent Accessibility of nitrosylated Site Substrate Motifs PubMed ID Experiment
11083NEASVMKGFT C HHVVRLLGVV HHHHHHHHCC C CEEEEEEEEE 1.63%HC0522178444-
21083NEASVMKGFT C HHVVRLLGVV HHHHHHHHCC C CEEEEEEEEE 1.63%HC0511225731
(Cys1056)
in vitro
31165FVHRDLAARN C MVAHDFTVKI CEEEEECCCC E EECCCCEEEE 1.61%HC0922178444-
41165FVHRDLAARN C MVAHDFTVKI CEEEEECCCC E EECCCCEEEE 1.61%HC0911225731
(Cys1138)
in vitro
51261DGGYLDQPDN C PERVTDLMRM CCCCCCCCCC C CHHHHHHHHH 4.89%HC0622178444-
61261DGGYLDQPDN C PERVTDLMRM CCCCCCCCCC C CHHHHHHHHH 4.89%HC0611225731
(Cys1234)
in vitro
71272PERVTDLMRM C WQFNPKMRPT CHHHHHHHHH H HHHCHHHCCC 1.50%HC0322178444-
81272PERVTDLMRM C WQFNPKMRPT CHHHHHHHHH H HHHCHHHCCC 1.50%HC0311225731
(Cys1245)
in vitro