Insulin receptor: Wikis

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Insulin receptor

PDB rendering based on 1gag.
Available structures
1gag, 1i44, 1ir3, 1irk, 1p14, 1rqq, 2auh, 2b4s, 2dtg, 2hr7
Identifiers
Symbols INSR; CD220; HHF5
External IDs OMIM147670 MGI96575 HomoloGene20090 GeneCards: INSR Gene
RNA expression pattern
PBB GE INSR 213792 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3643 16337
Ensembl ENSG00000171105 ENSMUSG00000005534
UniProt P06213 O35466
RefSeq (mRNA) NM_000208 XM_972939
RefSeq (protein) NP_000199 XP_978033
Location (UCSC) Chr 19:
7.07 - 7.25 Mb
Chr 8:
3.16 - 3.28 Mb
PubMed search [1] [2]

In molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin.[1] It belongs to the large class of tyrosine kinase receptors.

Two alpha subunits and two beta subunits make up the insulin receptor. The beta subunits pass through the cellular membrane and are linked by disulfide bonds. The alpha and beta subunits are encoded by a single gene (INSR). The insulin receptor has also recently been designated CD220 (cluster of differentiation 220).

Contents

Function

Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).

Tyrosine kinase receptors, including the insulin receptor, mediate their activity by causing the addition of a phosphate group to particular tyrosines on certain proteins within a cell. The "substrate" proteins which are phosphorylated by the Insulin Receptor include a protein called "IRS-1" for "insulin receptor substrate 1". IRS-1 binding and phosphorylation eventually leads to an increase in the high affinity glucose transporter (Glut4) molecules on the outer membrane of insulin-responsive tissues, including muscle cells and adipose tissue, and therefore to an increase in the uptake of glucose from blood into these tissues. Briefly, the glucose transporter Glut4 is transported from cellular vesicles to the cell surface, where it then can mediate the transport of glucose into the cell.

Pathology

The main activity of activation of the insulin receptor is inducing glucose uptake. For this reason "insulin insensitivity", or a decrease in insulin receptor signaling, leads to diabetes mellitus type 2 - the cells are unable to take up glucose, and the result is hyperglycemia (an increase in circulating glucose), and all the sequelae which result from diabetes.

Patients with insulin resistance may display acanthosis nigricans.

A few patients with homozygous mutations in the INSR gene have been described, which causes Donohue syndrome or Leprechaunism. This autosomal recessive disorder results in a totally non-functional insulin receptor. These patients have low set, often protuberant, ears, flared nostrils, thickened lips, and severe growth retardation. In most cases, the outlook for these patients is extremely poor with death occurring within the first year of life. Other mutations of the same gene cause the less severe Rabson-Mendenhall syndrome, in which patients have characteristically abnormal teeth, hypertrophic gingiva (gums) and enlargement of the pineal gland. Both diseases present with fluctuations of the glucose level: after a meal the glucose is initially very high, and then falls rapidly to abnormally low levels.[2]

Regulation of gene expression

The activated IRS-1 acts as a secondary messenger within the cell to stimulate the transcription of insulin-regulated genes. First, the protein Grb2 binds the P-Tyr residue of IRS-1 in its SH2 domain. Grb2 is then able to bind SOS, which in turn catalyzes the replacement of bound GDP with GTP on Ras, a G protein. This protein then begins a phosphorylation cascade, culminating in the activation of mitogen-activated protein kinase (MAPK), which enters the nucleus and phosphorylates various nuclear transcription factors (such as Elk1).

Stimulation of glycogen synthesis

Glycogen synthesis is also stimulated by the insulin receptor via IRS-1. In this case, it is the SH2 domain of PI-3 kinase (PI-3K) that binds the P-Tyr of IRS-1. Now activated, PI-3K can convert the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). This indirectly activates a protein kinase, PKB (Akt), via phosphorylation. PKB then phosphorylates several target proteins, including glycogen synthase kinase 3 (GSK-3). GSK-3 is responsible for phosphorylating (and thus deactivating) glycogen synthase. When GSK-3 is phosphorylated, it is deactivated, and prevented from deactivating glycogen synthase. In this roundabout manner, insulin increases glycogen synthesis.

Degradation of insulin

Once an insulin molecule has docked onto the receptor and effected its action, it may be released back into the extracellular environment or it may be degraded by the cell. Degradation normally involves endocytosis of the insulin-receptor complex followed by the action of insulin degrading enzyme. Most insulin molecules are degraded by liver cells. It has been estimated that a typical insulin molecule is finally degraded about 71 minutes after its initial release into circulation.[3]

Interactions

Insulin receptor has been shown to interact with Ectonucleotide pyrophosphatase/phosphodiesterase 1,[4] PTPN11,[5][6] GRB10,[7][8][9][10][11] GRB7,[12] PRKCD,[13][14] IRS1,[15][16] SH2B1[17][18] and Mothers against decapentaplegic homolog 2.[19]

References

  1. ^ Ward CW, Lawrence MC (April 2009). "Ligand-induced activation of the insulin receptor: a multi-step process involving structural changes in both the ligand and the receptor". Bioessays 31 (4): 422–34. doi:10.1002/bies.200800210. PMID 19274663.  
  2. ^ Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, Giannella-Neto D (2002). "Genotype-phenotype correlation in inherited severe insulin resistance". Hum. Mol. Genet. 11 (12): 1465–75. doi:10.1093/hmg/11.12.1465. PMID 12023989.  
  3. ^ Duckworth WC, Bennett RG, Hamel FG (1998). "Insulin degradation: progress and potential". Endocr. Rev. 19 (5): 608–24. doi:10.1210/er.19.5.608. PMID 9793760.  
  4. ^ Maddux, B A; Goldfine I D (Jan. 2000). "Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit". Diabetes (UNITED STATES) 49 (1): 13–9. ISSN 0012-1797. PMID 10615944.  
  5. ^ Maegawa, H; Ugi S, Adachi M, Hinoda Y, Kikkawa R, Yachi A, Shigeta Y, Kashiwagi A (Mar. 1994). "Insulin receptor kinase phosphorylates protein tyrosine phosphatase containing Src homology 2 regions and modulates its PTPase activity in vitro". Biochem. Biophys. Res. Commun. (UNITED STATES) 199 (2): 780–5. doi:10.1006/bbrc.1994.1297. ISSN 0006-291X. PMID 8135823.  
  6. ^ Kharitonenkov, A; Schnekenburger J, Chen Z, Knyazev P, Ali S, Zwick E, White M, Ullrich A (Dec. 1995). "Adapter function of protein-tyrosine phosphatase 1D in insulin receptor/insulin receptor substrate-1 interaction". J. Biol. Chem. (UNITED STATES) 270 (49): 29189–93. ISSN 0021-9258. PMID 7493946.  
  7. ^ Langlais, P; Dong L Q, Hu D, Liu F (Jun. 2000). "Identification of Grb10 as a direct substrate for members of the Src tyrosine kinase family". Oncogene (ENGLAND) 19 (25): 2895–903. doi:10.1038/sj.onc.1203616. ISSN 0950-9232. PMID 10871840.  
  8. ^ Hansen, H; Svensson U, Zhu J, Laviola L, Giorgino F, Wolf G, Smith R J, Riedel H (Apr. 1996). "Interaction between the Grb10 SH2 domain and the insulin receptor carboxyl terminus". J. Biol. Chem. (UNITED STATES) 271 (15): 8882–6. ISSN 0021-9258. PMID 8621530.  
  9. ^ Liu, F; Roth R A (Oct. 1995). "Grb-IR: a SH2-domain-containing protein that binds to the insulin receptor and inhibits its function". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 92 (22): 10287–91. ISSN 0027-8424. PMID 7479769.  
  10. ^ He, W; Rose D W, Olefsky J M, Gustafson T A (Mar. 1998). "Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains". J. Biol. Chem. (UNITED STATES) 273 (12): 6860–7. ISSN 0021-9258. PMID 9506989.  
  11. ^ Frantz, J D; Giorgetti-Peraldi S, Ottinger E A, Shoelson S E (Jan. 1997). "Human GRB-IRbeta/GRB10. Splice variants of an insulin and growth factor receptor-binding protein with PH and SH2 domains". J. Biol. Chem. (UNITED STATES) 272 (5): 2659–67. ISSN 0021-9258. PMID 9006901.  
  12. ^ Kasus-Jacobi, A; Béréziat V, Perdereau D, Girard J, Burnol A F (Apr. 2000). "Evidence for an interaction between the insulin receptor and Grb7. A role for two of its binding domains, PIR and SH2". Oncogene (ENGLAND) 19 (16): 2052–9. doi:10.1038/sj.onc.1203469. ISSN 0950-9232. PMID 10803466.  
  13. ^ Braiman, L; Alt A, Kuroki T, Ohba M, Bak A, Tennenbaum T, Sampson S R (Apr. 2001). "Insulin induces specific interaction between insulin receptor and protein kinase C delta in primary cultured skeletal muscle". Mol. Endocrinol. (United States) 15 (4): 565–74. ISSN 0888-8809. PMID 11266508.  
  14. ^ Rosenzweig, Tovit; Braiman Liora, Bak Asia, Alt Addy, Kuroki Toshio, Sampson Sanford R (Jun. 2002). "Differential effects of tumor necrosis factor-alpha on protein kinase C isoforms alpha and delta mediate inhibition of insulin receptor signaling". Diabetes (United States) 51 (6): 1921–30. ISSN 0012-1797. PMID 12031982.  
  15. ^ Aguirre, Vincent; Werner Eric D, Giraud Jodel, Lee Yong Hee, Shoelson Steve E, White Morris F (Jan. 2002). "Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action". J. Biol. Chem. (United States) 277 (2): 1531–7. doi:10.1074/jbc.M101521200. ISSN 0021-9258. PMID 11606564.  
  16. ^ Sawka-Verhelle, D; Tartare-Deckert S, White M F, Van Obberghen E (Mar. 1996). "Insulin receptor substrate-2 binds to the insulin receptor through its phosphotyrosine-binding domain and through a newly identified domain comprising amino acids 591-786". J. Biol. Chem. (UNITED STATES) 271 (11): 5980–3. ISSN 0021-9258. PMID 8626379.  
  17. ^ Kotani, K; Wilden P, Pillay T S (Oct. 1998). "SH2-Balpha is an insulin-receptor adapter protein and substrate that interacts with the activation loop of the insulin-receptor kinase". Biochem. J. (ENGLAND) 335 ( Pt 1): 103–9. ISSN 0264-6021. PMID 9742218.  
  18. ^ Nelms, K; O'Neill T J, Li S, Hubbard S R, Gustafson T A, Paul W E (Dec. 1999). "Alternative splicing, gene localization, and binding of SH2-B to the insulin receptor kinase domain". Mamm. Genome (UNITED STATES) 10 (12): 1160–7. ISSN 0938-8990. PMID 10594240.  
  19. ^ O'Neill, T J; Zhu Y, Gustafson T A (Apr. 1997). "Interaction of MAD2 with the carboxyl terminus of the insulin receptor but not with the IGFIR. Evidence for release from the insulin receptor after activation". J. Biol. Chem. (UNITED STATES) 272 (15): 10035–40. ISSN 0021-9258. PMID 9092546.  

Further reading

  • Pearson RB, Kemp BE (1991). "Protein kinase phosphorylation site sequences and consensus specificity motifs: tabulations". Meth. Enzymol. 200: 62–81. doi:10.1016/0076-6879(91)00127-I. PMID 1956339.  
  • Joost HG (1995). "Structural and functional heterogeneity of insulin receptors". Cell. Signal. 7 (2): 85–91. doi:10.1016/0898-6568(94)00071-I. PMID 7794689.  
  • O'Dell SD, Day IN (1998). "Insulin-like growth factor II (IGF-II)". Int. J. Biochem. Cell Biol. 30 (7): 767–71. doi:10.1016/S1357-2725(98)00048-X. PMID 9722981.  
  • Lopaczynski W (1999). "Differential regulation of signaling pathways for insulin and insulin-like growth factor I". Acta Biochim. Pol. 46 (1): 51–60. PMID 10453981.  
  • Sasaoka T, Kobayashi M (2000). "The functional significance of Shc in insulin signaling as a substrate of the insulin receptor". Endocr. J. 47 (4): 373–81. doi:10.1507/endocrj.47.373. PMID 11075717.  
  • Perz M, Torlińska T (2001). "Insulin receptor--structural and functional characteristics". Med. Sci. Monit. 7 (1): 169–77. PMID 11208515.  
  • Benaim G, Villalobo A (2002). "Phosphorylation of calmodulin. Functional implications". Eur. J. Biochem. 269 (15): 3619–31. doi:10.1046/j.1432-1033.2002.03038.x. PMID 12153558.  

External links

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