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Solute carrier family 2 (facilitated glucose transporter), member 4

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).
Identifiers
Symbols SLC2A4; GLUT4
External IDs OMIM138190 MGI95758 HomoloGene74381 GeneCards: SLC2A4 Gene
RNA expression pattern
PBB GE SLC2A4 206603 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 6517 20528
Ensembl ENSG00000181856 ENSMUSG00000018566
UniProt P14672 Q5NCW7
RefSeq (mRNA) NM_001042 NM_009204
RefSeq (protein) NP_001033 NP_033230
Location (UCSC) Chr 17:
7.13 - 7.13 Mb
Chr 11:
69.76 - 69.76 Mb
PubMed search [1] [2]

Glucose transporter type 4, also known as GLUT4, is a protein that in humans is encoded by the GLUT4 gene. GLUT4 the insulin-regulated glucose transporter found in adipose tissues and striated muscle (skeletal and cardiac) that is responsible for insulin-regulated glucose disposal. This protein is expressed only in muscle and fat cells, the major tissues in the body that respond to insulin. The first evidence for this distinct glucose transport protein was provided by David James in 1988.[1] The gene that encodes GLUT4 was cloned[2][3] and mapped in 1989.[4]

Contents

Tissue distribution

GLUT4 is primarily found in:

Regulation

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Insulin

In the absence of insulin, GLUT4 is sequestered in the interior of muscle and fat cells within lipid bilayers of vesicles. Insulin induces the translocation of GLUT4 from intracellular storage sites to the plasma membrane. Insulin binds to the insulin receptor in its dimeric form. The receptor phosphorylates and subsequently activates IRS-1, which in turn binds the enzyme PI-3 kinase which converts the membrane lipid PIP2 to PIP3. PIP3 generates a binding site for PKB (protein kinase B), and also for PDK1 which, being localized together with PKB, can phosphorylate and activate PKB. Once phosphorylated, PKB is in its active form and phosphorylates other targets that stimulate GLUT4 to be expressed on the plasma membrane.

At the cell surface, GLUT4 facilitates the passive diffusion (more correctly facilitated diffusion) of circulating glucose down its concentration gradient into muscle and fat cells. Once within cells, glucose is rapidly phosphorylated by glucokinase in the liver and hexokinase in other tissues to form glucose-6-phosphate, which then enters glycolysis. Glucose-6-phosphate cannot diffuse back out of cells, which also serves to maintain the concentration gradient for glucose to passively enter cells.[5]

Contraction

Contraction also stimulates the cell to translocate GLUT4 receptors to the surface. This is especially true in cardiac muscle, where continuous contraction can be relied upon; but is observed to a lesser extent in skeletal muscle. [6]

Interactions

GLUT4 has been shown to interact with Death-associated protein 6.[7]

References

  1. ^ James DE, Brown R, Navarro J, Pilch PF (May 1988). "Insulin-regulatable tissues express a unique insulin-sensitive glucose transport protein". Nature 333 (6169): 183–5. doi:10.1038/333183a0. PMID 3285221.  
  2. ^ James DE, Strube M, Mueckler M (March 1989). "Molecular cloning and characterization of an insulin-regulatable glucose transporter". Nature 338 (6210): 83–7. doi:10.1038/338083a0. PMID 2645527.  
  3. ^ Birnbaum MJ (April 1989). "Identification of a novel gene encoding an insulin-responsive glucose transporter protein". Cell 57 (2): 305–15. doi:10.1016/0092-8674(89)90968-9. PMID 2649253.  
  4. ^ Bell GI, Murray JC, Nakamura Y, Kayano T, Eddy RL, Fan YS, Byers MG, Shows TB (August 1989). "Polymorphic human insulin-responsive glucose-transporter gene on chromosome 17p13". Diabetes 38 (8): 1072–5. PMID 2568955.  
  5. ^ Watson RT, Kanzaki M, Pessin JE (2004). "Regulated membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes". Endocr. Rev. 25 (2): 177–204. doi:10.1210/er.2003-0011. PMID 15082519.  
  6. ^ Lund S, Holman GD, Schmitz O, Pedersen O (1995). "Contraction stimulates translocation of glucose transporter GLUT4 in skeletal muscle through a mechanism distinct from that of insulin". Proc. Natl. Acad. Sci. U.S.A. 92 (13): 5817–21. doi:10.1073/pnas.92.13.5817. PMID 7597034.  
  7. ^ Lalioti VS, Vergarajauregui S, Pulido D, Sandoval IV (May 2002). "The insulin-sensitive glucose transporter, GLUT4, interacts physically with Daxx. Two proteins with capacity to bind Ubc9 and conjugated to SUMO1". J. Biol. Chem. 277 (22): 19783–91. doi:10.1074/jbc.M110294200. PMID 11842083.  

Further reading

  • Slot JW, Geuze HJ, Gigengack S, Lienhard GE, James DE (April 1991). "Immuno-localization of the insulin regulatable glucose transporter in brown adipose tissue of the rat". J. Cell Biol. 113 (1): 123–35. PMID 2007617.  
  • Govers R, Coster AC, James DE (July 2004). "Insulin increases cell surface GLUT4 levels by dose dependently discharging GLUT4 into a cell surface recycling pathway". Mol. Cell. Biol. 24 (14): 6456–66. doi:10.1128/MCB.24.14.6456-6466.2004. PMID 15226445.  
  • Ng Y, Ramm G, Lopez JA, James DE (April 2008). "Rapid activation of Akt2 is sufficient to stimulate GLUT4 translocation in 3T3-L1 adipocytes". Cell Metab. 7 (4): 348–56. doi:10.1016/j.cmet.2008.02.008. PMID 18396141.  
  • Foster LJ, Klip A (2000). "Mechanism and regulation of GLUT-4 vesicle fusion in muscle and fat cells". Am. J. Physiol., Cell Physiol. 279 (4): C877–90. PMID 11003568.  
  • Bryant NJ, Govers R, James DE (2002). "Regulated transport of the glucose transporter GLUT4". Nat. Rev. Mol. Cell Biol. 3 (4): 267–77. doi:10.1038/nrm782. PMID 11994746.  
  • Baumann MU, Deborde S, Illsley NP (2003). "Placental glucose transfer and fetal growth". Endocrine 19 (1): 13–22. doi:10.1385/ENDO:19:1:13. PMID 12583599.  
  • Olson AL, Knight JB (2004). "Regulation of GLUT4 expression in vivo and in vitro". Front. Biosci. 8: s401–09. doi:10.2741/1072. PMID 12700047.  
  • McCarthy AM, Elmendorf JS (2007). "GLUT4's itinerary in health & disease". Indian J. Med. Res. 125 (3): 373–88. PMID 17496362.  
  • Buse JB, Yasuda K, Lay TP, et al. (1992). "Human GLUT4/muscle-fat glucose-transporter gene. Characterization and genetic variation". Diabetes 41 (11): 1436–45. doi:10.2337/diabetes.41.11.1436. PMID 1397719.  
  • O'Rahilly S, Krook A, Morgan R, et al. (1992). "Insulin receptor and insulin-responsive glucose transporter (GLUT 4) mutations and polymorphisms in a Welsh type 2 (non-insulin-dependent) diabetic population". Diabetologia 35 (5): 486–89. doi:10.1007/BF02342449. PMID 1521731.  
  • Liu ML, Olson AL, Moye-Rowley WS, et al. (1992). "Expression and regulation of the human GLUT4/muscle-fat facilitative glucose transporter gene in transgenic mice". J. Biol. Chem. 267 (17): 11673–36. PMID 1601840.  
  • Choi WH, O'Rahilly S, Buse JB, et al. (1992). "Molecular scanning of insulin-responsive glucose transporter (GLUT4) gene in NIDDM subjects". Diabetes 40 (12): 1712–18. doi:10.2337/diabetes.40.12.1712. PMID 1756912.  
  • Kusari J, Verma US, Buse JB, et al. (1991). "Analysis of the gene sequences of the insulin receptor and the insulin-sensitive glucose transporter (GLUT-4) in patients with common-type non-insulin-dependent diabetes mellitus". J. Clin. Invest. 88 (4): 1323–30. doi:10.1172/JCI115437. PMID 1918382.  
  • Fukumoto H, Kayano T, Buse JB, et al. (1989). "Cloning and characterization of the major insulin-responsive glucose transporter expressed in human skeletal muscle and other insulin-responsive tissues". J. Biol. Chem. 264 (14): 7776–79. PMID 2656669.  
  • Chiaramonte R, Martini R, Taramelli R, Comi P (1993). "Identification of the 5' end of the gene encoding a human insulin-responsive glucose transporter". Gene 130 (2): 307–08. doi:10.1016/0378-1119(93)90438-9. PMID 7916714.  
  • Verhey KJ, Birnbaum MJ (1994). "A Leu-Leu sequence is essential for COOH-terminal targeting signal of GLUT4 glucose transporter in fibroblasts". J. Biol. Chem. 269 (4): 2353–56. PMID 8300557.  
  • Lee W, Samuel J, Zhang W, et al. (1997). "A myosin-derived peptide C109 binds to GLUT4-vesicles and inhibits the insulin-induced glucose transport stimulation and GLUT4 recruitment in rat adipocytes". Biochem. Biophys. Res. Commun. 240 (2): 409–14. doi:10.1006/bbrc.1997.7671. PMID 9388492.  
  • Shi Y, Samuel SJ, Lee W, et al. (1999). "Cloning of an L-3-hydroxyacyl-CoA dehydrogenase that interacts with the GLUT4 C-terminus". Arch. Biochem. Biophys. 363 (2): 323–32. doi:10.1006/abbi.1998.1088. PMID 10068455.  
  • Abel ED, Kaulbach HC, Tian R, et al. (2000). "Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart". J. Clin. Invest. 104 (12): 1703–14. PMID 10606624.  
  • Abel ED, Peroni O, Kim JK, et al. (2001). "Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver". Nature 409 (6821): 729–33. doi:10.1038/35055575. PMID 11217863.  

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