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Gene Review

INSIG2  -  insulin induced gene 2

Homo sapiens

Synonyms: INSIG-2, Insulin-induced gene 2 protein
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Disease relevance of INSIG2

  • We used a dense whole-genome scan of DNA samples from the Framingham Heart Study participants to identify a common genetic variant near the INSIG2 gene associated with obesity [1].
  • Gene silencing experiments confirmed that INSIG1, but not INSIG2, regulates the expression of sterol regulatory element-binding proteins target genes in human hepatoma cells [2].

High impact information on INSIG2


Biological context of INSIG2


Anatomical context of INSIG2

  • Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins [9].
  • Sterol-dependent ubiquitination of reductase in permeabilized cells is dependent upon exogenous cytosol, ATP, and either Insig-1 or Insig-2, two membrane-bound ER proteins shown previously to mediate sterol regulation of reductase degradation in intact cells [10].

Associations of INSIG2 with chemical compounds

  • When Glu-214 is changed to alanine, Insig-2 becomes ubiquitinated, but it is still not degraded as rapidly as ubiquitinated Insig-1 [4].

Analytical, diagnostic and therapeutic context of INSIG2

  • (Reports, 14 April 2006, p. 279) found that the rs7566605 genetic variant, located upstream of the INSIG2 gene, was consistently associated with increased body mass index [11].


  1. A common genetic variant is associated with adult and childhood obesity. Herbert, A., Gerry, N.P., McQueen, M.B., Heid, I.M., Pfeufer, A., Illig, T., Wichmann, H.E., Meitinger, T., Hunter, D., Hu, F.B., Colditz, G., Hinney, A., Hebebrand, J., Koberwitz, K., Zhu, X., Cooper, R., Ardlie, K., Lyon, H., Hirschhorn, J.N., Laird, N.M., Lenburg, M.E., Lange, C., Christman, M.F. Science (2006) [Pubmed]
  2. Insulin-induced gene 2 involvement in human adipocyte metabolism and body weight regulation. Krapivner, S., Popov, S., Chernogubova, E., Hellénius, M.L., Fisher, R.M., Hamsten, A., van't Hooft, F.M. J. Clin. Endocrinol. Metab. (2008) [Pubmed]
  3. Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis. Engelking, L.J., Kuriyama, H., Hammer, R.E., Horton, J.D., Brown, M.S., Goldstein, J.L., Liang, G. J. Clin. Invest. (2004) [Pubmed]
  4. Proteasomal degradation of ubiquitinated Insig proteins is determined by serine residues flanking ubiquitinated lysines. Lee, J.N., Gong, Y., Zhang, X., Ye, J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  5. Juxtamembranous aspartic acid in Insig-1 and Insig-2 is required for cholesterol homeostasis. Gong, Y., Lee, J.N., Brown, M.S., Goldstein, J.L., Ye, J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  6. Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles. Adams, C.M., Goldstein, J.L., Brown, M.S. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  7. Insig-dependent ubiquitination and degradation of mammalian 3-hydroxy-3-methylglutaryl-CoA reductase stimulated by sterols and geranylgeraniol. Sever, N., Song, B.L., Yabe, D., Goldstein, J.L., Brown, M.S., DeBose-Boyd, R.A. J. Biol. Chem. (2003) [Pubmed]
  8. INSIG-2 promoter polymorphism and obesity related phenotypes: association study in 1428 members of 248 families. Hall, D.H., Rahman, T., Avery, P.J., Keavney, B. BMC Med. Genet. (2006) [Pubmed]
  9. Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Yabe, D., Brown, M.S., Goldstein, J.L. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  10. Ubiquitination of 3-hydroxy-3-methylglutaryl-CoA reductase in permeabilized cells mediated by cytosolic E1 and a putative membrane-bound ubiquitin ligase. Song, B.L., DeBose-Boyd, R.A. J. Biol. Chem. (2004) [Pubmed]
  11. Comment on "A common genetic variant is associated with adult and childhood obesity". Loos, R.J., Barroso, I., O'rahilly, S., Wareham, N.J. Science (2007) [Pubmed]
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