Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Gene: INSIG2 - insulin induced gene 2

Homo sapiens

Synonyms: INSIG-2, Insulin-induced gene 2 protein

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Hall, D.H., Lee, J.N., Sever, N., Engelking, L.J., Song, B.L., et al.

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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].

High impact information on INSIG2

In cultured cells Insig-1 and Insig-2 have been shown to block lipid synthesis in a cholesterol-dependent fashion by inhibiting proteolytic processing of sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors that activate lipid synthesis [2].
In sterol-depleted cells Insig-1 is degraded at least 15 times more rapidly than Insig-2, owing to ubiquitination of Lys-156 and Lys-158 in Insig-1 [3].
Alanine substitution of the corresponding aspartic acid in Insig-2 produced the same dual defects [4].
Juxtamembranous aspartic acid in Insig-1 and Insig-2 is required for cholesterol homeostasis [4].
Insig-1 and Insig-2 also enhance the conformational change in SCAP that occurs upon addition of certain cationic amphiphiles, such as chlorpromazine, trifluoperazine, and imipramine, which mimic the effect of cholesterol [5].

Biological context of INSIG2

Here, we use RNA interference to show that sterol-accelerated ubiquitination of reductase requires Insig-1 and Insig-2, membrane-bound proteins of the endoplasmic reticulum that were shown previously to accelerate degradation of reductase when overexpressed by transfection [6].
INSIG-2 promoter polymorphism and obesity related phenotypes: association study in 1428 members of 248 families [7].
Recently a large genetic association study showed evidence for association of the single nucleotide polymorphism (SNP) rs7566605, which lies 10 Kb 5' to the first exon of the insulin-induced gene 2 (INSIG-2), with obesity in several cohorts [7].

Anatomical context of INSIG2

Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins [8].
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 [9].

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 [3].

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 [10].

References

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)
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)
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)
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)
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)
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)
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)
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)
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)
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)