The protein encoded by this gene is highly similar to the protein product encoded by gene INSIG1. Both INSIG1 protein and this protein are endoplasmic reticulum proteins that block the processing of sterol regulatory element binding proteins (SREBPs) by binding to SREBP cleavage-activating protein (SCAP), and thus prevent SCAP from escorting SREBPs to the Golgi. [provided by Re... See more...

Aliases for INSIG2 Gene

Aliases for INSIG2 Gene

  • Insulin Induced Gene 2 2 3 5
  • Insulin-Induced Gene 2 Protein 3 4
  • INSIG-2 3 4
  • Insulin Induced Protein 2 3
  • INSIG2 Membrane Protein 3
  • INSIG2 5

External Ids for INSIG2 Gene

Previous GeneCards Identifiers for INSIG2 Gene

  • GC02P116766
  • GC02P118752
  • GC02P118949
  • GC02P118941
  • GC02P118562
  • GC02P111173
  • GC02P118846

Summaries for INSIG2 Gene

Entrez Gene Summary for INSIG2 Gene

  • The protein encoded by this gene is highly similar to the protein product encoded by gene INSIG1. Both INSIG1 protein and this protein are endoplasmic reticulum proteins that block the processing of sterol regulatory element binding proteins (SREBPs) by binding to SREBP cleavage-activating protein (SCAP), and thus prevent SCAP from escorting SREBPs to the Golgi. [provided by RefSeq, Jul 2008]

GeneCards Summary for INSIG2 Gene

INSIG2 (Insulin Induced Gene 2) is a Protein Coding gene. Diseases associated with INSIG2 include Dystonia, Dopa-Responsive, Due To Sepiapterin Reductase Deficiency and Congenital Hemidysplasia With Ichthyosiform Erythroderma And Limb Defects. Among its related pathways are Regulation of cholesterol biosynthesis by SREBP (SREBF) and Metabolism. Gene Ontology (GO) annotations related to this gene include transcription factor binding. An important paralog of this gene is INSIG1.

UniProtKB/Swiss-Prot Summary for INSIG2 Gene

  • Oxysterol-binding protein that mediates feedback control of cholesterol synthesis by controlling both endoplasmic reticulum to Golgi transport of SCAP and degradation of HMGCR (PubMed:12242332, PubMed:16606821, PubMed:32322062). Acts as a negative regulator of cholesterol biosynthesis by mediating the retention of the SCAP-SREBP complex in the endoplasmic reticulum, thereby blocking the processing of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:32322062). Binds oxysterol, including 22-hydroxycholesterol, 24-hydroxycholesterol, 25-hydroxycholesterol and 27-hydroxycholesterol, regulating interaction with SCAP and retention of the SCAP-SREBP complex in the endoplasmic reticulum (PubMed:26160948, PubMed:17428920, PubMed:32322062). In presence of oxysterol, interacts with SCAP, retaining the SCAP-SREBP complex in the endoplasmic reticulum, thereby preventing SCAP from escorting SREBF1/SREBP1 and SREBF2/SREBP2 to the Golgi (PubMed:32322062). Sterol deprivation or phosphorylation by PCK1 reduce oxysterol-binding, disrupting the interaction between INSIG2 and SCAP, thereby promoting Golgi transport of the SCAP-SREBP complex, followed by processing and nuclear translocation of SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:32322062). Also regulates cholesterol synthesis by regulating degradation of HMGCR: initiates the sterol-mediated ubiquitin-mediated endoplasmic reticulum-associated degradation (ERAD) of HMGCR via recruitment of the reductase to the ubiquitin ligase RNF139 (PubMed:16606821, PubMed:22143767).

Gene Wiki entry for INSIG2 Gene

No data available for CIViC Summary , Tocris Summary , PharmGKB "VIP" Summary , Rfam classification and piRNA Summary for INSIG2 Gene

Genomics for INSIG2 Gene

GeneHancer (GH) Regulatory Elements Pubs

Promoters and enhancers for INSIG2 Gene
- Elite GeneHancer and/or Elite GeneHancer-gene association Download GeneHancer data from 2017 publication | Request up-to-date GeneHancer data (full dataset)

GeneHancers around INSIG2 on the GeneHancer Hub at the UCSC Golden Path

Cistromic (ChIP-Seq) regulation report from SPP (The Signaling Pathways Project) for INSIG2

Top Transcription factor binding sites by QIAGEN in the INSIG2 gene promoter:
  • AML1a
  • AREB6
  • E2F
  • E2F-1
  • E2F-2
  • E2F-3a
  • E2F-4
  • E2F-5
  • PPAR-alpha
  • RFX1

Genomic Locations for INSIG2 Gene

Latest Assembly
chr2:118,088,452-118,110,997
(GRCh38/hg38)
Size:
22,546 bases
Orientation:
Plus strand

Previous Assembly
chr2:118,846,047-118,868,573
(GRCh37/hg19 by Entrez Gene)
Size:
22,527 bases
Orientation:
Plus strand

chr2:118,846,028-118,868,573
(GRCh37/hg19 by Ensembl)
Size:
22,546 bases
Orientation:
Plus strand

Genomic View for INSIG2 Gene

Genes around INSIG2 on UCSC Golden Path with GeneCards custom track

Cytogenetic band:
INSIG2 Gene in genomic location: bands according to Ensembl, locations according to GeneLoc (and/or Entrez Gene and/or Ensembl if different)
Genomic Location for INSIG2 Gene
GeneLoc Logo Genomic Neighborhood Exon StructureGene Density

RefSeq DNA sequence for INSIG2 Gene

Proteins for INSIG2 Gene

  • Protein details for INSIG2 Gene (UniProtKB/Swiss-Prot)

    Protein Symbol:
    Q9Y5U4-INSI2_HUMAN
    Recommended name:
    Insulin-induced gene 2 protein
    Protein Accession:
    Q9Y5U4
    Secondary Accessions:
    • A8K5W8
    • Q8TBI8

    Protein attributes for INSIG2 Gene

    Size:
    225 amino acids
    Molecular mass:
    24778 Da
    Quaternary structure:
    • Interacts with SCAP; interaction is direct and only takes place in the presence of sterols; it prevents interaction between SCAP and the coat protein complex II (COPII) (PubMed:12242332, PubMed:17428920, PubMed:26160948, PubMed:32322062). Associates with the SCAP-SREBP complex (composed of SCAP and SREBF1/SREBP1 or SREBF2/SREBP2); association is mediated via its interaction with SCAP and only takes place in the presence of sterols (PubMed:12242332, PubMed:32322062). Interacts with RNF139 (PubMed:20068067, PubMed:22143767). Interacts with RNF145 (PubMed:29374057).
    SequenceCaution:
    • Sequence=AAD43048.1; Type=Frameshift; Evidence={ECO:0000305};

    Three dimensional structures from OCA and Proteopedia for INSIG2 Gene

neXtProt entry for INSIG2 Gene

Post-translational modifications for INSIG2 Gene

  • Phosphorylation at Ser-151 by PCK1 reduces binding to oxysterol, disrupting the interaction between INSIG2 and SCAP, thereby promoting nuclear translocation of SREBP proteins (SREBF1/SREBP1 or SREBF2/SREBP2) and subsequent transcription of downstream lipogenesis-related genes.
  • Polyubiquitinated by AMFR/gp78 at Cys-215 in some tissues such as adipose tissues, undifferentiated myoblasts and liver, leading to its degradation (PubMed:31953408). In differentiated myotubes, Cys-215 oxidation prevents ubiquitination at the same site, resulting in protein stabilization (PubMed:31953408).
  • Oxidized at Cys-215 in differentiated myotubes, preventing ubiquitination at the same site, and resulting in protein stabilization.
  • Ubiquitination at Lys216
  • Modification sites at PhosphoSitePlus

No data available for DME Specific Peptides for INSIG2 Gene

Domains & Families for INSIG2 Gene

Gene Families for INSIG2 Gene

Human Protein Atlas (HPA):
  • Predicted membrane proteins

Protein Domains for INSIG2 Gene

InterPro:

Suggested Antigen Peptide Sequences for INSIG2 Gene

GenScript: Design optimal peptide antigens:
  • Insulin-induced gene 2 protein (INSI2_HUMAN)

Graphical View of Domain Structure for InterPro Entry

Q9Y5U4

UniProtKB/Swiss-Prot:

INSI2_HUMAN :
  • Binds oxysterols in a pocket within their transmembrane domains and interacts with SCAP via transmembrane domains 3 and 4.
  • Belongs to the INSIG family.
Domain:
  • Binds oxysterols in a pocket within their transmembrane domains and interacts with SCAP via transmembrane domains 3 and 4.
  • The KxHxx motif mediates association with the coatomer complex.
Family:
  • Belongs to the INSIG family.
genes like me logo Genes that share domains with INSIG2: view

Function for INSIG2 Gene

Molecular function for INSIG2 Gene

UniProtKB/Swiss-Prot Function:
Oxysterol-binding protein that mediates feedback control of cholesterol synthesis by controlling both endoplasmic reticulum to Golgi transport of SCAP and degradation of HMGCR (PubMed:12242332, PubMed:16606821, PubMed:32322062). Acts as a negative regulator of cholesterol biosynthesis by mediating the retention of the SCAP-SREBP complex in the endoplasmic reticulum, thereby blocking the processing of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:32322062). Binds oxysterol, including 22-hydroxycholesterol, 24-hydroxycholesterol, 25-hydroxycholesterol and 27-hydroxycholesterol, regulating interaction with SCAP and retention of the SCAP-SREBP complex in the endoplasmic reticulum (PubMed:26160948, PubMed:17428920, PubMed:32322062). In presence of oxysterol, interacts with SCAP, retaining the SCAP-SREBP complex in the endoplasmic reticulum, thereby preventing SCAP from escorting SREBF1/SREBP1 and SREBF2/SREBP2 to the Golgi (PubMed:32322062). Sterol deprivation or phosphorylation by PCK1 reduce oxysterol-binding, disrupting the interaction between INSIG2 and SCAP, thereby promoting Golgi transport of the SCAP-SREBP complex, followed by processing and nuclear translocation of SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:32322062). Also regulates cholesterol synthesis by regulating degradation of HMGCR: initiates the sterol-mediated ubiquitin-mediated endoplasmic reticulum-associated degradation (ERAD) of HMGCR via recruitment of the reductase to the ubiquitin ligase RNF139 (PubMed:16606821, PubMed:22143767).

Phenotypes From GWAS Catalog for INSIG2 Gene

Gene Ontology (GO) - Molecular Function for INSIG2 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0005515 protein binding IPI 12242332
GO:0008134 transcription factor binding IEA --
GO:0008142 oxysterol binding IDA 17428920
GO:0008289 lipid binding IEA --
genes like me logo Genes that share ontologies with INSIG2: view
genes like me logo Genes that share phenotypes with INSIG2: view

Animal Models for INSIG2 Gene

MGI Knock Outs for INSIG2:

Inhibitory RNAs for research

  • Search GeneCopoeia for shRNA, lentivirus and/or AAV clone products for INSIG2

No data available for Enzyme Numbers (IUBMB) , Human Phenotype Ontology , Transcription Factor Targets and HOMER Transcription for INSIG2 Gene

Localization for INSIG2 Gene

Subcellular locations from UniProtKB/Swiss-Prot for INSIG2 Gene

Endoplasmic reticulum membrane. Multi-pass membrane protein.

Subcellular locations from

COMPARTMENTS
Extracellular space Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi Apparatus Nucleus Mitochondrion 0 1 2 3 4 5 Confidence
COMPARTMENTS Subcellular localization image for INSIG2 gene
Compartment Confidence
endoplasmic reticulum 5
plasma membrane 4
extracellular 2
mitochondrion 2
nucleus 2
cytosol 2
golgi apparatus 2
cytoskeleton 1
peroxisome 1
endosome 1
lysosome 1

Gene Ontology (GO) - Cellular Components for INSIG2 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0005783 endoplasmic reticulum IEA,IDA 32322062
GO:0005789 endoplasmic reticulum membrane IEA,TAS --
GO:0016020 membrane IEA --
GO:0016021 integral component of membrane IEA --
GO:0032937 SREBP-SCAP-Insig complex IBA,IDA 12242332
genes like me logo Genes that share ontologies with INSIG2: view

No data available for Subcellular locations from the Human Protein Atlas (HPA) for INSIG2 Gene

Pathways & Interactions for INSIG2 Gene

genes like me logo Genes that share pathways with INSIG2: view

SIGNOR curated interactions for INSIG2 Gene

Inactivates:
Is activated by:

Gene Ontology (GO) - Biological Process for INSIG2 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0006629 lipid metabolic process IEA --
GO:0006641 triglyceride metabolic process IEA --
GO:0006695 cholesterol biosynthetic process IEA,IDA 32322062
GO:0006991 response to sterol depletion IEA --
GO:0008202 steroid metabolic process IEA --
genes like me logo Genes that share ontologies with INSIG2: view

Drugs & Compounds for INSIG2 Gene

(1) Drugs for INSIG2 Gene - From: PharmGKB

Name Status Disease Links Group Role Mechanism of Action Clinical Trials
antipsychotics Pharma 0
genes like me logo Genes that share compounds with INSIG2: view

Transcripts for INSIG2 Gene

mRNA/cDNA for INSIG2 Gene

6 REFSEQ mRNAs :
12 NCBI additional mRNA sequence :
8 Ensembl transcripts including schematic representations, and UCSC links to gene/alias where relevant :

Inhibitory RNAs for research

  • Search GeneCopoeia for shRNA, lentivirus and/or AAV clone products for INSIG2

Alternative Splicing Database (ASD) splice patterns (SP) for INSIG2 Gene

ExUns: 1 ^ 2 ^ 3 ^ 4 ^ 5 ^ 6a · 6b ^ 7a · 7b · 7c ^ 8
SP1: - -
SP2: -
SP3: - - - -
SP4: -
SP5:
SP6:

Relevant External Links for INSIG2 Gene

GeneLoc Exon Structure for
INSIG2

Expression for INSIG2 Gene

mRNA expression in normal human tissues from GTEx, Illumina, BioGPS, and SAGE for INSIG2 Gene

mRNA expression in embryonic tissues and stem cells from LifeMap Discovery

Protein differential expression in normal tissues from HIPED for INSIG2 Gene

This gene is overexpressed in Heart (64.0).

Integrated Proteomics: protein expression in normal tissues and cell lines from ProteomicsDB and MOPED for INSIG2 Gene



Protein tissue co-expression partners for INSIG2 Gene

Transcriptomic regulation report from SPP (The Signaling Pathways Project) for INSIG2

SOURCE GeneReport for Unigene cluster for INSIG2 Gene:

Hs.7089

Evidence on tissue expression from TISSUES for INSIG2 Gene

  • Nervous system(4.7)
  • Liver(3)
  • Heart(2.5)
  • Kidney(2.2)
  • Muscle(2.2)
  • Skin(2.2)
  • Spleen(2.1)
  • Intestine(2.1)
  • Blood(2.1)
genes like me logo Genes that share expression patterns with INSIG2: view

No data available for mRNA differential expression in normal tissues , mRNA Expression by UniProt/SwissProt and Phenotype-based relationships between genes and organs from Gene ORGANizer for INSIG2 Gene

Orthologs for INSIG2 Gene

This gene was present in the common ancestor of chordates.

Orthologs for INSIG2 Gene

Organism Taxonomy Gene Similarity Type Details
Chimpanzee
(Pan troglodytes)
Mammalia INSIG2 29 30
  • 99.7 (n)
OneToOne
Cow
(Bos Taurus)
Mammalia INSIG2 29 30
  • 96 (n)
OneToOne
Oppossum
(Monodelphis domestica)
Mammalia INSIG2 30
  • 95 (a)
OneToOne
Dog
(Canis familiaris)
Mammalia INSIG2 29 30
  • 94.52 (n)
OneToOne
Mouse
(Mus musculus)
Mammalia Insig2 29 16 30
  • 87.41 (n)
OneToOne
Rat
(Rattus norvegicus)
Mammalia Insig2 29
  • 86.07 (n)
Chicken
(Gallus gallus)
Aves INSIG2 30
  • 91 (a)
OneToOne
Lizard
(Anolis carolinensis)
Reptilia INSIG2 30
  • 84 (a)
OneToOne
Zebrafish
(Danio rerio)
Actinopterygii insig2 29 30
  • 67.58 (n)
OneToOne
Species where no ortholog for INSIG2 was found in the sources mined by GeneCards:
  • A. gosspyii yeast (Eremothecium gossypii)
  • Actinobacteria (Mycobacterium tuberculosis)
  • African clawed frog (Xenopus laevis)
  • African malaria mosquito (Anopheles gambiae)
  • Alicante grape (Vitis vinifera)
  • Alpha proteobacteria (Wolbachia pipientis)
  • Amoeba (Dictyostelium discoideum)
  • Archea (Pyrococcus horikoshii)
  • Baker's yeast (Saccharomyces cerevisiae)
  • Barley (Hordeum vulgare)
  • Beta proteobacteria (Neisseria meningitidis)
  • Bread mold (Neurospora crassa)
  • Chromalveolata (Phytophthora infestans)
  • Common water flea (Daphnia pulex)
  • Corn (Zea mays)
  • E. coli (Escherichia coli)
  • Filamentous fungi (Aspergillus nidulans)
  • Firmicute Bacteria (Streptococcus pneumoniae)
  • Fission Yeast (Schizosaccharomyces pombe)
  • Fruit Fly (Drosophila melanogaster)
  • Green Algae (Chlamydomonas reinhardtii)
  • Honey Bee (Apis mellifera)
  • K. Lactis Yeast (Kluyveromyces lactis)
  • Loblloly Pine (Pinus taeda)
  • Malaria Parasite (Plasmodium falciparum)
  • Medicago Trunc (Medicago Truncatula)
  • Moss (Physcomitrella patens)
  • Orangutan (Pongo pygmaeus)
  • Pig (Sus scrofa)
  • Platypus (Ornithorhynchus anatinus)
  • Rainbow Trout (Oncorhynchus mykiss)
  • Rice (Oryza sativa)
  • Rice Blast Fungus (Magnaporthe grisea)
  • Schistosome Parasite (Schistosoma mansoni)
  • Sea Anemone (Nematostella vectensis)
  • Sea Vase (Ciona intestinalis)
  • Sea Squirt (Ciona savignyi)
  • Sea Urchin (Strongylocentrotus purpuratus)
  • Sorghum (Sorghum bicolor)
  • Soybean (Glycine max)
  • Stem Rust Fungus (Puccinia graminis)
  • Sugarcane (Saccharum officinarum)
  • Thale Cress (Arabidopsis thaliana)
  • Tomato (Lycopersicon esculentum)
  • Toxoplasmosis (Toxoplasma gondii)
  • Trichoplax (Trichoplax adhaerens)
  • Tropical Clawed Frog (Silurana tropicalis)
  • Wheat (Triticum aestivum)
  • Worm (Caenorhabditis elegans)

Evolution for INSIG2 Gene

ENSEMBL:
Gene Tree for INSIG2 (if available)
TreeFam:
Gene Tree for INSIG2 (if available)
Aminode:
Evolutionary constrained regions (ECRs) for INSIG2: view image
Alliance of Genome Resources:
Additional Orthologs for INSIG2

Paralogs for INSIG2 Gene

Paralogs for INSIG2 Gene

(1) SIMAP similar genes for INSIG2 Gene using alignment to 2 proteins:

  • INSI2_HUMAN
  • F8WCG8_HUMAN
genes like me logo Genes that share paralogs with INSIG2: view

Variants for INSIG2 Gene

Sequence variations, with clinical significance, from ClinVar and Humsavar, with links to dbSNP for INSIG2 Gene

SNP ID Clinical significance and condition Chr 02 pos Variation AA Info Type
rs17047763 Benign: not provided 118,107,180(+) A/G
NM_016133.4(INSIG2):c.627A>G (p.Gln209=)
SYNONYMOUS_VARIANT,INTRON
rs35551800 Benign: not provided 118,103,297(+) T/C
NM_016133.4(INSIG2):c.345T>C (p.Phe115=)
SYNONYMOUS

dbSNP identifiers (rs#s) for variants without ClinVar clinical significance for INSIG2 Gene

All consequence types are included: molecular consequences (e.g. missense, synonymous), and location-based (e.g. intron, upstream).

Structural Variations from Database of Genomic Variants (DGV) for INSIG2 Gene

Variant ID Type Subtype PubMed ID
esv1042101 CNV deletion 17803354
esv1244468 CNV deletion 17803354
esv1527073 CNV deletion 17803354
esv1675960 CNV deletion 17803354
esv21565 CNV loss 19812545
esv2269282 CNV deletion 18987734
esv2596819 CNV deletion 19546169
esv2720611 CNV deletion 23290073
esv3560010 CNV deletion 23714750
esv3560011 CNV deletion 23714750
nsv1114130 CNV deletion 24896259
nsv1153185 CNV deletion 26484159
nsv820793 CNV deletion 20802225
nsv955105 CNV deletion 24416366

Variation tolerance for INSIG2 Gene

Residual Variation Intolerance Score: 51.2% of all genes are more intolerant (likely to be disease-causing)
Gene Damage Index Score: 0.39; 8.66% of all genes are more intolerant (likely to be disease-causing)

Additional Variant Information for INSIG2 Gene

Human Gene Mutation Database (HGMD)
INSIG2
SNPedia medical, phenotypic, and genealogical associations of SNPs for
INSIG2
Leiden Open Variation Database (LOVD)
INSIG2

SNP Genotyping and Copy Number Assays for research

No data available for Polymorphic Variants from UniProtKB/Swiss-Prot for INSIG2 Gene

Disorders for INSIG2 Gene

MalaCards: The human disease database

(4) MalaCards diseases for INSIG2 Gene - From: COP and GCD

- elite association - COSMIC cancer census association via MalaCards

Additional Disease Information for INSIG2

Human Genome Epidemiology Navigator
(HuGE)
Atlas
ATLAS of Genetics and Cytogenetics in Oncology and Haematology
Open Targets Platform
Open Targets Platform
genes like me logo Genes that share disorders with INSIG2: view

No data available for UniProtKB/Swiss-Prot and Genatlas for INSIG2 Gene

Publications for INSIG2 Gene

  1. Association study of polymorphisms in insulin induced gene 2 (INSIG2) with antipsychotic-induced weight gain in European and African-American schizophrenia patients. (PMID: 20373477) Tiwari AK … Kennedy JL (Human psychopharmacology 2010) 3 22 40
  2. Interactions among genetic variants from SREBP2 activating-related pathway on risk of coronary heart disease in Chinese Han population. (PMID: 19740467) Liu X … Gu D (Atherosclerosis 2010) 3 22 40
  3. Association between the insulin-induced gene 2 (INSIG2) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: perturbation of SREBP-controlled lipogenesis in drug-related metabolic adverse effects? (PMID: 18195716) Le Hellard S … Steen VM (Molecular psychiatry 2009) 3 22 40
  4. The INSIG1 gene, not the INSIG2 gene, associated with coronary heart disease: tagSNPs and haplotype-based association study. The Beijing Atherosclerosis Study. (PMID: 18989534) Liu X … Gu D (Thrombosis and haemostasis 2008) 3 22 40
  5. No association between INSIG2 Gene rs7566605 polymorphism and being overweight in Japanese population. (PMID: 18223638) Tabara Y … Kohara K (Obesity (Silver Spring, Md.) 2008) 3 22 40

Products for INSIG2 Gene

Sources for INSIG2 Gene