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0  structures 216  species 0  interactions 342  sequences 6  architectures

Family: IGF2_C (PF08365)

Summary: Insulin-like growth factor II E-peptide

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Insulin-like growth factor 2". More...

Insulin-like growth factor 2 Edit Wikipedia article

Protein IGF2 PDB 1igl.png
Available structures
PDBOrtholog search: PDBe RCSB
AliasesIGF2, C11orf43, GRDF, IGF-II, PP9974, insulin like growth factor 2
External IDsOMIM: 147470 MGI: 96434 HomoloGene: 510 GeneCards: IGF2
Gene location (Human)
Chromosome 11 (human)
Chr.Chromosome 11 (human)[1]
Chromosome 11 (human)
Genomic location for IGF2
Genomic location for IGF2
Band11p15.5Start2,129,112 bp[1]
End2,141,238 bp[1]
RNA expression pattern
PBB GE IGF2 202409 at fs.png

PBB GE IGF2 210881 s at fs.png

PBB GE IGF2 202410 x at fs.png
More reference expression data
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 11: 2.13 – 2.14 MbChr 7: 142.65 – 142.67 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse
Insulin-like growth factor II E-peptide (somatomedians-A )

Insulin-like growth factor 2 (IGF-2) is one of three protein hormones that share structural similarity to insulin. The MeSH definition reads: "A well-characterized neutral peptide believed to be secreted by the liver and to circulate in the blood. It has growth-regulating, insulin-like and mitogenic activities. The growth factor has a major, but not absolute, dependence on somatotropin. It is believed to be a major fetal growth factor in contrast to Insulin-like growth factor 1, which is a major growth factor in adults."[5]

Gene structure

In humans, the IGF2 gene is located on chromosome 11p15.5, a region which contains numerous imprinted genes. In mice this homologous region is found at distal chromosome 7. In both organisms, Igf2 is imprinted, with expression resulting favourably from the paternally inherited allele. However, in some human brain regions a loss of imprinting occurs resulting in both IGF2 and H19 being transcribed from both parental alleles.[6]

The protein CTCF is involved in repressing expression of the gene, by binding to the H19 imprinting control region (ICR) along with Differentially-methylated Region-1 (DMR1) and Matrix Attachment Region −3 (MAR3). These three DNA sequences bind to CTCF in a way that limits downstream enhancer access to the Igf2 region. The mechanism in which CTCF binds to these regions is currently unknown, but could include either a direct DNA-CTCF interaction or it could possibly be mediated by other proteins. In mammals (mice, humans, pigs), only the allele for insulin-like growth factor-2 (IGF2) inherited from one's father is active; that inherited from the mother is not — a phenomenon called imprinting. The mechanism: the mother's allele has an insulator between the IGF2 promoter and enhancer. So does the father's allele, but in his case, the insulator has been methylated. CTCF can no longer bind to the insulator, and so the enhancer is now free to turn on the father's IGF2 promoter.[7]


The major role of IGF-2 is as a growth promoting hormone during gestation.

IGF-2 exerts its effects by binding to the IGF-1 receptor and to the short isoform of the insulin receptor (IR-A or exon 11-).[8] IGF2 may also bind to the IGF-2 receptor (also called the cation-independent mannose 6-phosphate receptor), which acts as a signalling antagonist; that is, to prevent IGF2 responses.

In the process of folliculogenesis, IGF-2 is created by thecal cells to act in an autocrine manner on the theca cells themselves, and in a paracrine manner on granulosa cells in the ovary.[citation needed] IGF2 promotes granulosa cell proliferation during the follicular phase of the menstrual cycle, acting alongside follicle stimulating hormone (FSH).[9] After ovulation has occurred, IGF-2 promotes progesterone secretion during the luteal phase of the menstrual cycle, together with luteinizing hormone (LH). Thus, IGF2 acts as a co-hormone together with both FSH and LH.[10]

A study at the Mount Sinai School of Medicine found that IGF-2 may be linked to memory and reproduction.[11] A study at the European Neuroscience Institute-Goettingen (Germany) found that fear extinction-induced IGF2/IGFBP7 signalling promotes the survival of 17- to 19-day-old newborn hippocampal neurons. This suggests that therapeutic strategies that enhance IGF2 signalling and adult neurogenesis might be suitable to treat diseases linked to excessive fear memory such as PTSD.[12]

Clinical relevance

It is sometimes produced in excess in islet cell tumors and non-islet hypoglycemic cell tumors, causing hypoglycemia. Doege-Potter syndrome is a paraneoplastic syndrome[13] in which hypoglycemia is associated with the presence of one or more non-islet fibrous tumors in the pleural cavity. Loss of imprinting of IGF2 is a common feature in tumors seen in Beckwith-Wiedemann syndrome. As IGF2 promotes development of fetal pancreatic beta cells, it is believed to be related to some forms of diabetes mellitus. Preeclampsia induces a decrease in methylation level at IGF2 demethylated region, and this might be among the mechanisms behind the association between intrauterine exposure to preeclampsia and high risk for metabolic diseases in the later life of the infants.[14]


Insulin-like growth factor 2 has been shown to interact with IGFBP3[15][16][17][18] and transferrin.[15]

See also


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000167244 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000048583 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Insulin-Like Growth Factor II". MeSH. NCBI.
  6. ^ Pham NV, Nguyen MT, Hu JF, Vu TH, Hoffman AR (Nov 1998). "Dissociation of IGF2 and H19 imprinting in human brain". Brain Research. 810 (1–2): 1–8. doi:10.1016/s0006-8993(98)00783-5. PMID 9813220.
  7. ^ Russell PJ (2009). iGenetics: A Molecular Approach (3rd ed.). Upper Saddle River, N.J.: Pearson Education. p. 533. ISBN 978-0-321-61022-5.
  8. ^ Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R, Costantino A, Goldfine ID, Belfiore A, Vigneri R (1999). "Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells". Molecular and Cellular Biology. 19 (5): 3278–88. doi:10.1128/MCB.19.5.3278. PMC 84122. PMID 10207053.
  9. ^ Neidhart, M (2016). DNA Methylation and Complex Human Disease (1st ed.). San Diego: Academic Press. p. 222. ISBN 9780124201941.
  10. ^ Neidhart, M (2016). DNA Methylation and Complex Human Disease (1st ed.). San Diego: Academic Press. p. 22. ISBN 978-0124201941.
  11. ^ Chen DY, Stern SA, Garcia-Osta A, Saunier-Rebori B, Pollonini G, Bambah-Mukku D, Blitzer RD, Alberini CM (Jan 2011). "A critical role for IGF-II in memory consolidation and enhancement". Nature. 469 (7331): 491–7. doi:10.1038/nature09667. PMC 3908455. PMID 21270887.
  12. ^ Agis-Balboa RC, Arcos-Diaz D, Wittnam J, Govindarajan N, Blom K, Burkhardt S, Haladyniak U, Agbemenyah HY, Zovoilis A, Salinas-Riester G, Opitz L, Sananbenesi F, Fischer A (Oct 2011). "A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories". The EMBO Journal. 30 (19): 4071–83. doi:10.1038/emboj.2011.293. PMC 3209781. PMID 21873981.
  13. ^ Balduyck B, Lauwers P, Govaert K, Hendriks J, De Maeseneer M, Van Schil P (Jul 2006). "Solitary fibrous tumor of the pleura with associated hypoglycemia: Doege-Potter syndrome: a case report". Journal of Thoracic Oncology. 1 (6): 588–90. doi:10.1097/01243894-200607000-00016. PMID 17409923.
  14. ^ He J, Zhang A, Fang M, Fang R, Ge J, Jiang Y, Zhang H, Han C, Ye X, Yu D, Huang H, Liu Y, Dong M (12 July 2013). "Methylation levels at IGF2 and GNAS DMRs in infants born to preeclamptic pregnancies". BMC Genomics. 14: 472. doi:10.1186/1471-2164-14-472. PMC 3723441. PMID 23844573.
  15. ^ a b Storch S, Kübler B, Höning S, Ackmann M, Zapf J, Blum W, Braulke T (Dec 2001). "Transferrin binds insulin-like growth factors and affects binding properties of insulin-like growth factor binding protein-3". FEBS Letters. 509 (3): 395–8. doi:10.1016/S0014-5793(01)03204-5. PMID 11749962.
  16. ^ Buckway CK, Wilson EM, Ahlsén M, Bang P, Oh Y, Rosenfeld RG (Oct 2001). "Mutation of three critical amino acids of the N-terminal domain of IGF-binding protein-3 essential for high affinity IGF binding". The Journal of Clinical Endocrinology and Metabolism. 86 (10): 4943–50. doi:10.1210/jcem.86.10.7936. PMID 11600567.
  17. ^ Twigg SM, Baxter RC (Mar 1998). "Insulin-like growth factor (IGF)-binding protein 5 forms an alternative ternary complex with IGFs and the acid-labile subunit". The Journal of Biological Chemistry. 273 (11): 6074–9. doi:10.1074/jbc.273.11.6074. PMID 9497324.
  18. ^ Firth SM, Ganeshprasad U, Baxter RC (Jan 1998). "Structural determinants of ligand and cell surface binding of insulin-like growth factor-binding protein-3". The Journal of Biological Chemistry. 273 (5): 2631–8. doi:10.1074/jbc.273.5.2631. PMID 9446566.

Further reading

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Insulin-like growth factor II E-peptide Provide feedback

This domain is found at the C-terminal domain of the insulin-like growth factor II (IGF-2, also see PF00049) in vertebrates and seems to represent the E-peptide [1,2].

Literature references

  1. LeRoith D, Roberts CT Jr; , Ann N Y Acad Sci 1993;692:1-9.: Insulin-like growth factors. PUBMED:8215015 EPMC:8215015

  2. van Doorn J, Hoogerbrugge CM, Koster JG, Bloemen RJ, Hoekman K, Mudde AH, van Buul-Offers SC; , Clin Chem 2002;48:1739-1750.: Antibodies directed against the E region of pro-insulin-like growth factor-II used to evaluate non-islet cell tumor-induced hypoglycemia. PUBMED:12324491 EPMC:12324491

This tab holds annotation information from the InterPro database.

InterPro entry IPR013576

The insulin family of proteins groups together several evolutionarily related active peptides [ PUBMED:6107857 ]: these include insulin [ PUBMED:6243748 , PUBMED:503234 ], relaxin [ PUBMED:10601981 , PUBMED:8735594 ], insect prothoracicotropic hormone (bombyxin) [ PUBMED:8683595 ], insulin-like growth factors (IGF1 and IGF2) [ PUBMED:2036417 , PUBMED:1319992 ], mammalian Leydig cell-specific insulin-like peptide (gene INSL3), early placenta insulin-like peptide (ELIP) (gene INSL4), locust insulin-related peptide (LIRP), molluscan insulin-related peptides (MIP), and Caenorhabditis elegans insulin-like peptides. The 3D structures of a number of family members have been determined [ PUBMED:2036417 , PUBMED:1319992 , PUBMED:9141131 ]. The fold comprises two polypeptide chains (A and B) linked by two disulphide bonds: all share a conserved arrangement of 4 cysteines in their A chain, the first of which is linked by a disulphide bond to the third, while the second and fourth are linked by interchain disulphide bonds to cysteines in the B chain.

Insulin is found in many animals, and is involved in the regulation of normal glucose homeostasis. It also has other specific physiological effects, such as increasing the permeability of cells to monosaccharides, amino acids and fatty acids, and accelerating glycolysis and glycogen synthesis in the liver [ PUBMED:6243748 ]. Insulin exerts its effects by interaction with a cell-surface receptor, which may also result in the promotion of cell growth [ PUBMED:6243748 ].

Insulin is synthesised as a prepropeptide from which an endoplasmic reticulum-targeting sequence is cleaved to yield proinsulin. The sequence of prosinsulin contains 2 well-conserved regions (designated A and B), separated by an intervening connecting region (C), which is variable between species [ PUBMED:503234 ]. The connecting region is cleaved, liberating the active protein, which contains the A and B chains, held together by 2 disulphide bonds [ PUBMED:503234 ].

Insulin-like Growth Factor Binding Proteins (IGFBP) are a group of vertebrate secreted proteins, which bind to IGF-I and IGF-II with high affinity and modulate the biological actions of IGFs. The IGFBP family has six distinct subgroups, IGFBP-1 through 6, based on conservation of gene (intron-exon) organisation, structural similarity, and binding affinity for IGFs. Across species, IGFBP-5 exhibits the most sequence conservation, while IGFBP-6 exhibits the least sequence conservation. The IGFBPs contain inhibitor domain homologues, which are related to MEROPS protease inhibitor family I31 (equistatin, clan IX).

All IGFBPs share a common domain architecture ( INTERPRO : INTERPRO ). While the N-terminal ( INTERPRO , IGF binding protein domain), and the C-terminal ( INTERPRO , thyroglobulin type-1 repeat) domains are conserved across vertebrate species, the mid-region is highly variable with respect to protease cleavage sites and phosphorylation and glycosylation sites. IGFBPs contain 16-18 conserved cysteines located in the N-terminal and the C-terminal regions, which form 8-9 disulphide bonds [ PUBMED:11874691 ].

As demonstrated for human IGFBP-5, the N terminus is the primary binding site for IGF. This region, comprised of Val49, Tyr50, Pro62 and Lys68-Leu75, forms a hydrophobic patch on the surface of the protein [ PUBMED:9822601 ]. The C terminus is also required for high affinity IGF binding, as well as for binding to the extracellular matrix [ PUBMED:9725901 ] and for nuclear translocation [ PUBMED:7519375 , PUBMED:9660801 ] of IGFBP-3 and -5.

IGFBPs are unusually pleiotropic molecules. Like other binding proteins, IGFBP can prolong the half-life of IGFs via high affinity binding of the ligands. In addition to functioning as simple carrier proteins, serum IGFBPs also serve to regulate the endocrine and paracrine/autocrine actions of IGF by modulating the IGF available to bind to signalling IGF-I receptors [ PUBMED:12379487 , PUBMED:12379489 ]. Furthermore, IGFBPs can function as growth modulators independent of IGFs. For example, IGFBP-5 stimulates markers of bone formation in osteoblasts lacking functional IGFs [ PUBMED:11874691 ]. The binding of IGFBP to its putative receptor on the cell membrane may stimulate the signalling pathway independent of an IGF receptor, to mediate the effects of IGFBPs in certain target cell types. IGFBP-1 and -2, but not other IGFBPs, contain a C-terminal Arg-Gly-Asp integrin-binding motif. Thus, IGFBP-1 can also stimulate cell migration of CHO and human trophoblast cells through an action mediated by alpha 5 beta 1 integrin [ PUBMED:7504269 ]. Finally, IGFBPs transported into the nucleus (via the nuclear localisation signal) may also exert IGF-independent effects by transcriptional activation of genes.

This domain is the C-terminal domain of insulin-like growth factor II proteins (IGF-2, also see INTERPRO ) in vertebrates and seems to represent the E-peptide [ PUBMED:8215015 , PUBMED:12324491 ].

Domain organisation

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Pfam-B_4175 (release 18.0)
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: Wuster A
Number in seed: 6
Number in full: 342
Average length of the domain: 54.50 aa
Average identity of full alignment: 60 %
Average coverage of the sequence by the domain: 25.22 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.0 27.0
Trusted cut-off 28.1 28.7
Noise cut-off 25.7 26.2
Model length: 56
Family (HMM) version: 14
Download: download the raw HMM for this family

Species distribution

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Archea Archea Eukaryota Eukaryota
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Viroids Viroids Unclassified sequence Unclassified sequence


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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
P01344 View 3D Structure Click here
P01346 View 3D Structure Click here
P09535 View 3D Structure Click here
Q5U3B4 View 3D Structure Click here
Q8JIE4 View 3D Structure Click here

trRosetta Structure

The structural model below was generated by the Baker group with the trRosetta software using the Pfam UniProt multiple sequence alignment.

The InterPro website shows the contact map for the Pfam SEED alignment. Hovering or clicking on a contact position will highlight its connection to other residues in the alignment, as well as on the 3D structure.

Improved protein structure prediction using predicted inter-residue orientations. Jianyi Yang, Ivan Anishchenko, Hahnbeom Park, Zhenling Peng, Sergey Ovchinnikov, David Baker Proceedings of the National Academy of Sciences Jan 2020, 117 (3) 1496-1503; DOI: 10.1073/pnas.1914677117;