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0  structures 122  species 0  interactions 168  sequences 3  architectures

Family: IGF2_C (PF08365)

Summary: Insulin-like growth factor II E-peptide

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

Insulin-like growth factor 2 Edit Wikipedia article

Insulin-like growth factor 2 (somatomedin A)

PDB rendering based on 1igl.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols IGF2; C11orf43; IGF-II; PP9974
External IDs OMIM147470 MGI96434 HomoloGene510 GeneCards: IGF2 Gene
RNA expression pattern
PBB GE IGF2 202409 at tn.png
PBB GE IGF2 202410 x at tn.png
PBB GE IGF2 210881 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3481 16002
Ensembl ENSG00000167244 ENSMUSG00000048583
UniProt P01344 P09535
RefSeq (mRNA) NM_000612 NM_001122736
RefSeq (protein) NP_000603 NP_001116208
Location (UCSC) Chr 11:
2.15 – 2.18 Mb
Chr 7:
142.65 – 142.67 Mb
PubMed search [2] [3]
Insulin-like growth factor II E-peptide
Identifiers
Symbol IGF2_C
Pfam PF08365
InterPro IPR013576

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".[1]

Gene structure[edit]

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 the human brain a loss of imprinting occurs resulting in both IGF2 and H19 being transcribed from both parental alleles.[2]

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.

Function[edit]

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. 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 theca cells to act in an autocrine manner on the theca cells themselves, and in a paracrine manner on granulosa cells in the ovary. IGF2 promotes granulosa cell proliferation during the follicular phase of the menstrual cycle, acting alongside follicle stimulating hormone (FSH). 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.

A study at the Mount Sinai School of Medicine found that IGF-2 may be linked to memory.[3] A study at the European Neuroscience Institute-Goettingen (Germany) found that fear extinction-induced IGF2/IGFBP7 signalling promotes the survival of 17–19-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.[4]

Diseases[edit]

It is sometimes produced in excess in islet cell tumours, causing hypoglycemia. Doege-Potter syndrome is a paraneoplastic syndrome[5] 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 tumours 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.

Interactions[edit]

Insulin-like growth factor 2 has been shown to interact with IGFBP3[6][7][8][9] and Transferrin.[6]

See also[edit]

References[edit]

  1. ^ http://www.ncbi.nlm.nih.gov/mesh/68007335
  2. ^ [1]
  3. ^ Chen, Dillon; Sarah Stern, Ana Garcia-Osta, Bernadette Saunier-Rebori, Gabriella Pollonini, Dhananjay Bambah-Mukku, Robert D. Blitzer, Cristina M. Alberini (27 January 2011). "A critical role for IGF-II in memory consolidation and enhancement". Nature 469: 491–497. doi:10.1038/nature09667. 
  4. ^ 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 (August 2011). "A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories". EMBO J 30 (19): 4071–83. doi:10.1038/emboj.2011.293. PMID 21873981. 
  5. ^ Balduyck B, Lauwers P, Govaert K, Hendriks J, De Maeseneer M, Van Schil P (July 2006). "Solitary fibrous tumor of the pleura with associated hypoglycemia: Doege-Potter syndrome: a case report". J Thorac Oncol 1 (6): 588–90. doi:10.1097/01243894-200607000-00016. PMID 17409923. 
  6. ^ 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 Lett. (Netherlands) 509 (3): 395–8. doi:10.1016/S0014-5793(01)03204-5. ISSN 0014-5793. PMID 11749962. 
  7. ^ Buckway, C K; Wilson E M, Ahlsén M, Bang P, Oh Y, Rosenfeld R G (Oct 2001). "Mutation of three critical amino acids of the N-terminal domain of IGF-binding protein-3 essential for high affinity IGF binding". J. Clin. Endocrinol. Metab. (United States) 86 (10): 4943–50. doi:10.1210/jc.86.10.4943. ISSN 0021-972X. PMID 11600567. 
  8. ^ Twigg, S M; Baxter R C (Mar 1998). "Insulin-like growth factor (IGF)-binding protein 5 forms an alternative ternary complex with IGFs and the acid-labile subunit". J. Biol. Chem. (UNITED STATES) 273 (11): 6074–9. doi:10.1074/jbc.273.11.6074. ISSN 0021-9258. PMID 9497324. 
  9. ^ Firth, S M; Ganeshprasad U, Baxter R C (Jan 1998). "Structural determinants of ligand and cell surface binding of insulin-like growth factor-binding protein-3". J. Biol. Chem. (UNITED STATES) 273 (5): 2631–8. doi:10.1074/jbc.273.5.2631. ISSN 0021-9258. PMID 9446566. 

External links[edit]

Further reading[edit]

  • O'Dell SD, Day IN (1998). "Insulin-like growth factor II (IGF-II).". Int. J. Biochem. Cell Biol. 30 (7): 767–71. doi:10.1016/S1357-2725(98)00048-X. PMID 9722981. 
  • Butler AA, Yakar S, Gewolb IH, et al. (1999). "Insulin-like growth factor-I receptor signal transduction: at the interface between physiology and cell biology.". Comp. Biochem. Physiol. B, Biochem. Mol. Biol. 121 (1): 19–26. doi:10.1016/S0305-0491(98)10106-2. PMID 9972281. 
  • Kalli KR, Conover CA (2004). "The insulin-like growth factor/insulin system in epithelial ovarian cancer.". Front. Biosci. 8: d714–22. doi:10.2741/1034. PMID 12700030. 
  • Wood AW, Duan C, Bern HA (2005). "Insulin-like growth factor signaling in fish.". Int. Rev. Cytol. 243: 215–85. doi:10.1016/S0074-7696(05)43004-1. PMID 15797461. 
  • Fowden AL, Sibley C, Reik W, Constancia M (2006). "Imprinted genes, placental development and fetal growth.". Horm. Res. 65 Suppl 3 (3): 50–8. doi:10.1159/000091506. PMID 16612114. 

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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


External database links

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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(8)
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Representative proteomes NCBI
(173)
Meta
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RP15
(1)
RP35
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RP55
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RP75
(22)
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  Seed
(8)
Full
(168)
Representative proteomes NCBI
(173)
Meta
(0)
RP15
(1)
RP35
(4)
RP55
(10)
RP75
(22)
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Curation and family details

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Curation View help on the curation process

Seed source: Pfam-B_4175 (release 18.0)
Previous IDs: none
Type: Family
Author: Wuster A
Number in seed: 8
Number in full: 168
Average length of the domain: 53.80 aa
Average identity of full alignment: 62 %
Average coverage of the sequence by the domain: 28.71 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.0 21.0
Trusted cut-off 21.5 22.0
Noise cut-off 20.2 20.6
Model length: 56
Family (HMM) version: 6
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