Insulin-like growth factor 2 explained

Symbol:IGF2_C
Insulin-like growth factor II E-peptide (somatomedians-A)
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 (IGF-1), which is a major growth factor in adults."[1]

Gene structure

In humans, the 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 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.[3]

The canonical isoform of IGF-2 preproprotein (180 amino acids) includes a signal peptide (amino acids 1-24) and a propeptide (amino acids 92-180). Proteolytic processing removes the signal peptide and the propeptide to generate the mature hormone (amino acids 25-91).[4]

Function

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-).[5] IGF-2 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 IGF-2 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. IGF-2 promotes granulosa cell proliferation during the follicular phase of the menstrual cycle, acting alongside follicle stimulating hormone (FSH).[6] After ovulation has occurred, IGF-2 promotes progesterone secretion during the luteal phase of the menstrual cycle, together with luteinizing hormone (LH). Thus, IGF-2 acts as a co-hormone together with both FSH and LH.[7]

A study at the Mount Sinai School of Medicine found that IGF-2 may be linked to memory and reproduction.[8] A study at the European Neuroscience Institute-Goettingen (Germany) found that fear extinction-induced IGF-2/IGFBP7 signalling promotes the survival of 17- to 19-day-old newborn hippocampal neurons. This suggests that therapeutic strategies that enhance IGF-2 signalling and adult neurogenesis might be suitable to treat diseases linked to excessive fear memory such as PTSD.[9]

Preptin

Preptin, a 34-aa peptide hormone produced by the pancreas, kidneys, breast tissues, and salivary glands, is derived from proteolytic cleavage of IGF-2 proprotein. The sequence of preptin (amino acids 93-126 of canonical IGF-2 preproprotein) is flanked by an N-terminal arginine (Arg) cleavage site and a C-terminal putative dibasic (Arg-Arg) cleavage motif.[10] Preptin is present in islet beta-cells, undergoes glucose-mediated co-secretion with insulin, and acts as a physiological amplifier of glucose-mediated insulin secretion. It has an anabolic impact on bone growth and exhibits osteogenic properties, increasing osteoblast mitogenic activity through phosphoactivation of MAPK1 and MAPK3. This activity resides within the first 16 amino acids of preptin.[11] Genetic ablation of the preptin-coding region of Igf2 in female mice impairs pancreatic function.[12]

Clinical relevance

IGF-2 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 IGF-2 is a common feature in tumors seen in Beckwith-Wiedemann syndrome. As IGF-2 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 IGF-2 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] In animals it has been shown that toxins such as PCB (polychlorinated biphenyls) affects IGF II expression.[15]

Interactions

Insulin-like growth factor 2 has been shown to interact with IGFBP3[16] [17] [18] [19] and transferrin.[16]

See also

Further reading

Notes and References

  1. Web site: Insulin-Like Growth Factor II . MeSH . NCBI .
  2. Pham NV, Nguyen MT, Hu JF, Vu TH, Hoffman AR . Dissociation of IGF2 and H19 imprinting in human brain . Brain Research . 810 . 1–2 . 1–8 . Nov 1998 . 9813220 . 10.1016/s0006-8993(98)00783-5. 39228039 .
  3. Book: Russell . Peter J. . vanc . iGenetics: A Molecular Approach. 2009 . Pearson Education . Upper Saddle River, N.J. . 978-0-321-61022-5 . 533 . 3rd .
  4. Web site: Insulin-like growth factor II, UniProtKB P01344 IGF2_HUMAN .
  5. Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R, Costantino A, Goldfine ID, Belfiore A, Vigneri R . 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 . 1999 . 10207053 . 84122 . 10.1128/MCB.19.5.3278 .
  6. Book: Neidhart, M . 2016 . DNA Methylation and Complex Human Disease . 1st . San Diego . Academic Press . 222. .
  7. Book: Neidhart, M . 2016 . DNA Methylation and Complex Human Disease . 1st . San Diego . Academic Press . 22. .
  8. Chen DY, Stern SA, Garcia-Osta A, Saunier-Rebori B, Pollonini G, Bambah-Mukku D, Blitzer RD, Alberini CM . A critical role for IGF-II in memory consolidation and enhancement . Nature . 469 . 7331 . 491–7 . Jan 2011 . 21270887 . 10.1038/nature09667 . 3908455. 2011Natur.469..491C .
  9. 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 . A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories . The EMBO Journal . 30 . 19 . 4071–83 . Oct 2011 . 21873981 . 3209781 . 10.1038/emboj.2011.293 .
  10. Buchanan CM, Phillips AR, Cooper GJ . Preptin derived from proinsulin-like growth factor II (proIGF-II) is secreted from pancreatic islet beta-cells and enhances insulin secretion . Biochem. J. . 360 . Pt 2 . 431–439 . 1 Dec 2001 . 11716772 . 1222244 . 10.1042/0264-6021:3600431 . 39228039 .
  11. Amso Z, Kowalczyk R, Watson M, Park YF, Callon KE, Musson DS, Cornish J, Brimble M . Structure activity relationship study on the peptide hormone preptin, a novel bone-anabolic agent for the treatment of osteoporosis . Org Biomol Chem . 14 . 39 . 9225–9238 . 21 Oct 2016 . 27488745 . 10.1039/c6ob01455k .
  12. Buckels EJ, ((Hsu H-L)), Buchanan CM, Matthews BG . Genetic ablation of the preptin-coding portion of Igf2 impairs pancreatic function in female mice . Am J Physiol Endocrinol Metab . 323 . 6 . E467–E479 . 1 Dec 2022 . 36459047 . 10.1152/ajpendo.00401.2021 . 252458335 .
  13. Balduyck B, Lauwers P, Govaert K, Hendriks J, De Maeseneer M, Van Schil P . Solitary fibrous tumor of the pleura with associated hypoglycemia: Doege-Potter syndrome: a case report . Journal of Thoracic Oncology . 1 . 6 . 588–90 . Jul 2006 . 17409923 . 10.1097/01243894-200607000-00016 .
  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 . Methylation levels at IGF2 and GNAS DMRs in infants born to preeclamptic pregnancies . BMC Genomics . 14 . 472 . 12 July 2013 . 23844573 . 3723441 . 10.1186/1471-2164-14-472 . free .
  15. Höglund O, Sjölund C, Shokrai A, Bäcklin BM, Backhaus A, Wikström K, Granerus M, Engström W . The effects of polychlorinated biphenyls on growth factor expression and biological reproduction in the mink (Mustela vison) . Reproduction in Domestic Animals . June 1993 . 28 . 3 . 215–216 . 10.1111/j.1439-0531.1993.tb00129.x .
  16. Storch S, Kübler B, Höning S, Ackmann M, Zapf J, Blum W, Braulke T . Transferrin binds insulin-like growth factors and affects binding properties of insulin-like growth factor binding protein-3 . FEBS Letters . 509 . 3 . 395–8 . Dec 2001 . 11749962 . 10.1016/S0014-5793(01)03204-5 . 22895295 . free .
  17. Buckway CK, Wilson EM, Ahlsén M, Bang P, Oh Y, Rosenfeld RG . 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 . Oct 2001 . 11600567 . 10.1210/jcem.86.10.7936 . free .
  18. Twigg SM, Baxter RC . 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 . Mar 1998 . 9497324 . 10.1074/jbc.273.11.6074 . free .
  19. Firth SM, Ganeshprasad U, Baxter RC . 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 . Jan 1998 . 9446566 . 10.1074/jbc.273.5.2631 . free .

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