View source for Insulin-like growth factor 2

{{Short description|Protein hormone}}
{{Infobox gene}}
{{Infobox protein family
| Symbol = IGF2_C
| Name = Insulin-like growth factor II E-peptide (somatomedians-A )
| image = 
| width = 
| caption = 
| Pfam = PF08365
| Pfam_clan =  
| InterPro = IPR013576
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
'''Insulin-like growth factor 2''' ('''IGF-2''') is one of three protein [[hormone]]s 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 [[IGF-1|insulin-like growth factor 1]] (IGF-1), which is a major growth factor in adults."<ref>{{cite web | url = https://www.ncbi.nlm.nih.gov/mesh/68007335 | title = Insulin-Like Growth Factor II | work = MeSH | publisher =  NCBI }}</ref>[[File:Ideogram human chromosome 11.svg | thumb | right]]

== Gene structure ==

In humans, the {{gene|IGF2}} [[gene]] is located on [[chromosome 11]]p15.5, a region which contains numerous [[Genomic Imprinting|imprinted genes]]. In mice this [[Homology (biology)|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 {{gene|H19}} being transcribed from both parental alleles.<ref>{{cite journal | vauthors = Pham NV, Nguyen MT, Hu JF, Vu TH, Hoffman AR | title = Dissociation of IGF2 and H19 imprinting in human brain | journal = Brain Research | volume = 810 | issue = 1–2 | pages = 1–8 | date = Nov 1998 | pmid = 9813220 | doi=10.1016/s0006-8993(98)00783-5| s2cid = 39228039 }}</ref>

The protein [[CTCF]] is involved in repressing [[gene expression|expression]] of the gene, by binding to the ''[[H19 (gene)|H19]]'' imprinting control region (ICR) along with Differentially-methylated Region-1 (DMR1) and Matrix Attachment Region −3 (MAR3). These three [[DNA sequence]]s 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&mdash;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.<ref>{{cite book | last1 = Russell | first1 = Peter J. | name-list-style = vanc | title = iGenetics: A Molecular Approach|date=2009 | publisher = Pearson Education | location = Upper Saddle River, N.J. | isbn = 978-0-321-61022-5 | page = 533 | edition=3rd | url = https://archive.org/stream/IGenetics3rdPeterJ.Russell/iGenetics%2C%203rd%20%28Peter%20J.%20Russell%29#page/n553/mode/2up }}</ref>

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).<ref name="UniProtP01344 ">{{cite web | title = Insulin-like growth factor II, UniProtKB P01344 IGF2_HUMAN | url=https://www.uniprot.org/uniprot/P01344/entry#P01344-1}}</ref>

== Function ==

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

IGF-2 exerts its effects by binding to the [[Insulin-like growth factor 1 receptor|IGF-1 receptor]] and to the short isoform of the insulin receptor (IR-A or exon 11-).<ref name="pmid10207053">{{cite journal | vauthors = Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R, Costantino A, Goldfine ID, Belfiore A, Vigneri R | title = Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells | journal = Molecular and Cellular Biology | volume = 19 | issue = 5 | pages = 3278–88 | year = 1999 | pmid = 10207053 | pmc = 84122 | doi =  10.1128/MCB.19.5.3278 }}</ref> IGF-2 may also bind to the [[Insulin-like growth factor 2 receptor|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.{{citation needed|date=February 2014}} IGF-2 promotes granulosa cell proliferation during the follicular phase of the menstrual cycle, acting alongside follicle stimulating hormone (FSH).<ref>{{cite book |vauthors= Neidhart, M |date= 2016 |title= DNA Methylation and Complex Human Disease |edition= 1st |place= San Diego |publisher= Academic Press |page= 222}} {{ISBN|9780124201941}}.</ref> 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.<ref>{{cite book |vauthors= Neidhart, M |date= 2016 |title= DNA Methylation and Complex Human Disease |edition= 1st |place= San Diego |publisher= Academic Press |page= 22}} {{ISBN|978-0124201941}}.</ref>

A study at the Mount Sinai School of Medicine found that IGF-2 may be linked to memory and reproduction.<ref>{{cite journal |vauthors= Chen DY, Stern SA, Garcia-Osta A, Saunier-Rebori B, Pollonini G, Bambah-Mukku D, Blitzer RD, Alberini CM |title= A critical role for IGF-II in memory consolidation and enhancement |journal= Nature |volume = 469 |issue = 7331 |pages = 491–7 |date= Jan 2011 |pmid= 21270887 |doi= 10.1038/nature09667 |pmc=3908455|bibcode= 2011Natur.469..491C }}</ref> 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]].<ref name="pmid21873981">{{cite journal |vauthors= 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 |title= A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories |journal= The EMBO Journal |volume= 30 |issue= 19 |pages= 4071–83 |date= Oct 2011 |pmid= 21873981 |pmc= 3209781 |doi= 10.1038/emboj.2011.293 }}</ref>

== 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.<ref>{{cite journal | vauthors = Buchanan CM, Phillips AR, Cooper GJ | title = Preptin derived from proinsulin-like growth factor II (proIGF-II) is secreted from pancreatic islet beta-cells and enhances insulin secretion | journal = Biochem. J. | volume = 360 | issue = Pt 2 | pages = 431–439 | date = 1 Dec 2001 | pmid = 11716772 | pmc = 1222244 | doi=10.1042/0264-6021:3600431 | s2cid = 39228039 }}</ref> 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.<ref>{{cite journal | vauthors = Amso Z, Kowalczyk R, Watson M, Park YF, Callon KE, Musson DS, Cornish J, Brimble M | title = Structure activity relationship study on the peptide hormone preptin, a novel bone-anabolic agent for the treatment of osteoporosis | journal = Org Biomol Chem | volume = 14 | issue = 39 | pages = 9225–9238 | date = 21 Oct 2016 | pmid = 27488745 | doi=10.1039/c6ob01455k }}</ref> Genetic ablation of the preptin-coding region of Igf2 in female mice impairs pancreatic function.<ref>{{cite journal | vauthors = Buckels EJ, Hsu HL, Buchanan CM, Matthews BG | title = Genetic ablation of the preptin-coding portion of Igf2 impairs pancreatic function in female mice | journal = Am J Physiol Endocrinol Metab | volume = 323 | issue = 6 | pages = E467–E479 | date = 1 Dec 2022 | pmid = 36459047 | doi=10.1152/ajpendo.00401.2021 | s2cid = 252458335 }}</ref>

== Clinical relevance ==

IGF-2 is sometimes produced in excess in [[Islets of Langerhans|islet]] cell [[tumor]]s and [[Non islet hypoglycemic cell tumor|non-islet hypoglycemic cell tumors]], causing [[hypoglycemia]]. [[Doege-Potter syndrome]] is a [[paraneoplastic syndrome]]<ref name = pmid17409923>{{cite journal |vauthors= Balduyck B, Lauwers P, Govaert K, Hendriks J, De Maeseneer M, Van Schil P |title= Solitary fibrous tumor of the pleura with associated hypoglycemia: Doege-Potter syndrome: a case report |journal= Journal of Thoracic Oncology |volume= 1 |issue= 6 |pages= 588–90 |date= Jul 2006 |pmid= 17409923 |doi= 10.1097/01243894-200607000-00016 }}</ref> in which hypoglycemia is associated with the presence of one or more non-islet fibrous [[tumor]]s 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.<ref name="pmid573">{{cite journal |vauthors= 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 |title= Methylation levels at IGF2 and GNAS DMRs in infants born to preeclamptic pregnancies |journal= BMC Genomics |volume= 14 |pages= 472 |date= 12 July 2013 |pmid= 23844573 |pmc= 3723441 |doi= 10.1186/1471-2164-14-472 |doi-access= free }}</ref>
In animals it has been shown that toxins such as PCB ([[polychlorinated biphenyls]]) affects IGF II expression.<ref>{{cite journal | vauthors = Höglund O, Sjölund C, Shokrai A, Bäcklin BM, Backhaus A, Wikström K, Granerus M, Engström W |title=The effects of polychlorinated biphenyls on growth factor expression and biological reproduction in the mink (Mustela vison) |journal=Reproduction in Domestic Animals |date=June 1993 |volume=28 |issue=3 |pages=215–216 |doi=10.1111/j.1439-0531.1993.tb00129.x  }}</ref>

== Interactions ==

Insulin-like growth factor 2 has been shown to [[Protein-protein interaction|interact]] with [[IGFBP3]]<ref name=pmid11749962>{{cite journal |vauthors = Storch S, Kübler B, Höning S, Ackmann M, Zapf J, Blum W, Braulke T | title = Transferrin binds insulin-like growth factors and affects binding properties of insulin-like growth factor binding protein-3 | journal = FEBS Letters | volume = 509 | issue = 3 | pages = 395–8 | date = Dec 2001 | pmid = 11749962 | doi = 10.1016/S0014-5793(01)03204-5 | s2cid = 22895295 | doi-access = free | bibcode = 2001FEBSL.509..395S }}</ref><ref name=pmid11600567>{{cite journal |vauthors= Buckway CK, Wilson EM, Ahlsén M, Bang P, Oh Y, Rosenfeld RG |title= Mutation of three critical amino acids of the N-terminal domain of IGF-binding protein-3 essential for high affinity IGF binding |journal= The Journal of Clinical Endocrinology and Metabolism |volume= 86 |issue= 10 |pages= 4943–50 |date= Oct 2001 |pmid= 11600567 |doi= 10.1210/jcem.86.10.7936 |doi-access= free }}</ref><ref name=pmid9497324>{{cite journal |vauthors = Twigg SM, Baxter RC |title= Insulin-like growth factor (IGF)-binding protein 5 forms an alternative ternary complex with IGFs and the acid-labile subunit |journal= The Journal of Biological Chemistry |volume= 273 |issue= 11 |pages= 6074–9 |date= Mar 1998 | pmid= 9497324 |doi= 10.1074/jbc.273.11.6074 |doi-access= free }}</ref><ref name=pmid9446566>{{cite journal | vauthors = Firth SM, Ganeshprasad U, Baxter RC |title= Structural determinants of ligand and cell surface binding of insulin-like growth factor-binding protein-3 |journal= The Journal of Biological Chemistry |volume= 273 |issue=5 |pages= 2631–8 |date= Jan 1998 |pmid= 9446566 |doi= 10.1074/jbc.273.5.2631 |doi-access= free }}</ref> and [[transferrin]].<ref name=pmid11749962/>

== See also ==
* [[Insulin-like growth factor 2 receptor]]
* [[Insulin-like growth factor II IRES]]
{{Clear}}

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = O'Dell SD, Day IN | title = Insulin-like growth factor II (IGF-II) | journal = The International Journal of Biochemistry & Cell Biology | volume = 30 | issue = 7 | pages = 767–71 | date = Jul 1998 | pmid = 9722981 | doi = 10.1016/S1357-2725(98)00048-X }}
* {{cite journal | vauthors = Butler AA, Yakar S, Gewolb IH, Karas M, Okubo Y, LeRoith D | title = Insulin-like growth factor-I receptor signal transduction: at the interface between physiology and cell biology | journal = Comparative Biochemistry and Physiology B | volume = 121 | issue = 1 | pages = 19–26 | date = Sep 1998 | pmid = 9972281 | doi = 10.1016/S0305-0491(98)10106-2 | url = https://zenodo.org/record/1260019 }}
* {{cite journal | vauthors = Kalli KR, Conover CA | title = The insulin-like growth factor/insulin system in epithelial ovarian cancer | journal = Frontiers in Bioscience | volume = 8 | issue =  4| pages = d714–22 | date = May 2003 | pmid = 12700030 | doi = 10.2741/1034 | doi-access = free }}
* {{cite book | vauthors = Wood AW, Duan C, Bern HA | title = Insulin-Like Growth Factor Signaling in Fish | series = International Review of Cytology | volume = 243 | pages = 215–85 | year = 2005 | pmid = 15797461 | doi = 10.1016/S0074-7696(05)43004-1 | isbn = 9780123646477 }}
* {{cite journal | vauthors = Fowden AL, Sibley C, Reik W, Constancia M | title = Imprinted genes, placental development and fetal growth | journal = Hormone Research | volume = 65 Suppl 3 | issue = 3 | pages = 50–8 | year = 2006 | pmid = 16612114 | doi = 10.1159/000091506 | s2cid = 1030630 }}
{{refend}}

== External links ==
* {{MeshName|Insulin-Like+Growth+Factor+II}}

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{{DEFAULTSORT:Insulin-Like Growth Factor 2}}
[[Category:Peptide hormones]]
[[Category:Hormones of the somatotropic axis]]
[[Category:Insulin-like growth factor receptor agonists]]
[[Category:Insulin receptor agonists]]