Insulin-like growth factor 2

Last updated
IGF2
Protein IGF2 PDB 1igl.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases IGF2 , C11orf43, GRDF, IGF-II, PP9974, insulin like growth factor 2, SRS3
External IDs OMIM: 147470 MGI: 96434 HomoloGene: 510 GeneCards: IGF2
Orthologs
SpeciesHumanMouse
Entrez

3481

16002

Ensembl

ENSG00000167244

ENSMUSG00000048583

UniProt

P01344

P09535

RefSeq (mRNA)

NM_001291862
NM_000612
NM_001007139
NM_001127598
NM_001291861

Contents

NM_001122736
NM_001122737
NM_010514
NM_001315488
NM_001315489

RefSeq (protein)

NP_000603
NP_001007140
NP_001121070
NP_001278790
NP_001278791

NP_001116208
NP_001116209
NP_001302417
NP_001302418
NP_034644

Location (UCSC) Chr 11: 2.13 – 2.16 Mb Chr 7: 142.2 – 142.22 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Insulin-like growth factor II E-peptide (somatomedians-A )
Identifiers
SymbolIGF2_C
Pfam PF08365
InterPro IPR013576
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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." [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 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). [8]

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-). [9] 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.[ citation needed ] IGF-2 promotes granulosa cell proliferation during the follicular phase of the menstrual cycle, acting alongside follicle stimulating hormone (FSH). [10] 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. [11]

A study at the Mount Sinai School of Medicine found that IGF-2 may be linked to memory and reproduction. [12] 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. [13]

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. [14] 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. [15] Genetic ablation of the preptin-coding region of Igf2 in female mice impairs pancreatic function. [16]

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 [17] 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. [18] In animals it has been shown that toxins such as PCB (polychlorinated biphenyls) affects IGF II expression. [19]

Interactions

Insulin-like growth factor 2 has been shown to interact with IGFBP3 [20] [21] [22] [23] and transferrin. [20]

See also

Related Research Articles

<span class="mw-page-title-main">Insulin-like growth factor</span> Proteins similar to insulin that stimulate cell proliferation

The insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system consists of two cell-surface receptors, two ligands, a family of seven high-affinity IGF-binding proteins, as well as associated IGFBP degrading enzymes, referred to collectively as proteases.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Insulin receptor</span> Mammalian protein found in Homo sapiens

The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis; a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms. Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor.

<span class="mw-page-title-main">Insulin-like growth factor 1</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults.

<span class="mw-page-title-main">Insulin-like growth factor 1 receptor</span> Cell surface tyrosine kinase associated receptor, quiche mediates the effects of Igf-1

The insulin-like growth factor 1 (IGF-1) receptor is a protein found on the surface of human cells. It is a transmembrane receptor that is activated by a hormone called insulin-like growth factor 1 (IGF-1) and by a related hormone called IGF-2. It belongs to the large class of tyrosine kinase receptors. This receptor mediates the effects of IGF-1, which is a polypeptide protein hormone similar in molecular structure to insulin. IGF-1 plays an important role in growth and continues to have anabolic effects in adults – meaning that it can induce hypertrophy of skeletal muscle and other target tissues. Mice lacking the IGF-1 receptor die late in development, and show a dramatic reduction in body mass. This testifies to the strong growth-promoting effect of this receptor.

<span class="mw-page-title-main">Agouti-signaling protein</span> Protein-coding gene in the species Homo sapiens

Agouti-signaling protein is a protein that in humans is encoded by the ASIP gene. It is responsible for the distribution of melanin pigment in mammals. Agouti interacts with the melanocortin 1 receptor to determine whether the melanocyte produces phaeomelanin, or eumelanin. This interaction is responsible for making distinct light and dark bands in the hairs of animals such as the agouti, which the gene is named after. In other species such as horses, agouti signalling is responsible for determining which parts of the body will be red or black. Mice with wildtype agouti will be grey-brown, with each hair being partly yellow and partly black. Loss of function mutations in mice and other species cause black fur coloration, while mutations causing expression throughout the whole body in mice cause yellow fur and obesity.

<span class="mw-page-title-main">Insulin-like growth factor-binding protein</span> Transport protein for insulin-like growth factor 1

The insulin-like growth factor-binding protein (IGFBP) serves as a transport protein for insulin-like growth factor 1 (IGF-1).

<span class="mw-page-title-main">CTCF</span> Transcription factor

Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the CTCF gene. CTCF is involved in many cellular processes, including transcriptional regulation, insulator activity, V(D)J recombination and regulation of chromatin architecture.

Growth hormone-binding protein (GHBP) is a soluble carrier protein for growth hormone (GH). The full range of functions of GHBP remains to be determined however, current research suggests that the protein is associated with regulation of the GH availability and half-life in the circulatory system, as well as modulating GH receptor function.

<span class="mw-page-title-main">Insulin-like growth factor 2 receptor</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor 2 receptor (IGF2R), also called the cation-independent mannose-6-phosphate receptor (CI-MPR) is a protein that in humans is encoded by the IGF2R gene. IGF2R is a multifunctional protein receptor that binds insulin-like growth factor 2 (IGF2) at the cell surface and mannose-6-phosphate (M6P)-tagged proteins in the trans-Golgi network.

<span class="mw-page-title-main">IGFBP3</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 3, also known as IGFBP-3, is a protein that in humans is encoded by the IGFBP3 gene. IGFBP-3 is one of six IGF binding proteins that have highly conserved structures and bind the insulin-like growth factors IGF-1 and IGF-2 with high affinity. IGFBP-7, sometimes included in this family, shares neither the conserved structural features nor the high IGF affinity. Instead, IGFBP-7 binds IGF1R, which blocks IGF-1 and IGF-2 binding, resulting in apoptosis.

<span class="mw-page-title-main">IGFBP1</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 1 (IBP-1) also known as placental protein 12 (PP12) is a protein that in humans is encoded by the IGFBP1 gene.

<span class="mw-page-title-main">IGFBP7</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 7 is a protein that in humans is encoded by the IGFBP7 gene. The major function of the protein is the regulation of availability of insulin-like growth factors (IGFs) in tissue as well as in modulating IGF binding to its receptors. IGFBP7 binds to IGF with low affinity compared to IGFBPs 1-6. It also stimulates cell adhesion. The protein is implicated in some cancers.

<span class="mw-page-title-main">H19 (gene)</span> Negative regulation (or limiting) of body weight and cell proliferation

H19 is a gene for a long noncoding RNA, found in humans and elsewhere. H19 has a role in the negative regulation of body weight and cell proliferation. This gene also has a role in the formation of some cancers and in the regulation of gene expression. .

Peptide signaling plays a significant role in various aspects of plant growth and development and specific receptors for various peptides have been identified as being membrane-localized receptor kinases, the largest family of receptor-like molecules in plants. Signaling peptides include members of the following protein families.

Dalotuzumab is an anti-IGF1 receptor (IGF1R) humanized monoclonal antibody designed for the potential treatment of various cancers. Common adverse effects include hyperglycemia, nausea, vomiting, and fatigue. Dalotuzumab was developed by Merck and Co., Inc.

Epigenetics of human development is the study of how epigenetics effects human development.

Long arginine 3-IGF-1, abbreviated as IGF-1 LR3 or LR3-IGF-1, is a synthetic protein and lengthened analogue of human insulin-like growth factor 1 (IGF-1). It differs from native IGF-1 in that it possesses an arginine instead of a glutamic acid at the third position in its amino acid sequence, and also has an additional 13 amino acids at its N-terminus (MFPAMPLLSLFVN) ("long"), for a total of 83 amino acids. The consequences of these modifications are that IGF-1 LR3 retains the pharmacological activity of IGF-1 as an agonist of the IGF-1 receptor, has very low affinity for the insulin-like growth factor-binding proteins (IGFBPs), and has improved metabolic stability. As a result, it is approximately three times more potent than IGF-1, and possesses a significantly longer half-life of about 20–30 hours.

des(1-3)IGF-1 is a naturally occurring, endogenous protein, as well as drug, and truncated analogue of insulin-like growth factor 1 (IGF-1). des(1-3)IGF-1 lacks the first three amino acids at the N-terminus of IGF-1. As a result of this difference, it has considerably reduced binding to the insulin-like growth factor-binding proteins (IGFBPs) and enhanced potency relative to IGF-1.

A bone growth factor is a growth factor that stimulates the growth of bone tissue.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000167244 - Ensembl, May 2017
  2. 1 2 3 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. S2CID   39228039.
  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. ↑ "Insulin-like growth factor II, UniProtKB P01344 IGF2_HUMAN".
  9. ↑ 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.
  10. ↑ Neidhart, M (2016). DNA Methylation and Complex Human Disease (1st ed.). San Diego: Academic Press. p. 222. ISBN   9780124201941.
  11. ↑ Neidhart, M (2016). DNA Methylation and Complex Human Disease (1st ed.). San Diego: Academic Press. p. 22. ISBN   978-0124201941.
  12. ↑ 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. Bibcode:2011Natur.469..491C. doi:10.1038/nature09667. PMC   3908455 . PMID   21270887.
  13. ↑ 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.
  14. ↑ Buchanan CM, Phillips AR, Cooper GJ (1 Dec 2001). "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. doi:10.1042/0264-6021:3600431. PMC   1222244 . PMID   11716772. S2CID   39228039.
  15. ↑ Amso Z, Kowalczyk R, Watson M, Park YF, Callon KE, Musson DS, Cornish J, Brimble M (21 Oct 2016). "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. doi:10.1039/c6ob01455k. PMID   27488745.
  16. ↑ Buckels EJ, Hsu H-L, Buchanan CM, Matthews BG (1 Dec 2022). "Genetic ablation of the preptin-coding portion of Igf2 impairs pancreatic function in female mice". Am J Physiol Endocrinol Metab. 323 (6): E467–E479. doi:10.1152/ajpendo.00401.2021. PMID   36459047. S2CID   252458335.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ Höglund O, Sjölund C, Shokrai A, Bäcklin BM, Backhaus A, Wikström K, Granerus M, Engström W (June 1993). "The effects of polychlorinated biphenyls on growth factor expression and biological reproduction in the mink (Mustela vison)". Reproduction in Domestic Animals. 28 (3): 215–216. doi:10.1111/j.1439-0531.1993.tb00129.x.
  20. 1 2 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. S2CID   22895295.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.

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