IGFBP7

Last updated
IGFBP7
Identifiers
Aliases IGFBP7 , AGM, FSTL2, IBP-7, IGFBP-7, IGFBP-7v, IGFBPRP1, MAC25, PSF, RAMSVPS, TAF, insulin like growth factor binding protein 7
External IDs OMIM: 602867 MGI: 1352480 HomoloGene: 1193 GeneCards: IGFBP7
Orthologs
SpeciesHumanMouse
Entrez

3490

29817

Ensembl

ENSG00000163453

ENSMUSG00000036256

UniProt

Q16270

Q61581

RefSeq (mRNA)

NM_001553
NM_001253835

NM_001159518
NM_008048

RefSeq (protein)

NP_001240764
NP_001544

NP_001152990
NP_032074

Location (UCSC) Chr 4: 57.03 – 57.11 Mb Chr 5: 77.5 – 77.56 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Insulin-like growth factor-binding protein 7 is a protein that in humans is encoded by the IGFBP7 gene. [5] [6] [7] 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. [8] [9] It also stimulates cell adhesion. The protein is implicated in some cancers. [10]

Contents

Interactions

IGFBP7 has been shown to interact with Insulin-like growth factor 1, [8] [11] VPS24, [12] and the IGF-1 receptor (IGF1R). [13]

RNA Editing

The pre-mRNA of this protein is subject to RNA editing. The two editing sites were previously recorded as single nucleotide polymorphisms in dbSNP. [14]

Editing type

A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cell's translational machinery. There are three members of the ADAR family ADARs 1-3 with ADAR 1 and ADAR 2 being the only enzymatically active members. ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR 2 are widely expressed in tissues while ADAR 3 is restricted to the brain. The double stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site with residues usually in a neighboring intron but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complentary Sequence (ECS). It is thought that the pre-mRNA of IGFBP7 is a substrate for ADAR1 based on the expression spectrum of the editing enzyme. [15]

Editing sites

The pre-mRNA of this protein is edited at two positions. These editing sites occur within the insulin growth factor domain.

R/G site

There is an Arginine (R) to a Glycine (G) substitution at amino acid position 78 of the final protein.

K/R site

There is a K to R substitution at amino acid position 95.

The editing complementary sequence (ECS) is located in a region within the coding sequence about 200 base pairs upstream from the editing sites. The ECS forms 140 bp duplex structure. [14] The A to G discrepancies for these two editing sites were confirmed experimentally to be RNA editing by analyzing matched cDNA and genomic dna sequences from the same tissue sample. [10] Intriguingly, those RNAs that do not need an intron sequence to pair with could, in theory, continue to undergo editing as mature mRNA. A third candidate editing site did not show evidence of RNA editing in sequence analysis, which may be an indication that either the RNA editing process is tissue specific, or editing occurs at a low frequency. One other possible explanation is that these edits are related to specific genomic polymorphisms. [10] The editing site also overlaps with an antisense transcript which could also form a double stranded RNA structure creating a suitable substrate for ADARs. [14]

Editing regulation

Editing is observed in a wide range of tissues. Editing at the K/R site at amino acid position 95 is very high in the human brain. [10]

Consequences

Structural

The edited sites are found within the insulin growth factor binding domain of IGFBP7 and also Heparin binding domain. This region is also a site for proteolytic cleavage. Structural analysis of the edited sites determined that the two amino acids that corresponded to the edited sites are not directly involved in binding to IGF-1 but are found in regions flanking them. [16] At position 78 in unedited version of the transcript there is an Arginine close to residue valine-49.This Valine is important in hydrophobic interaction of Phenylalanine of IGF-1. A substitution to a Glycine at this position is thought to introduce additional flexibility leading to a change of loop conformation, thereby disrupting the hydrophobic interaction that stabilises the complex. At amino acid position 98 the unedited transcript contains a lysine. This residue makes some non specific interactions via the aliphatic part of the side chain with Glu-38 of IGF-1. In the edited version the position is an arginine. The long side chain of which is thought to be able to maintain these weak interactions. [14]

Function

The edited region contains a proposed heparin binding site and is also part of the recognition sequence for proteolytic cleavage. Heparin binding inhibits cell binding and cell adhesion functions of the protein. [17] Cleavage which occurs at amino acid position 97 reduces heparin binding but modulates the growth stimulatory activity of the protein. [11] Since the editing site occurs within this proposed heparin binding region the effects of editing may have implications for heparin binding and proteolytic cleavage and therefore have other affects downstream. Since the protein has been implicated in these processes it is believed editing might effect apoptosis, regulation of cell growth and angiogenesis. [10]

Functions in Learning and Memory

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. [18] The same group has found that IGFBP7 levels are increased in Alzheimer's disease and regulated via DNA methylation. Elevation of IGFBP7 in wild type mice causes memory impairment. Blocking IGFBP7 function in mice that develop Alzheimer's disease-like memory impairment restores memory function. These data suggest that IGFBP7 is a critical regulator of memory consolidation and might be used as biomarker for Alzheimer's disease. Targeting IGFBP7 could be a novel therapeutic avenue for the treatment of Alzheimer's disease patients. [19]

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">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">Lipoprotein lipase</span> Mammalian protein found in Homo sapiens

Lipoprotein lipase (LPL) (EC 3.1.1.34, systematic name triacylglycerol acylhydrolase (lipoprotein-dependent)) is a member of the lipase gene family, which includes pancreatic lipase, hepatic lipase, and endothelial lipase. It is a water-soluble enzyme that hydrolyzes triglycerides in lipoproteins, such as those found in chylomicrons and very low-density lipoproteins (VLDL), into two free fatty acids and one monoacylglycerol molecule:

<span class="mw-page-title-main">Insulin-like growth factor 2</span> Protein hormone

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."

<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">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">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">Heparin-binding EGF-like growth factor</span> Protein-coding gene in the species Homo sapiens

Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of proteins that in humans is encoded by the HBEGF gene.

<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">IGFBP2</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 2 is a protein that in humans is encoded by the IGFBP2 gene.

<span class="mw-page-title-main">IGFBP5</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 5(IBF-5) is a protein that in humans is encoded by the IGFBP5 gene. An IGFBP5 gene was recently identified as being important for adaptation to varying water salinity in fish.

<span class="mw-page-title-main">IGFBP4</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 4 is a protein that in humans is encoded by the IGFBP4 gene.

<span class="mw-page-title-main">IGFBP6</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 6 (IGFBP-6) is a protein that in humans is encoded by the IGFBP6 gene.

<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">IGF2BP1</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor 2 mRNA-binding protein 1 is a protein that in humans is encoded by the IGF2BP1 gene.

<span class="mw-page-title-main">IGF2BP2</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor 2 mRNA-binding protein 2 is a protein that in humans is encoded by the IGF2BP2 gene.

<span class="mw-page-title-main">ARL6IP4</span> Protein-coding gene in humans

ADP-ribosylation-like factor 6 interacting protein 4 (ARL6IP4), also called SRp25 is the product of the ARL6IP4 gene located on chromosome 12q24. 31. Its function is unknown.

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.

<span class="mw-page-title-main">Cyclic glycine-proline</span> Small neuroactive peptide

Cyclic glycine-proline (cGP) is a small neuroactive peptide that belongs to a group of bioactive 2,5-diketopiperazines (2,5-DKPs) and is also known as cyclo-glycine-proline. cGP is a neutral, stable naturally occurring compound and is endogenous to the human body; found in human plasma, breast milk and cerebrospinal fluid. DKPs are bioactive compounds often found in foods. Cyclic dipeptides such as 2,5 DKPs are formed by the cyclisation of two amino acids of linear peptides produced in heated or fermented foods. The bioactivity of cGP is a property of functional foods and presents in several matrices of foods including blackcurrants.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000163453 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000036256 - 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. ↑ Murphy M, Pykett MJ, Harnish P, Zang KD, George DL (Dec 1993). "Identification and characterization of genes differentially expressed in meningiomas". Cell Growth Differ. 4 (9): 715–22. PMID   7694637.
  6. ↑ Yamauchi T, Umeda F, Masakado M, Isaji M, Mizushima S, Nawata H (Nov 1994). "Purification and molecular cloning of prostacyclin-stimulating factor from serum-free conditioned medium of human diploid fibroblast cells". Biochem J. 303 (2): 591–8. doi:10.1042/bj3030591. PMC   1137368 . PMID   7980422.
  7. ↑ "Entrez Gene: IGFBP7 insulin-like growth factor binding protein 7".
  8. 1 2 Oh Y, Nagalla SR, Yamanaka Y, Kim HS, Wilson E, Rosenfeld RG (November 1996). "Synthesis and characterization of insulin-like growth factor-binding protein (IGFBP)-7. Recombinant human mac25 protein specifically binds IGF-I and -II". J. Biol. Chem. 271 (48): 30322–5. doi: 10.1074/jbc.271.48.30322 . PMID   8939990.
  9. ↑ Kim H, Rosenfeld RG, Oh Y (June 1997). "Biological roles of insulin-like growth factor binding proteins (IGFBPs)". Experimental & Molecular Medicine. 29 (2): 85–96. doi: 10.1038/emm.1997.13 . ISSN   2092-6413. S2CID   12150421.
  10. 1 2 3 4 5 Gommans WM, Tatalias NE, Sie CP, Dupuis D, Vendetti N, Smith L, Kaushal R, Maas S (October 2008). "Screening of human SNP database identifies recoding sites of A-to-I RNA editing". RNA. 14 (10): 2074–85. doi:10.1261/rna.816908. PMC   2553741 . PMID   18772245.
  11. 1 2 Ahmed S, Yamamoto K, Sato Y, Ogawa T, Herrmann A, Higashi S, Miyazaki K (October 2003). "Proteolytic processing of IGFBP-related protein-1 (TAF/angiomodulin/mac25) modulates its biological activity". Biochem. Biophys. Res. Commun. 310 (2): 612–8. doi:10.1016/j.bbrc.2003.09.058. PMID   14521955.
  12. ↑ Wilson EM, Oh Y, Hwa V, Rosenfeld RG (September 2001). "Interaction of IGF-binding protein-related protein 1 with a novel protein, neuroendocrine differentiation factor, results in neuroendocrine differentiation of prostate cancer cells". J. Clin. Endocrinol. Metab. 86 (9): 4504–11. doi: 10.1210/jcem.86.9.7845 . PMID   11549700.
  13. ↑ Evdokimova V, Tognon CE, Benatar T, Yang W, Krutikov K, Pollak M, Sorensen PH, Seth A (2012-12-18). "IGFBP7 Binds to the IGF-1 Receptor and Blocks Its Activation by Insulin-Like Growth Factors". Science Signaling. 5 (255): ra92. doi:10.1126/scisignal.2003184. ISSN   1945-0877. PMID   23250396. S2CID   24794913.
  14. 1 2 3 4 Levanon EY, Hallegger M, Kinar Y, Shemesh R, Djinovic-Carugo K, Rechavi G, Jantsch MF, Eisenberg E (2005). "Evolutionarily conserved human targets of adenosine to inosine RNA editing". Nucleic Acids Res. 33 (4): 1162–8. arXiv: q-bio/0502045 . Bibcode:2005q.bio.....2045L. doi:10.1093/nar/gki239. PMC   549564 . PMID   15731336.
  15. ↑ Hartner JC, Schmittwolf C, Kispert A, Müller AM, Higuchi M, Seeburg PH (February 2004). "Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1". J. Biol. Chem. 279 (6): 4894–902. doi: 10.1074/jbc.M311347200 . PMID   14615479.
  16. ↑ Kuang Z, Yao S, Keizer DW, Wang CC, Bach LA, Forbes BE, Wallace JC, Norton RS (December 2006). "Structure, dynamics and heparin binding of the C-terminal domain of insulin-like growth factor-binding protein-2 (IGFBP-2)". J. Mol. Biol. 364 (4): 690–704. doi:10.1016/j.jmb.2006.09.006. PMID   17020769.
  17. ↑ Kishibe J, Yamada S, Okada Y, Sato J, Ito A, Miyazaki K, Sugahara K (May 2000). "Structural requirements of heparan sulfate for the binding to the tumor-derived adhesion factor/angiomodulin that induces cord-like structures to ECV-304 human carcinoma cells". J. Biol. Chem. 275 (20): 15321–9. doi: 10.1074/jbc.275.20.15321 . PMID   10809767.
  18. ↑ 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. PMC   3209781 . PMID   21873981.
  19. ↑ Agbemenyah HY, Agis-Balboa RC, Burkhardt S, Delalle I, Fischer A (2013). "Insulin growth factor binding protein 7 is a novel target to treat dementia". Neurobiol Dis. 62: 135–43. doi:10.1016/j.nbd.2013.09.011. PMID   24075854. S2CID   38244657.

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