IGFBP7 explained

Insulin-like growth factor-binding protein 7 is a protein that in humans is encoded by the IGFBP7 gene.^{[1] [2] [3]} 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.^{[4] [5]} It also stimulates cell adhesion. The protein is implicated in some cancers.^[6]

Interactions

IGFBP7 has been shown to interact with Insulin-like growth factor 1,^{[4] [7]} VPS24,^[8] and the IGF-1 receptor (IGF1R).^[9]

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.^[10]

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.^[11]

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.^[10] 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.^[6] 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.^[6] The editing site also overlaps with an antisense transcript which could also form a double stranded RNA structure creating a suitable substrate for ADARs.^[10]

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.^[6]

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.^[12] 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.^[10]

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.^[13] Cleavage which occurs at amino acid position 97 reduces heparin binding but modulates the growth stimulatory activity of the protein.^[7] 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.^[6]

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.^[14] 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.^[15]

Further reading

• Swisshelm K, Ryan K, Tsuchiya K, Sager R . Enhanced expression of an insulin growth factor-like binding protein (mac25) in senescent human mammary epithelial cells and induced expression with retinoic acid. . Proc. Natl. Acad. Sci. U.S.A. . 92 . 10 . 4472–6 . 1995 . 7538673 . 41966 . 10.1073/pnas.92.10.4472 . 1995PNAS...92.4472S . free .
• Oh Y, Nagalla SR, Yamanaka Y, Kim HS, Wilson E, Rosenfeld RG . 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 . 1997 . 8939990 . 10.1074/jbc.271.48.30322 . free .
• Wilson EM, Oh Y, Rosenfeld RG . Generation and characterization of an IGFBP-7 antibody: identification of 31kD IGFBP-7 in human biological fluids and Hs578T human breast cancer conditioned media. . J. Clin. Endocrinol. Metab. . 82 . 4 . 1301–3 . 1997 . 9100611 . 10.1210/jc.82.4.1301 . free .
• Sekiguchi N, Umeda F, Masakado M, Ono Y, Hashimoto T, Nawata H . Immunohistochemical study of prostacyclin-stimulating factor (PSF) in the diabetic and atherosclerotic human coronary artery. . Diabetes . 46 . 10 . 1627–32 . 1997 . 9313760 . 10.2337/diabetes.46.10.1627 .
• Yamanaka Y, Wilson EM, Rosenfeld RG, Oh Y . Inhibition of insulin receptor activation by insulin-like growth factor binding proteins. . J. Biol. Chem. . 272 . 49 . 30729–34 . 1998 . 9388210 . 10.1074/jbc.272.49.30729 . free .
• Sato J, Hasegawa S, Akaogi K, Yasumitsu H, Yamada S, Sugahara K, Miyazaki K . Identification of cell-binding site of angiomodulin (AGM/TAF/Mac25) that interacts with heparan sulfates on cell surface. . J. Cell. Biochem. . 75 . 2 . 187–95 . 1999 . 10502291 . 10.1002/(SICI)1097-4644(19991101)75:2<187::AID-JCB1>3.0.CO;2-R . 25296323 .
• Girard JP, Baekkevold ES, Yamanaka T, Haraldsen G, Brandtzaeg P, Amalric F . Heterogeneity of endothelial cells: the specialized phenotype of human high endothelial venules characterized by suppression subtractive hybridization. . Am. J. Pathol. . 155 . 6 . 2043–55 . 1999 . 10595934 . 1866921 . 10.1016/S0002-9440(10)65523-X .
• Degeorges A, Wang F, Frierson HF, Seth A, Sikes RA . Distribution of IGFBP-rP1 in normal human tissues. . J. Histochem. Cytochem. . 48 . 6 . 747–54 . 2000 . 10820148 . 10.1177/002215540004800603 . 25403967 .
• Kato MV . A secreted tumor-suppressor, mac25, with activin-binding activity. . Mol. Med. . 6 . 2 . 126–35 . 2000 . 10859029 . 1949932 . 10.1007/BF03401780.
• Allen JT, Bloor CA, Kedia RK, Knight RA, Spiteri MA . Expression of growth hormone-releasing factor, growth hormone, insulin-like growth factor-1 and its binding proteins in human lung. . Neuropeptides . 34 . 2 . 98–107 . 2001 . 10985926 . 10.1054/npep.2000.0802 . 27683573 .
• Wilson EM, Oh Y, Hwa V, Rosenfeld RG . 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 . 2001 . 11549700 . 10.1210/jcem.86.9.7845 . free .
• Wilson HM, Birnbaum RS, Poot M, Quinn LS, Swisshelm K . Insulin-like growth factor binding protein-related protein 1 inhibits proliferation of MCF-7 breast cancer cells via a senescence-like mechanism. . Cell Growth Differ. . 13 . 5 . 205–13 . 2002 . 12065244 .
• Usui T, Murai T, Tanaka T, Yamaguchi K, Nagakubo D, Lee CM, Kiyomi M, Tamura S, Matsuzawa Y, Miyasaka M . Characterization of mac25/angiomodulin expression by high endothelial venule cells in lymphoid tissues and its identification as an inducible marker for activated endothelial cells. . Int. Immunol. . 14 . 11 . 1273–82 . 2003 . 12407018 . 10.1093/intimm/dxf102 . free .
• Plymate SR, Haugk KH, Sprenger CC, Nelson PS, Tennant MK, Zhang Y, Oberley LW, Zhong W, Drivdahl R, Oberley TD . Increased manganese superoxide dismutase (SOD-2) is part of the mechanism for prostate tumor suppression by Mac25/insulin-like growth factor binding-protein-related protein-1. . Oncogene . 22 . 7 . 1024–34 . 2003 . 12592389 . 10.1038/sj.onc.1206210 . 8062437 .
• Domínguez F, Avila S, Cervero A, Martín J, Pellicer A, Castrillo JL, Simón C . A combined approach for gene discovery identifies insulin-like growth factor-binding protein-related protein 1 as a new gene implicated in human endometrial receptivity. . J. Clin. Endocrinol. Metab. . 88 . 4 . 1849–57 . 2003 . 12679483 . 10.1210/jc.2002-020724 . free .
• López-Bermejo A, Khosravi J, Corless CL, Krishna RG, Diamandi A, Bodani U, Kofoed EM, Graham DL, Hwa V, Rosenfeld RG . Generation of anti-insulin-like growth factor-binding protein-related protein 1 (IGFBP-rP1/MAC25) monoclonal antibodies and immunoassay: quantification of IGFBP-rP1 in human serum and distribution in human fluids and tissues. . J. Clin. Endocrinol. Metab. . 88 . 7 . 3401–8 . 2003 . 12843194 . 10.1210/jc.2002-021315 . free .
• Nagakubo D, Murai T, Tanaka T, Usui T, Matsumoto M, Sekiguchi K, Miyasaka M . A high endothelial venule secretory protein, mac25/angiomodulin, interacts with multiple high endothelial venule-associated molecules including chemokines. . J. Immunol. . 171 . 2 . 553–61 . 2003 . 12847218 . 10.4049/jimmunol.171.2.553 . free .

Notes and References

1. Murphy M, Pykett MJ, Harnish P, Zang KD, George DL . Identification and characterization of genes differentially expressed in meningiomas . Cell Growth Differ . 4 . 9 . 715–22 . Dec 1993 . 7694637 .
2. Yamauchi T, Umeda F, Masakado M, Isaji M, Mizushima S, Nawata H . Purification and molecular cloning of prostacyclin-stimulating factor from serum-free conditioned medium of human diploid fibroblast cells . Biochem J . 303 . 2 . 591–8 . Nov 1994 . 7980422 . 1137368 . 10.1042/bj3030591.
3. Web site: Entrez Gene: IGFBP7 insulin-like growth factor binding protein 7.
4. Oh Y, Nagalla SR, Yamanaka Y, Kim HS, Wilson E, Rosenfeld RG . 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 . November 1996 . 8939990 . 10.1074/jbc.271.48.30322 . free .
5. Kim . Ho-Seong . Rosenfeld . Ron G. . Oh . Youngman . June 1997 . Biological roles of insulin-like growth factor binding proteins (IGFBPs) . Experimental & Molecular Medicine . en . 29 . 2 . 85–96 . 10.1038/emm.1997.13 . 12150421 . 2092-6413. free .
6. Gommans WM, Tatalias NE, Sie CP, Dupuis D, Vendetti N, Smith L, Kaushal R, Maas S . Screening of human SNP database identifies recoding sites of A-to-I RNA editing . RNA . 14 . 10 . 2074–85 . October 2008 . 18772245 . 2553741 . 10.1261/rna.816908 .
7. Ahmed S, Yamamoto K, Sato Y, Ogawa T, Herrmann A, Higashi S, Miyazaki K . Proteolytic processing of IGFBP-related protein-1 (TAF/angiomodulin/mac25) modulates its biological activity . Biochem. Biophys. Res. Commun. . 310 . 2 . 612–8 . October 2003 . 14521955 . 10.1016/j.bbrc.2003.09.058 .
8. Wilson EM, Oh Y, Hwa V, Rosenfeld RG . 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 . September 2001 . 11549700 . 10.1210/jcem.86.9.7845 . free .
9. Evdokimova . Valentina . Tognon . Cristina E. . Benatar . Tania . Yang . Wenyi . Krutikov . Konstantin . Pollak . Michael . Sorensen . Poul H. B. . Seth . Arun . 2012-12-18 . IGFBP7 Binds to the IGF-1 Receptor and Blocks Its Activation by Insulin-Like Growth Factors . Science Signaling . en . 5 . 255 . ra92 . 10.1126/scisignal.2003184 . 23250396 . 24794913 . 1945-0877.
10. Levanon EY, Hallegger M, Kinar Y, Shemesh R, Djinovic-Carugo K, Rechavi G, Jantsch MF, Eisenberg E . Evolutionarily conserved human targets of adenosine to inosine RNA editing . Nucleic Acids Res. . 33 . 4 . 1162–8 . 2005 . 15731336 . 549564 . 10.1093/nar/gki239 . 2005q.bio.....2045L . q-bio/0502045 .
11. Hartner JC, Schmittwolf C, Kispert A, Müller AM, Higuchi M, Seeburg PH . Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1 . J. Biol. Chem. . 279 . 6 . 4894–902 . February 2004 . 14615479 . 10.1074/jbc.M311347200 . free .
12. Kuang Z, Yao S, Keizer DW, Wang CC, Bach LA, Forbes BE, Wallace JC, Norton RS . 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 . December 2006 . 17020769 . 10.1016/j.jmb.2006.09.006 .
13. Kishibe J, Yamada S, Okada Y, Sato J, Ito A, Miyazaki K, Sugahara K . 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 . May 2000 . 10809767 . 10.1074/jbc.275.20.15321 . free .
14. 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 . EMBO J . 30 . 19 . 4071–83 . August 2011 . 21873981 . 3209781 . 10.1038/emboj.2011.293 .
15. Agbemenyah HY, Agis-Balboa RC, Burkhardt S, Delalle I, Fischer A . Insulin growth factor binding protein 7 is a novel target to treat dementia . Neurobiol Dis . 62 . 135–43 . 2013 . 24075854 . 10.1016/j.nbd.2013.09.011 . 38244657 .