OGFr explained

Symbol:	OGFr_N
Opioid growth factor receptor (OGFr) conserved region
Pfam:	PF04664
Interpro:	IPR006757

Symbol:	OGFr_III
Opioid growth factor receptor repeat
Pfam:	PF04680
Interpro:	IPR006770

Opioid growth factor receptor, also known as OGFr or the ζ-opioid receptor, is a protein which in humans is encoded by the OGFR gene.^{[1] [2]} The protein encoded by this gene is a receptor for opioid growth factor (OGF), also known as [Met(5)]-enkephalin. The endogenous ligand is thus a known opioid peptide, and OGFr was originally discovered and named as a new opioid receptor zeta (ζ). However it was subsequently found that it shares little sequence similarity with the other opioid receptors, and has quite different function.

Function

The natural function of this receptor appears to be in regulation of tissue growth,^{[3] [4] [5]} and it has been shown to be important in embryonic development,^[6] wound repair,^[7] and certain forms of cancer.^{[8] [9] [10] [11]}

OGF is a negative regulator of cell proliferation and tissue organization in a variety of processes. The encoded unbound receptor for OGF has been localized to the outer nuclear envelope, where it binds OGF and is translocated into the nucleus. The coding sequence of this gene contains a polymorphic region of 60 nt tandem imperfect repeat units. Several transcripts containing between zero and eight repeat units have been reported.^[1]

Mechanism of activation

The opioid growth factor receptor consists of a chain of 677 amino acids, which includes a nuclear localization sequence region. When OGF binds to the receptor, an OGF-OGFr complex is formed, which leads to the increase in the synthesis of the selective cyclin-dependent kinase (CDK) inhibitor proteins, p12 and p16. Retinoblastoma protein becomes inactivated through phosphorylation by CDKs, and leads to the progression of the cell cycle from the G1 phase to the S phase. Because the activation of the OGF receptor, blocks the phosphorylation of retinoblastoma proteins, retardation of the G₁ phase occurs, which prevents the cell from further dividing.^{[12] [13]}

Therapeutic applications

Upregulation of OGFr and consequent stimulation of the OGF-OGFr system are important for the anti-proliferative effects of imidazoquinoline drugs like imiquimod and resiquimod, which are immune response modifiers with potent antiviral and antitumour effects, used as topical creams for the treatment of skin cancers and warts.^[14]

Structure

OGF contains a conserved N-terminal domain followed by a series of imperfect repeats.^[15]

Further reading

• Zagon IS, Verderame MF, McLaughlin PJ . The biology of the opioid growth factor receptor (OGFr). . Brain Res. Brain Res. Rev. . 38 . 3 . 351–76 . 2002 . 11890982 . 10.1016/S0165-0173(01)00160-6. 37812525 .
• Zagon IS, Verderame MF, Allen SS, McLaughlin PJ . Cloning, sequencing, chromosomal location, and function of cDNAs encoding an opioid growth factor receptor (OGFr) in humans. . Brain Res. . 856 . 1–2 . 75–83 . 2000 . 10677613 . 10.1016/S0006-8993(99)02330-6. 37516655 .
• Wu CJ, Yang XF, McLaughlin S, etal . Detection of a potent humoral response associated with immune-induced remission of chronic myelogenous leukemia. . J. Clin. Invest. . 106 . 5 . 705–14 . 2000 . 10974024 . 381287 . 10.1172/JCI10196.
• Hattori A, Okumura K, Nagase T, etal . Characterization of long cDNA clones from human adult spleen. . DNA Res. . 7 . 6 . 357–66 . 2001 . 11214971 . 10.1093/dnares/7.6.357 . free .
• Deloukas P, Matthews LH, Ashurst J, etal . The DNA sequence and comparative analysis of human chromosome 20. . Nature . 414 . 6866 . 865–71 . 2002 . 11780052 . 10.1038/414865a . 2001Natur.414..865D . free .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 139241 . 10.1073/pnas.242603899 . 2002PNAS...9916899M . free .
• Zagon IS, Ruth TB, Leure-duPree AE, etal . Immunoelectron microscopic localization of the opioid growth factor receptor (OGFr) and OGF in the cornea. . Brain Res. . 967 . 1–2 . 37–47 . 2003 . 12650964 . 10.1016/S0006-8993(02)04172-0 . 30270018 .
• Ota T, Suzuki Y, Nishikawa T, etal . Complete sequencing and characterization of 21,243 full-length human cDNAs. . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . free .
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 528928 . 10.1101/gr.2596504 .
• McLaughlin PJ, Zagon IS . Progression of squamous cell carcinoma of the head and neck is associated with down-regulation of the opioid growth factor receptor. . Int. J. Oncol. . 28 . 6 . 1577–83 . 2006 . 16685459 . 10.3892/ijo.28.6.1577. free .
• Zagon IS, McLaughlin PJ . Opioid growth factor receptor is unaltered with the progression of human pancreatic and colon cancers. . Int. J. Oncol. . 29 . 2 . 489–94 . 2006 . 16820893 . 10.3892/ijo.29.2.489. free .
• Olsen JV, Blagoev B, Gnad F, etal . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. . Cell . 127 . 3 . 635–48 . 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . free .
• McLaughlin PJ, Verderame MF, Hankins JL, Zagon IS . Overexpression of the opioid growth factor receptor downregulates cell proliferation of human squamous carcinoma cells of the head and neck. . Int. J. Mol. Med. . 19 . 3 . 421–8 . 2007 . 17273790 . 10.3892/ijmm.19.3.421. free .

Notes and References

1. Web site: Entrez Gene: OGFR opioid growth factor receptor.
2. Zagon IS, Verderame MF, Allen SS, McLaughlin PJ . Cloning, sequencing, chromosomal location, and function of cDNAs encoding an opioid growth factor receptor (OGFr) in humans . Brain Res. . 856 . 1–2 . 75–83 . February 2000 . 10677613 . 10.1016/S0006-8993(99)02330-6 . 37516655 .
3. Wu Y, McLaughlin PJ, Zagon IS . Ontogeny of the opioid growth factor, Met5-enkephalin, preproenkephalin gene expression, and the zeta opioid receptor in the developing and adult aorta of rat . Dev. Dyn. . 211 . 4 . 327–37 . April 1998 . 9566952 . 10.1002/(SICI)1097-0177(199804)211:4<327::AID-AJA4>3.0.CO;2-J . free .
4. Malendowicz LK, Rebuffat P, Tortorella C, Nussdorfer GG, Ziolkowska A, Hochol A . Effects of met-enkephalin on cell proliferation in different models of adrenocortical-cell growth . Int. J. Mol. Med. . 15 . 5 . 841–5 . May 2005 . 15806307 . 10.3892/ijmm.15.5.841.
5. Cheng F, McLaughlin PJ, Verderame MF, Zagon IS . The OGF-OGFr axis utilizes the p16INK4a and p21WAF1/CIP1 pathways to restrict normal cell proliferation . Molecular Biology of the Cell . 20 . 1 . 319–27 . January 2009 . 18923142 . 2613082 . 10.1091/mbc.E08-07-0681 .
6. Zagon IS, Wu Y, McLaughlin PJ . Opioid growth factor and organ development in rat and human embryos . Brain Res. . 839 . 2 . 313–22 . August 1999 . 10519055 . 10.1016/S0006-8993(99)01753-9 . 22000619 .
7. Sassani JW, Zagon IS, McLaughlin PJ . Opioid growth factor modulation of corneal epithelium: uppers and downers . Curr. Eye Res. . 26 . 5 . 249–62 . May 2003 . 12854052 . 10.1076/ceyr.26.4.249.15427. 34449136 .
8. Zagon IS, Smith JP, McLaughlin PJ . Human pancreatic cancer cell proliferation in tissue culture is tonically inhibited by opioid growth factor . Int. J. Oncol. . 14 . 3 . 577–84 . March 1999 . 10024694 . 10.3892/ijo.14.3.577.
9. McLaughlin PJ, Levin RJ, Zagon IS . Regulation of human head and neck squamous cell carcinoma growth in tissue culture by opioid growth factor . Int. J. Oncol. . 14 . 5 . 991–8 . May 1999 . 10200353 . 10.3892/ijo.14.5.991.
10. Cheng F, Zagon IS, Verderame MF, McLaughlin PJ . The opioid growth factor (OGF)-OGF receptor axis uses the p16 pathway to inhibit head and neck cancer . Cancer Research . 67 . 21 . 10511–8 . November 2007 . 17974995 . 10.1158/0008-5472.CAN-07-1922 . free .
11. Donahue RN, McLaughlin PJ, Zagon IS . Cell Proliferation of Human Ovarian Cancer is Regulated by the Opioid Growth Factor - Opioid Growth Factor Receptor Axis . American Journal of Physiology. Regulatory, Integrative and Comparative Physiology . 296. 6. R1716–25. March 2009 . 19297547 . 10.1152/ajpregu.00075.2009 .
12. Zagon IS, Donahue RN, McLaughlin PJ . Opioid growth factor-opioid growth factor receptor axis is a physiological determinant of cell proliferation in diverse human cancers . American Journal of Physiology. Regulatory, Integrative and Comparative Physiology . 297 . 4 . R1154–61 . 2009 . 19675283 . 10.1152/ajpregu.00414.2009 .
13. Avella DM, Kimchi ET, Donahue RN, Tagaram HR, McLaughlin PJ, Zagon IS, Staveley-O'Carroll KF . The opioid growth factor-opioid growth factor receptor axis regulates cell proliferation of human hepatocellular cancer . American Journal of Physiology. Regulatory, Integrative and Comparative Physiology . 298 . 2 . R459–66 . 2010 . 19923357 . 2828179 . 10.1152/ajpregu.00646.2009 .
14. Zagon IS, Donahue RN, Rogosnitzky M, McLaughlin PJ . Imiquimod upregulates the opioid growth factor receptor to inhibit cell proliferation independent of immune function . Experimental Biology and Medicine . 233 . 8 . 968–79 . August 2008 . 18480416 . 10.3181/0802-RM-58 . 35164284 .
15. Zagon IS, Verderame MF, McLaughlin PJ . The biology of the opioid growth factor receptor (OGFr) . Brain Res. Brain Res. Rev. . 38 . 3 . 351–76 . February 2002 . 11890982 . 10.1016/S0165-0173(01)00160-6. 37812525 .