GPNMB explained

Transmembrane glycoprotein NMB is a protein that in humans is encoded by the GPNMB gene.^[1] Two transcript variants encoding 560 and 572 amino acid isoforms have been characterized for this gene in humans. The mouse and rat orthologues of GPNMB are known as DC-HIL and Osteoactivin (OA), respectively.^[2]

GPNMB is a type I transmembrane glycoprotein which shows homology to the pmel17 precursor, a melanocyte-specific protein.

GPNMB has been reported to be expressed in various cell types, including: melanocytes, osteoclasts, osteoblasts, dendritic cells, and it is overexpressed in various cancer types. In melanocytic cells and osteoclasts the GPNMB gene is transcriptionally regulated by microphthalmia-associated transcription factor.^{[3] [4]}

Function

In osteoblast progenitor cells, Osteoactivin works as a positive regulator of osteoblast differentiation during later stages of matrix maturation and mineralization^[5] that is mediated at least in part by bone morphogenetic protein 2 in a SMAD1 dependent manner to promote osteoblast differentiation.^[6] In addition, using a rat fracture model, Osteoactivin (OA) enhances the repairing process in bone fracture, demonstrated by its high expression during chondrogenesis (soft callus) and osteogenesis (hard callus) compared to the intact femurs^[7] that is why Osteoactivin (OA) could be a novel therapeutic agent used to treat generalized osteoporosis or localized osteopenia during fracture repair by stimulating bone growth and regeneration.^[8] Similarly, Osteoactivin expression increases during osteoclast differentiation and it is functionally implicated in this process, possibly by promoting the fusion of osteoclast progenitor cells.^[9]

Clinical and functional significance in cancer

GPNMB was originally identified as a gene that was expressed in poorly metastatic human melanoma cell lines and xenografts and not expressed in highly metastatic cell lines. However, several recent studies have identified high GPNMB expression in aggressive melanoma,^[10] glioma,^[11] and breast cancer specimens.^[12]

Breast cancer

Based on Immunohistochemical analysis, two studies have shown that GPNMB is commonly expressed in breast tumors. In the first study, GPNMB was detected in 71% (10/14) of breast tumors.^[13] In the second study, 64% of human breast tumors express GPNMB in the tumor stroma and an additional 10% of tumors express GPNMB in the tumor epithelium.^[14] In this study it was reported that GPNMB expression in the tumor epithelium was an independent prognostic indicator of breast cancer recurrence. Moreover, epithelial GPNMB expression was most abundant in triple negative breast cancers and it was found to be a prognostic marker for shorter metastasis-free survival times within this breast cancer subtype. Finally, GPNMB expression in breast cancer cells is capable of promoting cell migration, invasion, and metastasis both in vitro and in vivo.^{[12] [14]}

GPNMB as a target for therapy

GPNMB is the target of the antibody glembatumumab (CR011) which is used in the antibody-drug conjugate glembatumumab vedotin (CDX-011, CR011-vcMMAE)^[15] which is in clinical trials for melanoma and breast cancer. (See glembatumumab vedotin)

Further reading

• ((The Sanger Centre)),((The Washington University Genome Sequencing Center)) . Toward a complete human genome sequence . Genome Research . 8 . 11 . 1097–108 . November 1998 . 9847074 . 10.1101/gr.8.11.1097 . free .
• Ahn JH, Lee Y, Jeon C, Lee SJ, Lee BH, Choi KD, Bae YS . Identification of the genes differentially expressed in human dendritic cell subsets by cDNA subtraction and microarray analysis . Blood . 100 . 5 . 1742–54 . September 2002 . 12176896 . 10.1182/blood.V100.5.1742.h81702001742_1742_1754 . free .
• Bandari PS, Qian J, Yehia G, Joshi DD, Maloof PB, Potian J, Oh HS, Gascon P, Harrison JS, Rameshwar P . Hematopoietic growth factor inducible neurokinin-1 type: a transmembrane protein that is similar to neurokinin 1 interacts with substance P . Regulatory Peptides . 111 . 1–3 . 169–78 . March 2003 . 12609765 . 10.1016/S0167-0115(02)00288-4 . 1314468 .
• Bächner D, Schröder D, Gross G . mRNA expression of the murine glycoprotein (transmembrane) nmb (Gpnmb) gene is linked to the developing retinal pigment epithelium and iris . Brain Research. Gene Expression Patterns . 1 . 3–4 . 159–65 . October 2002 . 12638126 . 10.1016/S1567-133X(02)00012-1.
• Basrur V, Yang F, Kushimoto T, Higashimoto Y, Yasumoto K, Valencia J, Muller J, Vieira WD, Watabe H, Shabanowitz J, Hearing VJ, Hunt DF, Appella E . Proteomic analysis of early melanosomes: identification of novel melanosomal proteins . Journal of Proteome Research . 2 . 1 . 69–79 . 2003 . 12643545 . 10.1021/pr025562r .
• Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A . The Secreted Protein Discovery Initiative (SPDI), a Large-Scale Effort to Identify Novel Human Secreted and Transmembrane Proteins: A Bioinformatics Assessment . Genome Research . 13 . 10 . 2265–70 . October 2003 . 12975309 . 403697 . 10.1101/gr.1293003 .
• Owen TA, Smock SL, Prakash S, Pinder L, Brees D, Krull D, Castleberry TA, Clancy YC, Marks SC, Safadi FF, Popoff SN . Identification and characterization of the genes encoding human and mouse osteoactivin . Critical Reviews in Eukaryotic Gene Expression . 13 . 2–4 . 205–20 . 2003 . 14696968 . 10.1615/CritRevEukaryotGeneExpr.v13.i24.130 .
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM . Functional Proteomics Mapping of a Human Signaling Pathway . Genome Research . 14 . 7 . 1324–32 . July 2004 . 15231748 . 442148 . 10.1101/gr.2334104 .
• Metz RL, Yehia G, Fernandes H, Donnelly RJ, Rameshwar P . Cloning and characterization of the 5' flanking region of the HGFIN gene indicate a cooperative role among p53 and cytokine-mediated transcription factors: relevance to cell cycle regulation . Cell Cycle . 4 . 2 . 315–22 . February 2005 . 15684612 . 10.4161/cc.4.2.1468 . free .
• Haralanova-Ilieva B, Ramadori G, Armbrust T . Expression of osteoactivin in rat and human liver and isolated rat liver cells . Journal of Hepatology . 42 . 4 . 565–72 . April 2005 . 15763343 . 10.1016/j.jhep.2004.12.021. free .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
• Lennerz V, Fatho M, Gentilini C, Frye RA, Lifke A, Ferel D, Wölfel C, Huber C, Wölfel T . The response of autologous T cells to a human melanoma is dominated by mutated neoantigens . Proceedings of the National Academy of Sciences of the United States of America . 102 . 44 . 16013–8 . November 2005 . 16247014 . 1266037 . 10.1073/pnas.0500090102 . 2005PNAS..10216013L . free .
• Oh JH, Yang JO, Hahn Y, Kim MR, Byun SS, Jeon YJ, Kim JM, Song KS, Noh SM, Kim S, Yoo HS, Kim YS, Kim NS . Transcriptome analysis of human gastric cancer . Mammalian Genome . 16 . 12 . 942–54 . December 2005 . 16341674 . 10.1007/s00335-005-0075-2 . 69278 .
• Kuan CT, Wakiya K, Dowell JM, Herndon JE, Reardon DA, Graner MW, Riggins GJ, Wikstrand CJ, Bigner DD . Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme . Clinical Cancer Research . 12 . 7 Pt 1 . 1970–82 . April 2006 . 16609006 . 10.1158/1078-0432.CCR-05-2797 . free .
• Chi A, Valencia JC, Hu ZZ, Watabe H, Yamaguchi H, Mangini NJ, Huang H, Canfield VA, Cheng KC, Yang F, Abe R, Yamagishi S, Shabanowitz J, Hearing VJ, Wu C, Appella E, Hunt DF . Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes . Journal of Proteome Research . 5 . 11 . 3135–44 . November 2006 . 17081065 . 10.1021/pr060363j .
• Rose AA, Pepin F, Russo C, Abou Khalil JE, Hallett M, Siegel PM . Osteoactivin promotes breast cancer metastasis to bone . Molecular Cancer Research . 5 . 10 . 1001–14 . October 2007 . 17951401 . 10.1158/1541-7786.MCR-07-0119. free .

Notes and References

1. Weterman MA, Ajubi N, van Dinter IM, Degen WG, van Muijen GN, Ruitter DJ, Bloemers HP . nmb, a novel gene, is expressed in low-metastatic human melanoma cell lines and xenografts . International Journal of Cancer . 60 . 1 . 73–81 . January 1995 . 7814155 . 10.1002/ijc.2910600111 . 2066/20693 . 28723750 . free .
2. Web site: Entrez Gene: GPNMB glycoprotein (transmembrane) nmb.
3. Loftus SK, Antonellis A, Matera I, Renaud G, Baxter LL, Reid D, Wolfsberg TG, Chen Y, Wang C, Prasad MK, Bessling SL, McCallion AS, Green ED, Bennett DC, Pavan WJ . Gpnmb is a Melanoblast-Expressed, MITF-Dependent Gene . Pigment Cell & Melanoma Research . 22 . 1 . 99–110 . February 2009 . 18983539 . 2714741 . 10.1111/j.1755-148X.2008.00518.x .
4. Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E . Novel MITF targets identified using a two-step DNA microarray strategy . Pigment Cell & Melanoma Research . 21 . 6 . 665–76 . December 2008 . 19067971 . 10.1111/j.1755-148X.2008.00505.x . 24698373 . free .
5. Abdelmagid SM, Barbe MF, Rico MC, Salihoglu S, Arango-Hisijara I, Selim AH, Anderson MG, Owen TA, Popoff SN, Safadi FF . Osteoactivin, an anabolic factor that regulates osteoblast differentiation and function . Exp Cell Res . 314 . 13 . 2334–51 . 1 August 2008 . 18555216 . 10.1016/j.yexcr.2008.02.006 .
6. Abdelmagid SM, Barbe MF, Arango-Hisijara I, Owen TA, Popoff SN, Safadi FF . Osteoactivin acts as downstream mediator of BMP-2 effects on osteoblast function . J. Cell. Physiol. . 210 . 1 . 26–37 . 2007 . 17034042 . 10.1002/jcp.20841. 24661488 . free .
7. Abdelmagid SM, Barbe MF, Hadjiargyrou M, Owen TA, Razmpour R, Rehman S, Popoff SN, Safadi FF . Temporal and spatial expression of osteoactivin during fracture repair . J Cell Biochem . 111 . 2 . 295–309 . 1 Oct 2010 . 20506259 . 10.1002/jcb.22702 . 28916051 .
8. Book: Abdelmagid, Samir. Role of Osteoactivin in Bone Formation and Fracture Repair. 2010. LAP Lambert Academic Publishing. USA. 978-3-8383-5436-1. 144.
9. Sheng MH, Wergedal JE, Mohan S, Lau KH . Osteoactivin is a novel osteoclastic protein and plays a key role in osteoclast differentiation and activity . FEBS Lett. . 582 . 10 . 1451–8 . October 2008 . 18381073 . 10.1016/j.febslet.2008.03.030. 12655085 . free .
10. Tse KF, Jeffers M, Pollack VA, McCabe DA, Shadish ML, Khramtsov NV, Hackett CS, Shenoy SG, Kuang B, Boldog FL, MacDougall JR, Rastelli L, Herrmann J, Gallo M, Gazit-Bornstein G, Senter PD, Meyer DL, Lichenstein HS, LaRochelle WJ . CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma . Clinical Cancer Research . 12 . 4 . 1373–82 . February 2006 . 16489096 . 10.1158/1078-0432.CCR-05-2018 . free .
11. Kuan CT, Wakiya K, Dowell JM, Herndon JE, Reardon DA, Graner MW, Riggins GJ, Wikstrand CJ, Bigner DD . Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme . Clinical Cancer Research . 12 . 7 Pt 1 . 1970–82 . April 2006 . 16609006 . 10.1158/1078-0432.CCR-05-2797 . free .
12. Rose AA, Pepin F, Russo C, Abou Khalil JE, Hallett M, Siegel PM . Osteoactivin promotes breast cancer metastasis to bone . Molecular Cancer Research . 5 . 10 . 1001–14 . October 2007 . 17951401 . 10.1158/1541-7786.MCR-07-0119. free .
13. Burris H, Saleh M, Bendell J, Hart L, Rose A, Dong Z, Siegel P, Crane M, Donovan D, Crowley D, Simantov R, Vahdat L . A Phase (Ph) I/II Study of CR011-VcMMAE, an Antibody-Drug Conjugate, in Patients (Pts) with Locally Advanced or Metastatic Breast Cancer (MBC) . Cancer Research . December 2009 . 69 . 24 (Meeting Abstract Supplement) . 6096 . 10.1158/0008-5472.SABCS-09-6096 . https://archive.today/20130223110204/http://cancerres.aacrjournals.org/cgi/content/abstract/69/24_MeetingAbstracts/6096?sid=86581d39-486c-4dc5-95b3-63454efd0cec . dead . 2013-02-23 .
14. Rose AA, Grosset AA, Dong Z, Russo C, Macdonald PA, Bertos NR, St-Pierre Y, Simantov R, Hallett M, Park M, Gaboury L, Siegel PM . Glycoprotein Nonmetastatic B Is an Independent Prognostic Indicator of Recurrence and a Novel Therapeutic Target in Breast Cancer . Clinical Cancer Research . 16 . 7 . 2147–2156 . April 2010 . 20215530 . 10.1158/1078-0432.CCR-09-1611 . free .
15. [National Cancer Institute|NCI]