GPNMB

Transmembrane glycoprotein NMB is a protein that in humans is encoded by the GPNMB gene.[5] Two transcript variants encoding 560 and 572 amino acid isoforms have been characterized for this gene in humans.[6] The mouse and rat orthologues of GPNMB are known as DC-HIL and Osteoactivin (OA), respectively.[6]

GPNMB
Identifiers
Aliases	GPNMB, HGFIN, NMB, glycoprotein nmb, PLCA3
External IDs	OMIM: 604368 MGI: 1934765 HomoloGene: 1880 GeneCards: GPNMB
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7p15.3 Start 23,235,967 bp[1] End 23,275,108 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6 B2.3|6 23.82 cM Start 49,036,546 bp[2] End 49,070,929 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • integrin binding • GO:0001948 protein binding • heparin binding • chemoattractant activity • syndecan binding • receptor ligand activity Cellular component • melanosome • membrane • cell membrane • integral component of plasma membrane • integral component of membrane • cytoplasmic vesicle • endosome • early endosome membrane • melanosome membrane Biological process • bone mineralization • negative regulation of tumor necrosis factor production • osteoblast differentiation • negative regulation of cell proliferation • negative regulation of cytokine production • positive regulation of protein phosphorylation • signal transduction • cell-cell signaling • positive regulation of cell migration • positive regulation of protein autophosphorylation • regulation of tissue remodeling • negative regulation of T cell proliferation • regulation of angiogenesis • negative regulation of T cell activation • positive chemotaxis • positive regulation of ERK1 and ERK2 cascade • negative regulation of neuron death • negative regulation of G1/S transition of mitotic cell cycle • cell adhesion • regulation of receptor activity Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	10457	93695
Ensembl	ENSG00000136235	ENSMUSG00000029816
UniProt	Q14956	Q99P91
RefSeq (mRNA)	NM_001005340 NM_002510	NM_053110
RefSeq (protein)	NP_001005340 NP_002501	NP_444340
Location (UCSC)	Chr 7: 23.24 – 23.28 Mb	Chr 6: 49.04 – 49.07 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[7][8]

Function

In osteoblast progenitor cells, Osteoactivin works as a positive regulator of osteoblast differentiation during later stages of matrix maturation and mineralization [9] that is mediated at least in part by Bone_morphogenetic_protein_2 in a SMAD1 dependent manner to promote osteoblast differentiation.[10] 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 [11] 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.[12] Similarly, Osteoactivin expression increases during osteoclast differentiation and it is functionally implicated in this process, possibly by promoting the fusion of osteoclast progenitor cells.[13]

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,[14] glioma,[15] and breast cancer specimens.[16]

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.[17] 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.[18] 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.[16][18]

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)[19] which is in clinical trials for melanoma and breast cancer. (See glembatumumab vedotin)

References

1. GRCh38: Ensembl release 89: ENSG00000136235 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000029816 - 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. Weterman MA, Ajubi N, van Dinter IM, Degen WG, van Muijen GN, Ruitter DJ, Bloemers HP (January 1995). "nmb, a novel gene, is expressed in low-metastatic human melanoma cell lines and xenografts". International Journal of Cancer. 60 (1): 73–81. doi:10.1002/ijc.2910600111. hdl:2066/20693. PMID 7814155.
6. "Entrez Gene: GPNMB glycoprotein (transmembrane) nmb".
7. 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 (February 2009). "Gpnmb is a Melanoblast-Expressed, MITF-Dependent Gene". Pigment Cell & Melanoma Research. 22 (1): 99–110. doi:10.1111/j.1755-148X.2008.00518.x. PMC 2714741. PMID 18983539.
8. Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (December 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
9. Abdelmagid SM, Barbe MF, Rico MC, Salihoglu S, Arango-Hisijara I, Selim AH, Anderson MG, Owen TA, Popoff SN, Safadi FF (1 August 2008). "Osteoactivin, an anabolic factor that regulates osteoblast differentiation and function". Exp Cell Res. 314 (13): 2334–51. doi:10.1016/j.yexcr.2008.02.006. PMID 18555216.
10. Abdelmagid SM, Barbe MF, Arango-Hisijara I, Owen TA, Popoff SN, Safadi FF (2007). "Osteoactivin acts as downstream mediator of BMP-2 effects on osteoblast function". J. Cell. Physiol. 210 (1): 26–37. doi:10.1002/jcp.20841. PMID 17034042.
11. Abdelmagid SM, Barbe MF, Hadjiargyrou M, Owen TA, Razmpour R, Rehman S, Popoff SN, Safadi FF (1 Oct 2010). "Temporal and spatial expression of osteoactivin during fracture repair". J Cell Biochem. 111 (2): 295–309. doi:10.1002/jcb.22702. PMID 20506259.
12. Abdelmagid, Samir (2010). Role of Osteoactivin in Bone Formation and Fracture Repair. USA: LAP Lambert Academic Publishing. p. 144. ISBN 978-3-8383-5436-1.
13. Sheng MH, Wergedal JE, Mohan S, Lau KH (October 2008). "Osteoactivin is a novel osteoclastic protein and plays a key role in osteoclast differentiation and activity". FEBS Lett. 582 (10): 1451–8. doi:10.1016/j.febslet.2008.03.030. PMID 18381073.
14. 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 (February 2006). "CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma". Clinical Cancer Research. 12 (4): 1373–82. doi:10.1158/1078-0432.CCR-05-2018. PMID 16489096.
15. Kuan CT, Wakiya K, Dowell JM, Herndon JE, Reardon DA, Graner MW, Riggins GJ, Wikstrand CJ, Bigner DD (April 2006). "Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme". Clinical Cancer Research. 12 (7 Pt 1): 1970–82. doi:10.1158/1078-0432.CCR-05-2797. PMID 16609006.
16. Rose AA, Pepin F, Russo C, Abou Khalil JE, Hallett M, Siegel PM (October 2007). "Osteoactivin promotes breast cancer metastasis to bone". Molecular Cancer Research. 5 (10): 1001–14. doi:10.1158/1541-7786.MCR-07-0119. PMID 17951401.
17. Burris H, Saleh M, Bendell J, Hart L, Rose A, Dong Z, Siegel P, Crane M, Donovan D, Crowley D, Simantov R, Vahdat L (December 2009). "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. 69 (24 (Meeting Abstract Supplement)): 6096. doi:10.1158/0008-5472.SABCS-09-6096. Archived from the original on 2013-02-23.
18. 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 (April 2010). "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. doi:10.1158/1078-0432.CCR-09-1611. PMID 20215530.
19. NCI Drug Dictionary: Glemtumumab vedotin

Further reading

• The Sanger Centre, The Washington University Genome Sequencing Center (November 1998). "Toward a complete human genome sequence". Genome Research. 8 (11): 1097–108. doi:10.1101/gr.8.11.1097. PMID 9847074.
• Ahn JH, Lee Y, Jeon C, Lee SJ, Lee BH, Choi KD, Bae YS (September 2002). "Identification of the genes differentially expressed in human dendritic cell subsets by cDNA subtraction and microarray analysis". Blood. 100 (5): 1742–54. doi:10.1182/blood.V100.5.1742.h81702001742_1742_1754. PMID 12176896.
• Bandari PS, Qian J, Yehia G, Joshi DD, Maloof PB, Potian J, Oh HS, Gascon P, Harrison JS, Rameshwar P (March 2003). "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. doi:10.1016/S0167-0115(02)00288-4. PMID 12609765.
• Bächner D, Schröder D, Gross G (October 2002). "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. doi:10.1016/S1567-133X(02)00012-1. PMID 12638126.
• 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 (2003). "Proteomic analysis of early melanosomes: identification of novel melanosomal proteins". Journal of Proteome Research. 2 (1): 69–79. doi:10.1021/pr025562r. PMID 12643545.
• 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 (October 2003). "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. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309.
• Owen TA, Smock SL, Prakash S, Pinder L, Brees D, Krull D, Castleberry TA, Clancy YC, Marks SC, Safadi FF, Popoff SN (2003). "Identification and characterization of the genes encoding human and mouse osteoactivin". Critical Reviews in Eukaryotic Gene Expression. 13 (2–4): 205–20. doi:10.1615/CritRevEukaryotGeneExpr.v13.i24.130. PMID 14696968.
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM (July 2004). "Functional Proteomics Mapping of a Human Signaling Pathway". Genome Research. 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC 442148. PMID 15231748.
• Metz RL, Yehia G, Fernandes H, Donnelly RJ, Rameshwar P (February 2005). "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. doi:10.4161/cc.4.2.1468. PMID 15684612.
• Haralanova-Ilieva B, Ramadori G, Armbrust T (April 2005). "Expression of osteoactivin in rat and human liver and isolated rat liver cells". Journal of Hepatology. 42 (4): 565–72. doi:10.1016/j.jhep.2004.12.021. PMID 15763343.
• 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 (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514.
• Lennerz V, Fatho M, Gentilini C, Frye RA, Lifke A, Ferel D, Wölfel C, Huber C, Wölfel T (November 2005). "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. Bibcode:2005PNAS..10216013L. doi:10.1073/pnas.0500090102. PMC 1266037. PMID 16247014.
• 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 (December 2005). "Transcriptome analysis of human gastric cancer". Mammalian Genome. 16 (12): 942–54. doi:10.1007/s00335-005-0075-2. PMID 16341674.
• Kuan CT, Wakiya K, Dowell JM, Herndon JE, Reardon DA, Graner MW, Riggins GJ, Wikstrand CJ, Bigner DD (April 2006). "Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme". Clinical Cancer Research. 12 (7 Pt 1): 1970–82. doi:10.1158/1078-0432.CCR-05-2797. PMID 16609006.
• 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 (November 2006). "Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes". Journal of Proteome Research. 5 (11): 3135–44. doi:10.1021/pr060363j. PMID 17081065.
• Rose AA, Pepin F, Russo C, Abou Khalil JE, Hallett M, Siegel PM (October 2007). "Osteoactivin promotes breast cancer metastasis to bone". Molecular Cancer Research. 5 (10): 1001–14. doi:10.1158/1541-7786.MCR-07-0119. PMID 17951401.