GPNMB

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GPNMB
Identifiers
Aliases GPNMB, HGFIN, NMB, glycoprotein nmb
External IDs MGI: 1934765 HomoloGene: 1880 GeneCards: GPNMB
RNA expression pattern
PBB GE GPNMB 201141 at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001005340
NM_002510

NM_053110

RefSeq (protein)

NP_001005340
NP_002501

NP_444340.3
NP_444340

Location (UCSC) Chr 7: 23.24 – 23.28 Mb Chr 6: 49.04 – 49.07 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Transmembrane glycoprotein NMB is a protein that in humans is encoded by the GPNMB gene.[3] Two transcript variants encoding 560 and 572 amino acid isoforms have been characterized for this gene in humans.[4] The mouse and rat orthologues of GPNMB are known as DC-HIL and Osteoactivin (OA), respectively.[4]

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.[5][6]

Function[edit]

In osteoblast progenitor cells, Osteoactivin works as a positive regulator of osteoblast differentiation during later stages of matrix maturation and mineralization [7] that is mediated at least in part by BMP-2 in a SMAD1 dependent manner to promote osteoblast differentiation.[8] 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 [9] 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.[10] Similarly, Osteoactivin expression increases during osteoclast differentiation and it is functionally implicated in this process, possibly by promoting the fusion of osteoclast progenitor cells.[11]

Clinical and functional significance in cancer[edit]

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,[12] glioma,[13] and breast cancer specimens.[14]

Breast cancer[edit]

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.[15] 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.[16] 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.[14][16]

GPNMB as a target for therapy[edit]

GPNMB is the target of the antibody glembatumumab (CR011) which is used in the antibody-drug conjugate glembatumumab vedotin (CDX-011, CR011-vcMMAE)[17] which is in clinical trials for melanoma and breast cancer. (See glembatumumab vedotin)

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ 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. PMID 7814155. 
  4. ^ a b "Entrez Gene: GPNMB glycoprotein (transmembrane) nmb". 
  5. ^ 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 2714741Freely accessible. PMID 18983539. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ a b 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. 
  15. ^ 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. [permanent dead link]
  16. ^ a b 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. 
  17. ^ NCI Drug Dictionary: Glemtumumab vedotin

Further reading[edit]