GPNMB
Encyclopedia
Transmembrane glycoprotein NMB is a protein
that in humans is encoded by the GPNMB gene
. The mouse and rat orthologues of GPNMB are known as DC-HIL and Osteoactivin (OA), respectively. Two transcript variants encoding 560 and 572 amino acid isoforms have been characterized for this gene in humans. 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 transcritionally regulated by Microphthalmia-associated transcription factor
. In osteoblast progenitor cells, Osteoactivin works as a positive regulator of osteoblast differentiation during later stages of matrix maturation and mineralization that is mediated at least in part by BMP-2
in a SMAD1 dependent manner to promote osteoblast differentiation. 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 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. Similarly, Osteoactivin expression increases during osteoclast differentiation and it is functionally implicated in this process, possibly by promoting the fusion of osteoclast progenitor cells.
, glioma
, and breast cancer
specimens. Based on Immunohistochemical analysis, two studies have shown that GPNMB epression is commonly expressed in breast tumors. In the first study, GPNMB was detected in 71% (10/14) of breast tumors. 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
. 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 cancer
s 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.
glembatumumab vedotin
(CDX-011, CR011-vcMMAE) which is in clinical trials for melanoma
and breast cancer
. (See glembatumumab vedotin
)
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the GPNMB gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. The mouse and rat orthologues of GPNMB are known as DC-HIL and Osteoactivin (OA), respectively. Two transcript variants encoding 560 and 572 amino acid isoforms have been characterized for this gene in humans. GPNMB is a type I transmembrane glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
which shows homology to the pmel17
SILV
Melanocyte protein Pmel 17 is a protein that in humans is encoded by the SILV gene. Its gene product may be referred to as silver, ME20, gp100 or Pmel17 and is a 100 kDa type I transmembrane protein...
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
Melanocyte
-External links: - "Eye: fovea, RPE" - "Integument: pigmented skin"...
cells and osteoclasts the GPNMB gene is transcritionally regulated by Microphthalmia-associated transcription factor
Microphthalmia-associated transcription factor
Microphthalmia-associated transcription factor is a basic helix-loop-helix leucine zipper transcription factor involved in melanocyte and osteoclast development.-Clinical significance:...
. In osteoblast progenitor cells, Osteoactivin works as a positive regulator of osteoblast differentiation during later stages of matrix maturation and mineralization that is mediated at least in part by BMP-2
BMP-2
The BMP-2 is a second-generation, amphibious infantry fighting vehicle introduced in the 1980s in the Soviet Union, following the BMP-1 of the 1960s....
in a SMAD1 dependent manner to promote osteoblast differentiation. In addition, using a rat fracture model, Osteoactivin (OA) enhances the repairing process in bone fracture, demonstrated by its high expression during chondrogenesis
Chondrogenesis
-Cartilage in fetal development:In embryogenesis, the skeletal system is derived from the mesoderm germ layer. Chondrification is the process by which cartilage is formed from condensed mesenchyme tissue, which differentiates into chondrocytes and begins secreting the molecules that form the...
(soft callus) and osteogenesis (hard callus) compared to the intact femurs that is why Osteoactivin (OA) could be a novel therapeutic agent used to treat generalized osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
or localized osteopenia during fracture repair by stimulating bone growth and regeneration. Similarly, Osteoactivin expression increases during osteoclast differentiation and it is functionally implicated in this process, possibly by promoting the fusion of osteoclast progenitor cells.
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 melanomaMelanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
, glioma
Glioma
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
, and breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
specimens. Based on Immunohistochemical analysis, two studies have shown that GPNMB epression is commonly expressed in breast tumors. In the first study, GPNMB was detected in 71% (10/14) of breast tumors. In the second study, 64% of human breast tumors express GPNMB in the tumor stroma
Stroma (animal tissue)
In animal tissue, stroma refers to the connective, supportive framework of a biological cell, tissue, or organ.The stroma in animal tissue is contrasted with the parenchyma.Examples include:* Stroma of iris...
and an additional 10% of tumors express GPNMB in the tumor epithelium
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
. 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 cancer
Triple Negative Breast Cancer
Triple-negative breast cancer refers to any breast cancer that does not express the genes for estrogen receptor , progesterone receptor or Her2/neu. Triple negative is sometimes used as a surrogate term for basal-like, however more detailed classification is possible providing better guidance for...
s 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
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
, invasion, and metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
both in vitro and in vivo.
GPNMB as a target for therapy
GPNMB is the target of the antibody glembatumumab (CR011) which is used in the antibody-drug conjugateAntibody-drug conjugate
Antibody-drug conjugates are a new type of targeted therapy, used for example for cancer. They consist of an antibody linked to a payload drug . Hence, they are a type of immunoconjugate and often an immunotoxin.The antibody causes the ADC to bind to the target cancer cells...
glembatumumab vedotin
Glembatumumab vedotin
Glembatumumab vedotin is an antibody-drug conjugate that targets cancer cells expressing transmembrane glycoprotein NMB ....
(CDX-011, CR011-vcMMAE) which is in clinical trials for melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
and breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
. (See glembatumumab vedotin
Glembatumumab vedotin
Glembatumumab vedotin is an antibody-drug conjugate that targets cancer cells expressing transmembrane glycoprotein NMB ....
)