GPRC5D

Official Full Name

G protein-coupled receptor class C group 5 member D

Organism

Homo sapiens

GeneID

55507

Background

The protein encoded by this gene is a member of the G protein-coupled receptor family; however, the specific function of this gene has not yet been determined. [provided by RefSeq, Jul 2008]

Synonyms

GPRC5D; G protein-coupled receptor, family C, group 5, member D; G-protein coupled receptor family C group 5 member D; orphan G-protein coupled receptor; MGC129713; MGC129714;

Protein Sequence

MYKDCIESTGDYFLLCDAEGPWGIILESLAILGIVVTILLLLAFLFLMRKIQDCSQWNVLPTQLLFLLSVLGLFGLAFAFIIELNQQTAPVRYFLFGVLFALCFSCLLAHASNLVKLVRGCVSFSWTTILCIAIGCSLLQIIIATEYVTLIMTRGMMFVNMTPCQLNVDFVVLLVYVLFLMALTFFVSKATFCGPCENWKQHGRLIFITVLFSIIIWVVWISMLLRGNPQFQRQPQWDDPVVCIALVTNAWVFLLLYIVPELCILYRSCRQECPLQGNACPVTAYQHSFQVENQELSRARDSDGAEEDVALTSYGTPIQPQTVDPTQECFIPQAKLSPQQDAGGV

Open

Disease

Multiple myeloma

Approved Drug

1 +

Clinical Trial Drug

2 +

Discontinued Drug

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Detailed Information

Glycoprotein Nmb (GPNMB), a type I transmembrane glycoprotein, was first identified in 1995. It is also known by several other names, including Osteoactivin, DC-HIL, and HGFIN. Encoded by the GPNMB gene located on chromosome 7p15, this protein exists in two isoforms due to alternative splicing, which comprises 572 and 560 amino acids, respectively.

Figure 1 describes the location and structure of GPRC5D, including its chromosomal position, gene locus structure, and the seven transmembrane alpha-helices along with a short N-terminal domain of human GPRC5D. Figure 1. Location and structure of GPRC5D. (Zhou D, et al., 2024)

Key Structural Features and Biological Functions

GPNMB's structure has many characteristics in its extracellular domain. These are a polycystic kidney disease domain, 12 glycosylation sites, and an integrin-recognition motif RGD. The metalloproteinase ADAM10 also cleaves GPNMB, producing a soluble fragment that interacts with many receptors.

GPNMB shows notable adaptability across many cell types. In bone tissue, it promotes the mineralization of the bone matrix and the development of osteoblasts. Moreover, GPNMB regulates T lymphocyte function, helps hematopoietic cells mature, and stimulates fibroblast activation.

GPNMB in Disease Processes

GPNMB levels are very high in neurodegenerative disorders. In Alzheimer's Disease, higher amounts are seen in the post-mortem brain and cerebrospinal fluid. Likewise, in Amyotrophic Lateral Sclerosis (ALS), GPNMB levels increase in the spinal cord tissue, serum, and cerebrospinal fluid. Parkinson's disease shows increased expression in the substantia nigra. GPNMB often seems to be protective. Treatments using recombinant GPNMB fragments, for instance, may greatly lower cell death in ALS models. Overexpression of GPNMB in cerebral ischemia-reperfusion injury reduces infarct size and damage.

GPNMB's function in cancer is different and sometimes conflicting. At first, it was shown to be an anti-metastatic protein. Recent studies, meantime, show that the kind of cancer determines much of its function. In breast cancer, GPNMB has been shown to encourage cancer spread, improve angiogenesis, assist immune suppression, and raise tumor migration and invasion. Through these results, clinical studies of an anti-GPNMB antibody for breast cancer therapy were stopped in 2018 when they failed to demonstrate better survival rates compared to normal therapies.

Depending on the setting and cell type, GPNMB serves various functions in inflammatory diseases. Studies reveal higher expression in many liver diseases including hepatitis and cirrhosis. GPNMB levels in colitis correspond with illness severity. End-stage renal illness also shows higher levels, as does white adipose tissue during obesity. Importantly, GPNMB is essential for macrophage function; its expression rises in conditions characterized by macrophage dysfunction including Niemann-Pick type C and Gaucher disease.

Clinical Implications

GPNMB's many functions have important clinical consequences. Its increased expression in several illnesses suggests it is a possible marker, especially for neurodegenerative disorders. Therapeutic plans aimed against GPNMB, however, must be carefully customized to particular illness settings given its multifaceted and sometimes conflicting functions.

GPNMB levels might also be a predictor for resistance to immune checkpoint inhibitor treatment in cancer therapy, suggesting its possible use in customizing cancer treatment. Its participation in inflammatory processes also implies that GPNMB may be a target for creating novel anti-inflammatory treatments.

Future Directions

Our growing knowledge of GPNMB, from its first discovery as a melanoma-related protein to its present acknowledgment as a sophisticated regulator of many biological processes, emphasizes the need of ongoing study. A deeper investigation into its functioning and its therapeutic uses might provide notable breakthroughs in the treatment of certain disorders.

References:

Rodriguez-Otero P, van de Donk NWCJ, Pillarisetti K, et al. GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review. Blood Cancer J. 2024;14(1):24.
Zhou D, Wang Y, Chen C, et al. Targeting GPRC5D for multiple myeloma therapy. J Hematol Oncol. 2024;17(1):88. Published 2024 Sep 28.

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