GPNMB

Official Full Name

glycoprotein nmb

Organism

Homo sapiens

GeneID

10457

Background

The protein encoded by this gene is a type I transmembrane glycoprotein which shows homology to the pMEL17 precursor, a melanocyte-specific protein. GPNMB shows expression in the lowly metastatic human melanoma cell lines and xenografts but does not show expression in the highly metastatic cell lines. GPNMB may be involved in growth delay and reduction of metastatic potential. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Synonyms

NMB; HGFIN; PLCA3;

Protein Sequence

MECLYYFLGFLLLAARLPLDAAKRFHDVLGNERPSAYMREHNQLNGWSSDENDWNEKLYPVWKRGDMRWKNSWKGGRVQAVLTSDSPALVGSNITFAVNLIFPRCQKEDANGNIVYEKNCRNEAGLSADPYVYNWTAWSEDSDGENGTGQSHHNVFPDGKPFPHHPGWRRWNFIYVFHTLGQYFQKLGRCSVRVSVNTANVTLGPQLMEVTVYRRHGRAYVPIAQVKDVYVVTDQIPVFVTMFQKNDRNSSDETFLKDLPIMFDVLIHDPSHFLNYSTINYKWSFGDNTGLFVSTNHTVNHTYVLNGTFSLNLTVKAAAPGPCPPPPPPPRPSKPTPSLATTLKSYDSNTPGPAGDNPLELSRIPDENCQINRYGHFQATITIVEGILEVNIIQMTDVLMPVPWPESSLIDFVVTCQGSIPTEVCTIISDPTCEITQNTVCSPVDVDEMCLLTVRRTFNGSGTYCVNLTLGDDTSLALTSTLISVPDRDPASPLRMANSALISVGCLAIFVTVISLLVYKKHKEYNPIENSPGNVVRSKGLSVFLNRAKAVFFPGNQEKDPLLKNQEFKGVS

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Detailed Information

Ranging from bone metabolism to immunological responses and cancer development, GPNMB (Glycoprotein Nmb) is a type I transmembrane glycoprotein that significantly influences many biological processes. Originally noted in melanoma research, GPNMB has now been acknowledged for its participation in other pathological and physiological processes. Located on chromosome 7p15, the gene encoding GPNMB generates two isoforms via alternative splicing that vary in amino acid length. Though especially in certain illness conditions including cancer, neurodegeneration, and inflammation, this protein is expressed in many different cell types.

The Role of GPNMB in Neuroinflammation and Neurodegenerative Diseases

GPNMB's involvement in neuroinflammation is multifaceted; depending on the situation, it may be beneficial or harmful. GPNMB is mostly expressed in the central nervous system (CNS) by microglial cells, the resident immune cells of the brain. Using phagocytosis and cytokine release, these cells regulate homeostasis and drive inflammatory reactions. GPNMB expression has been demonstrated in many studies to be elevated in neurodegenerative illnesses like Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD), where it may operate as a protective factor. GPNMB is present in microglia around amyloid plaques in AD; its levels are higher in post-mortem brain tissues from AD patients and cerebrospinal fluid (CSF).

Evidence that GPNMB's extracellular domain interacts with Na+, K+-ATPase (NKA), which controls inflammatory pathways including ERK/MERK and Akt/PI3K, supports its protective function. These signaling pathways are very essential for controlling neuroinflammation. GPNMB overexpression has been linked to lower infarct volume in models of cerebral ischemia-reperfusion injury, indicating it could offset damage after neuroinflammation.

Not all research, nevertheless, supports GPNMB's protective function. Particularly in diseases like ALS, several studies suggest GPNMB may aggravate neuroinflammation. GPNMB silencing in microglial cells has been demonstrated to lower pro-inflammatory cytochromes, so stressing that its function may change depending on the illness setting and cell type engaged.

Figure 1 illustrates the intracellular signaling of GPNMB under physiological and inflammatory conditions, showing its interactions with various receptors and proteins, which activate intracellular pathways that influence cell responses, such as neuroprotection, immune modulation, and tissue repair. Figure 1. Scheme of GPNMB intracellular signaling in physiological and inflammatory conditions. (Saade M, et al., 2021)

GPNMB in Peripheral Inflammation and Macrophage Activation

Apart from the CNS, GPNMB is also important in peripheral inflammation, especially in monocyte and macrophage activation. Macrophages, a major cell type in the immune response, express GPNMB under inflammatory circumstances including infection or tissue damage. Research have shown that GPNMB levels are higher in inflammatory-related disorders like colitis, liver fibrosis, and end-stage renal failure. These results imply that GPNMB could help with disease etiology by changing the inflammatory response and macrophage activation.

Curiously, GPNMB has been shown to hasten the resolution of inflammation. For instance, in models of periodontal disease, GPNMB overexpression in human periodontal ligament cells (hPDLCs) lowered pro-inflammatory cytokine levels and shielded cells from death caused by inflammatory triggers. Moreover, GPNMB has been shown to encourage M2 macrophage polarization linked to anti-inflammatory and tissue healing activities. This implies that GPNMB might have a dual function, aggravating or alleviating inflammation depending on the cellular environment.

GPNMB and Cancer Inflammation

Particularly because of its impact on immune cells within the tumor microenvironment, GPNMB's participation in cancer has been the focus of much study. Cancer's hallmark is chronic inflammation, and GPNMB seems to help control immunological reactions and tumor development. GPNMB expression is related to more aggressive disease characteristics in many malignancies, including melanoma, breast cancer, and glioma, such as metastasis and immune suppression.

GPNMB affects cancer in part by blocking T-cell activation. GPNMB stops activated T cells from multiplying and activating by binding to syndecan-4, a molecule on them. Using T cell function inhibition, cancer cells may escape immune monitoring, therefore enabling tumor development and spread. In melanoma, inhibiting GPNMB has been shown to restore T cell activation, lower tumor growth, and boost immunological responses. Given its importance in cancer immunotherapy, this implies that GPNMB might help cancer escape the immune system.

Apart from its impact on immune cells, GPNMB has been linked to increased cancer cell movement and invasion. Crucial for cancer spread, it stimulates matrix metalloproteinases (MMPs), enzymes involved in extracellular matrix remodeling. GPNMB overexpression in glioma and prostate cancer models increases MMP activity, hence promoting tumor invasion. These results imply that GPNMB not only helps in immune evasion but also actively encourages the invasive activity of cancer cells.

Therapeutic Implications and Future Directions

Given GPNMB's participation in cancer and inflammation, it offers a possible therapeutic target. Blocking GPNMB might improve immune responses and lower tumor growth in cancer as shown by research using anti-GPNMB antibodies such as glembatumumab vedotin. Although clinical studies for advanced breast cancer and melanoma were stopped after unsatisfactory outcomes, further study on the precise circumstances under which GPNMB blocking might be useful is justified.

In neuroinflammatory illnesses, GPNMB's protective effects, especially in situations like AD and cerebral ischemia, imply that improving its activity would be advantageous. However, the diversity in its function across many illnesses and settings calls for a better knowledge of its processes before GPNMB-based treatments may be created.

References:

Saade M, Araujo de Souza G, et al. The Role of GPNMB in Inflammation. Front Immunol. 2021;12:674739. Published 2021 May 12.
Lazaratos AM, Annis MG, Siegel PM. GPNMB: a potent inducer of immunosuppression in cancer. Oncogene. 2022;41(41):4573-4590.
Gillett DA, Wallings RL, Uriarte Huarte O, et al. Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease. J Neuroinflammation. 2023;20(1):286.

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