GPNMB (glycoprotein non-metastatic melanoma protein B; also osteoactivin or DC-HIL) is a heavily glycosylated type I transmembrane protein of the PMEL/NMB family, found at the plasma membrane, in melanosome membranes of melanocytes and in endosomes. Its large extracellular domain contains an RGD integrin-binding motif and a PKD domain and can be shed by ADAM10 as a soluble fragment. On antigen-presenting cells GPNMB acts as a membrane-bound ligand for syndecan-4 on activated T cells, recognizing its heparan sulfate chains and inhibiting T-cell activation, proliferation and cytokine production. The shed ectodomain promotes endothelial cell migration, and GPNMB is highly expressed by macrophages, osteoclasts, melanocytes and many cancers. Biallelic loss-of-function variants cause amyloidosis cutis dyschromica.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001818 negative regulation of cytokine production | IDA PMID:19350579 The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-ce... | KEEP AS NON CORE | Summary: DC-HIL reduces pro-inflammatory cytokine secretion by T cells. Reason: A consequence of inhibiting T-cell activation via syndecan-4. Supporting Evidence: PMID:19350579 DC-HIL blocks anti-CD3-induced T-cell responses, reducing secretion of pro-inflammatory cytokines and blocking entry into the S phase of the cell cycle. |
| GO:0005178 integrin binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Integrin binding via the RGD cell-attachment motif. Reason: The ECD carries an RGD motif and integrin interactions are reported for the family; supported by sequence but peripheral to the best-characterized syndecan-4 ligand function. Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Cell attachment site |
| GO:0005178 integrin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Integrin binding via the RGD cell-attachment motif. Reason: The ECD carries an RGD motif and integrin interactions are reported for the family; supported by sequence but peripheral to the best-characterized syndecan-4 ligand function. Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Cell attachment site |
| GO:0005515 protein binding | IPI PMID:12609765 Hematopoietic growth factor inducible neurokinin-1 type: a t... | REMOVE | Summary: Interaction with substance P. Reason: Bare protein binding is uninformative; the substance P interaction has not been substantiated as a receptor activity. |
| GO:0005515 protein binding | IPI PMID:26751287 The LINK-A lncRNA activates normoxic HIF1Ξ± signalling in tri... | REMOVE | Summary: GPNMB heterodimerizes with EGFR downstream of HB-EGF. Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the EGFR:GPNMB heterodimer. Supporting Evidence: PMID:26751287 LINK-A is required for a HB-EGF-triggered, EGFR:GPNMB heterodimer-mediated recruitment of BRK to GPNMB |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: GPNMB at the plasma membrane. Reason: Type I transmembrane protein with its extracellular domain exposed at the cell surface, where it engages syndecan-4 on T cells and is shed by ADAM10. Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Single-pass type I membrane protein PMID:20711474 GPNMB/OA is constitutively shed from breast cancer cells in an ADAM10-dependent manner and the shed GPNMB/OA ECD is capable of inducing endothelial cell migration in vitro. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: GPNMB at the plasma membrane. Reason: Type I transmembrane protein with its extracellular domain exposed at the cell surface, where it engages syndecan-4 on T cells and is shed by ADAM10. Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Single-pass type I membrane protein PMID:20711474 GPNMB/OA is constitutively shed from breast cancer cells in an ADAM10-dependent manner and the shed GPNMB/OA ECD is capable of inducing endothelial cell migration in vitro. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8857549 | ACCEPT | Summary: GPNMB at the plasma membrane. Reason: Type I transmembrane protein with its extracellular domain exposed at the cell surface, where it engages syndecan-4 on T cells and is shed by ADAM10. Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Single-pass type I membrane protein PMID:20711474 GPNMB/OA is constitutively shed from breast cancer cells in an ADAM10-dependent manner and the shed GPNMB/OA ECD is capable of inducing endothelial cell migration in vitro. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8857555 | ACCEPT | Summary: GPNMB at the plasma membrane. Reason: Type I transmembrane protein with its extracellular domain exposed at the cell surface, where it engages syndecan-4 on T cells and is shed by ADAM10. Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Single-pass type I membrane protein PMID:20711474 GPNMB/OA is constitutively shed from breast cancer cells in an ADAM10-dependent manner and the shed GPNMB/OA ECD is capable of inducing endothelial cell migration in vitro. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8857565 | ACCEPT | Summary: GPNMB at the plasma membrane. Reason: Type I transmembrane protein with its extracellular domain exposed at the cell surface, where it engages syndecan-4 on T cells and is shed by ADAM10. Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Single-pass type I membrane protein PMID:20711474 GPNMB/OA is constitutively shed from breast cancer cells in an ADAM10-dependent manner and the shed GPNMB/OA ECD is capable of inducing endothelial cell migration in vitro. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8857577 | ACCEPT | Summary: GPNMB at the plasma membrane. Reason: Type I transmembrane protein with its extracellular domain exposed at the cell surface, where it engages syndecan-4 on T cells and is shed by ADAM10. Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Single-pass type I membrane protein PMID:20711474 GPNMB/OA is constitutively shed from breast cancer cells in an ADAM10-dependent manner and the shed GPNMB/OA ECD is capable of inducing endothelial cell migration in vitro. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8857583 | ACCEPT | Summary: GPNMB at the plasma membrane. Reason: Type I transmembrane protein with its extracellular domain exposed at the cell surface, where it engages syndecan-4 on T cells and is shed by ADAM10. Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Single-pass type I membrane protein PMID:20711474 GPNMB/OA is constitutively shed from breast cancer cells in an ADAM10-dependent manner and the shed GPNMB/OA ECD is capable of inducing endothelial cell migration in vitro. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9634702 | ACCEPT | Summary: GPNMB at the plasma membrane. Reason: Type I transmembrane protein with its extracellular domain exposed at the cell surface, where it engages syndecan-4 on T cells and is shed by ADAM10. Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Single-pass type I membrane protein PMID:20711474 GPNMB/OA is constitutively shed from breast cancer cells in an ADAM10-dependent manner and the shed GPNMB/OA ECD is capable of inducing endothelial cell migration in vitro. |
| GO:0007155 cell adhesion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cell adhesion inherited from the NMB/PMEL family node. Reason: RGD- and heparan sulfate-mediated adhesion is plausible but peripheral. Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Cell attachment site |
| GO:0007165 signal transduction | IMP PMID:19350579 The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-ce... | MODIFY | Summary: Signal transduction in the DC-HIL/syndecan-4 pathway. Reason: Correct but general; the specific supported process is cell-cell signaling from APCs to T cells. Proposed replacements: cell-cell signaling Supporting Evidence: PMID:19350579 In humans, we now show that DC-HIL also binds to SD-4 on activated T cells through recognition of its heparinase-sensitive saccharide moiety. |
| GO:0007267 cell-cell signaling | IMP PMID:19350579 The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-ce... | ACCEPT | Summary: APC-to-T-cell inhibitory signaling via syndecan-4. Reason: Membrane-bound GPNMB on APCs signals to syndecan-4 on T cells. Supporting Evidence: PMID:19350579 In humans, we now show that DC-HIL also binds to SD-4 on activated T cells through recognition of its heparinase-sensitive saccharide moiety. |
| GO:0008201 heparin binding | IDA PMID:19350579 The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-ce... | ACCEPT | Summary: GPNMB binds heparan sulfate saccharides. Reason: DC-HIL binds syndecan-4 through its heparinase-sensitive saccharide chains. Supporting Evidence: PMID:19350579 In humans, we now show that DC-HIL also binds to SD-4 on activated T cells through recognition of its heparinase-sensitive saccharide moiety. |
| GO:0008201 heparin binding | IEA GO_REF:0000107 | ACCEPT | Summary: GPNMB binds heparan sulfate saccharides. Reason: DC-HIL binds syndecan-4 through its heparinase-sensitive saccharide chains. Supporting Evidence: PMID:19350579 In humans, we now show that DC-HIL also binds to SD-4 on activated T cells through recognition of its heparinase-sensitive saccharide moiety. |
| GO:0008285 negative regulation of cell population proliferation | TAS PMID:7814155 nmb, a novel gene, is expressed in low-metastatic human mela... | MARK AS OVER ANNOTATED | Summary: Negative regulation of cell proliferation, from the nmb melanoma cloning study. Reason: The cloning paper reports reduced metastatic potential in one of three transfectants, not an effect on proliferation; later work associates GPNMB with tumor growth. Supporting Evidence: PMID:7814155 Transfection of a partial nmb cDNA into a highly metastatic melanoma cell line |
| GO:0016020 membrane | IDA PMID:12609765 Hematopoietic growth factor inducible neurokinin-1 type: a t... | MODIFY | Summary: Membrane. Reason: Correct but general; plasma membrane is the specific supported location already annotated. Proposed replacements: plasma membrane Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Single-pass type I membrane protein |
| GO:0016020 membrane | TAS PMID:7814155 nmb, a novel gene, is expressed in low-metastatic human mela... | MODIFY | Summary: Membrane. Reason: Correct but general; plasma membrane is the specific supported location already annotated. Proposed replacements: plasma membrane Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Single-pass type I membrane protein |
| GO:0030335 positive regulation of cell migration | IDA PMID:20711474 ADAM10 releases a soluble form of the GPNMB/Osteoactivin ext... | KEEP AS NON CORE | Summary: Shed GPNMB ectodomain induces endothelial migration. Reason: Supported but context-specific (tumor microenvironment). Supporting Evidence: PMID:20711474 GPNMB/OA is constitutively shed from breast cancer cells in an ADAM10-dependent manner and the shed GPNMB/OA ECD is capable of inducing endothelial cell migration in vitro. |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000107 | MODIFY | Summary: Cytoplasmic vesicle from mouse. Reason: Correct but general; the supported vesicular locations are melanosome membrane and early endosome membrane. Proposed replacements: melanosome membrane early endosome membrane Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Identified by mass spectrometry in melanosome fractions from stage I to stage IV. |
| GO:0031901 early endosome membrane | EXP PMID:29336782 Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis D... | KEEP AS NON CORE | Summary: Early endosome membrane. Reason: An intracellular trafficking pool of the type I membrane protein. Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Early endosome membrane |
| GO:0031901 early endosome membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Early endosome membrane. Reason: An intracellular trafficking pool of the type I membrane protein. Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Early endosome membrane |
| GO:0032720 negative regulation of tumor necrosis factor production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of TNF production from mouse. Reason: Macrophage GPNMB is anti-inflammatory in mouse models; peripheral. |
| GO:0033162 melanosome membrane | EXP PMID:12643545 Proteomic analysis of early melanosomes: identification of n... | ACCEPT | Summary: Melanosome membrane. Reason: GPNMB is a PMEL-family protein found in melanosome fractions at all stages; relevant to its pigmentary role. Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Identified by mass spectrometry in melanosome fractions from stage I to stage IV. |
| GO:0033162 melanosome membrane | EXP PMID:17081065 Proteomic and bioinformatic characterization of the biogenes... | ACCEPT | Summary: Melanosome membrane. Reason: GPNMB is a PMEL-family protein found in melanosome fractions at all stages; relevant to its pigmentary role. Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Identified by mass spectrometry in melanosome fractions from stage I to stage IV. |
| GO:0033162 melanosome membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Melanosome membrane. Reason: GPNMB is a PMEL-family protein found in melanosome fractions at all stages; relevant to its pigmentary role. Supporting Evidence: file:human/GPNMB/GPNMB-uniprot.txt Identified by mass spectrometry in melanosome fractions from stage I to stage IV. |
| GO:0034103 regulation of tissue remodeling | IDA PMID:25010402 Glycoprotein nonmetastatic melanoma protein B (GPNMB) as a n... | KEEP AS NON CORE | Summary: Regulation of tissue remodeling. Reason: Extracellular GPNMB fragments are protective in brain ischaemia-reperfusion injury models; peripheral. Supporting Evidence: PMID:25010402 genomic over-expression of GPNMB significantly ameliorated infarct volume |
| GO:0034103 regulation of tissue remodeling | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Regulation of tissue remodeling. Reason: Extracellular GPNMB fragments are protective in brain ischaemia-reperfusion injury models; peripheral. Supporting Evidence: PMID:25010402 genomic over-expression of GPNMB significantly ameliorated infarct volume |
| GO:0042056 chemoattractant activity | NAS PMID:20711474 ADAM10 releases a soluble form of the GPNMB/Osteoactivin ext... | KEEP AS NON CORE | Summary: Chemoattractant activity of the shed ECD. Reason: Shed ECD induces endothelial migration in vitro; a soluble-fragment activity in tumor contexts. Supporting Evidence: PMID:20711474 GPNMB/OA is constitutively shed from breast cancer cells in an ADAM10-dependent manner and the shed GPNMB/OA ECD is capable of inducing endothelial cell migration in vitro. |
| GO:0042130 negative regulation of T cell proliferation | IDA PMID:19350579 The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-ce... | ACCEPT | Summary: DC-HIL blocks T-cell proliferation. Reason: Core immunoregulatory outcome of the syndecan-4 ligand function. Supporting Evidence: PMID:19350579 DC-HIL blocks anti-CD3-induced T-cell responses, reducing secretion of pro-inflammatory cytokines and blocking entry into the S phase of the cell cycle. |
| GO:0045545 syndecan binding | IPI PMID:19350579 The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-ce... | ACCEPT | Summary: DC-HIL binds syndecan-4. Reason: Defined ligand-receptor interaction. Supporting Evidence: PMID:19350579 In humans, we now show that DC-HIL also binds to SD-4 on activated T cells through recognition of its heparinase-sensitive saccharide moiety. |
| GO:0045765 regulation of angiogenesis | NAS PMID:20711474 ADAM10 releases a soluble form of the GPNMB/Osteoactivin ext... | KEEP AS NON CORE | Summary: Regulation of angiogenesis. Reason: GPNMB-expressing tumors show elevated endothelial recruitment; context-specific. Supporting Evidence: PMID:20711474 We demonstrate that GPNMB/OA expression enhances primary tumor growth, which is associated with diminished apoptosis and elevated recruitment of endothelial cells. |
| GO:0048018 receptor ligand activity | IMP PMID:19350579 The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-ce... | ACCEPT | Summary: GPNMB acts as a ligand for syndecan-4. Reason: Membrane-bound DC-HIL engages syndecan-4 and triggers its phosphorylation and inhibitory signaling. Supporting Evidence: PMID:19350579 Binding of DC-HIL phosphorylates SD-4's intracellular tyrosine and serine residues. |
| GO:0050868 negative regulation of T cell activation | IMP PMID:19350579 The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-ce... | ACCEPT | Summary: Negative regulation of T-cell activation. Reason: Core immunoregulatory process. Supporting Evidence: PMID:19350579 DC-HIL blocks anti-CD3-induced T-cell responses, reducing secretion of pro-inflammatory cytokines and blocking entry into the S phase of the cell cycle. |
| GO:0050918 positive chemotaxis | NAS PMID:20711474 ADAM10 releases a soluble form of the GPNMB/Osteoactivin ext... | KEEP AS NON CORE | Summary: Positive chemotaxis. Reason: Shed ECD-driven endothelial migration; context-specific. Supporting Evidence: PMID:20711474 GPNMB/OA is constitutively shed from breast cancer cells in an ADAM10-dependent manner and the shed GPNMB/OA ECD is capable of inducing endothelial cell migration in vitro. |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of ERK1/2. Reason: Downstream signaling output reported in several cell types; peripheral. |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | TAS PMID:22891158 The potential of GPNMB as novel neuroprotective factor in am... | KEEP AS NON CORE | Summary: ERK activation in the ALS context. Reason: Downstream signaling output; peripheral. |
| GO:2000134 negative regulation of G1/S transition of mitotic cell cycle | IDA PMID:19350579 The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-ce... | KEEP AS NON CORE | Summary: DC-HIL blocks T-cell S-phase entry. Reason: Downstream cell-cycle consequence of inhibited T-cell activation. Supporting Evidence: PMID:19350579 DC-HIL blocks anti-CD3-induced T-cell responses, reducing secretion of pro-inflammatory cytokines and blocking entry into the S phase of the cell cycle. |
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Download this section (compressed HTML)Q: What is the molecular basis of GPNMB's role in melanosomes and why does its loss cause cutaneous amyloid deposition?
Q: Is the shed ectodomain or the membrane-bound form responsible for GPNMB's anti-inflammatory and neuroprotective effects?
Experiment: Compare uncleavable (ADAM10-resistant) and soluble-only GPNMB variants for syndecan-4-dependent T-cell inhibition and endothelial migration.
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