Affinage

GPNMB

Transmembrane glycoprotein NMB · UniProt Q14956

Length
572 aa
Mass
63.9 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPNMB is a type I transmembrane glycoprotein that operates both as a melanosomal/lysosomal sorting cargo and, after ectodomain shedding, as a secreted signaling ligand coordinating tissue repair, anti-inflammatory responses, and protein/particle degradation (PMID:19320736, PMID:32694855, PMID:34582891). In melanocytes it localizes predominantly to melanosomes via a cytoplasmic ExxPLL di-leucine sorting motif and is required for melanosome biogenesis, acting downstream of MITF, whose direct binding to a conserved enhancer drives GPNMB transcription (PMID:12638126, PMID:18983539, PMID:22912767). Distinct N-glycosylation of its PKD domain diverts GPNMB away from the PMEL amyloidogenic compartment, and its surface delivery can be controlled by lysosome-to-plasma-membrane repositioning (PMID:23452376, PMID:35110681). The extracellular domain mediates adhesion and signaling through multiple receptors: an RGD motif engages integrins (α5β1, αVβ1) to activate Src/FAK and Akt/Erk and drive tumor growth and ECM production, while the shed soluble ectodomain signals through CD44 to inhibit NF-κB-dependent inflammation in macrophages and astrocytes and, through GPR39, to support cardiac repair after myocardial infarction (PMID:25772243, PMID:29519253, PMID:34582891, PMID:36566014, PMID:39455836). Beyond cell-surface signaling, GPNMB promotes lysosomal and degradative function by interacting with the vacuolar ATPase subunit ATP6V1A to drive microglial phagocytosis of neuronal debris and β-amyloid, and it is required for internalization of α-synuclein fibrils through direct binding to α-synuclein (PMID:33986446, PMID:35981040, PMID:39992792). During ER stress it translocates to the nucleus to enhance BiP pre-mRNA splicing independently of the canonical UPR transducers (PMID:28939899). Its expression is integrated into multiple transcriptional programs, including MITF, the MiT/TFE factors TFE3/TFEB downstream of TSC2/mTORC1, PPARγ during oligodendrocyte differentiation, and p53/cytokine-driven regulation (PMID:18983539, PMID:35072947, PMID:39756479, PMID:15684612).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2002 Medium

    Established that GPNMB carries an intrinsic endosomal/melanosomal sorting determinant, framing it as a vesicular trafficking cargo rather than a simple surface protein.

    Evidence EGFP-GPNMB localization in COS7 and HEK293 cells with identification of an ExxPLL di-leucine motif

    PMID:12638126

    Open questions at the time
    • No functional mutagenesis of the sorting motif in this study
    • Sorting machinery (adaptors) not identified
  2. 2008 High

    Identified MITF as a direct upstream transcriptional driver of GPNMB in the melanocyte lineage, placing GPNMB within the pigmentation gene regulatory network.

    Evidence Luciferase reporter with MITF-site deletion plus in vivo enhancer activity and MITF mutant mouse analysis

    PMID:18983539

    Open questions at the time
    • Did not address MITF-independent expression in other tissues
    • Did not link transcription to melanosome phenotype directly
  3. 2009 High

    Showed GPNMB is a melanosome-associated glycoprotein whose RGD motif mediates melanocyte-keratinocyte adhesion, giving the extracellular domain a defined adhesive function.

    Evidence Immunofluorescence, subcellular fractionation, and RGD-dependent keratinocyte adhesion assay

    PMID:19320736

    Open questions at the time
    • Adhesion receptor on keratinocytes not identified in this study
    • Functional significance for melanosome transfer not tested
  4. 2012 High

    Demonstrated GPNMB is required for melanosome biogenesis, establishing a cell-intrinsic structural/biogenic role distinct from its signaling functions.

    Evidence siRNA knockdown in PIG1 melanocytes with TEM, qPCR, and Western blot for melanosome markers

    PMID:22912767

    Open questions at the time
    • Mechanism by which GPNMB supports melanosome formation not resolved
    • Whether effect is via sorting of structural proteins unknown
  5. 2007 High

    First established GPNMB as a negative regulator of macrophage inflammation, reframing it from a structural pigment-cell protein to an immunomodulator.

    Evidence Overexpression in RAW264.7 cells with cytokine/NO readouts plus DBA/2J Gpnmb-mutant mouse

    PMID:17475886

    Open questions at the time
    • Receptor mediating anti-inflammatory effect not identified
    • Mechanism linking localization shift to cytokine suppression unclear
  6. 2013 High

    Explained why GPNMB diverges from its PMEL paralog by attributing loss of PKD-domain sorting to N-glycosylation, separating GPNMB from the amyloidogenic premelanosome compartment.

    Evidence PMEL/GPNMB domain-swap mutagenesis with glycosylation analysis and localization in melanocytes and HeLa cells

    PMID:23452376

    Open questions at the time
    • Functional consequence of compartment segregation not tested
    • ET-1/MITF axis (idx 6) link to sorting not addressed
  7. 2015 High

    Mapped tumor-promoting functions to distinct GPNMB domains, showing RGD-integrin engagement drives metastasis while both RGD and cytoplasmic tail support primary growth via Src/FAK.

    Evidence RGD and cytoplasmic-tail mutagenesis, integrin Co-IP, and in vivo breast cancer mouse models

    PMID:25772243

    Open questions at the time
    • Cytoplasmic tail downstream effectors not defined
    • How NRP-1 upregulation occurs mechanistically unclear
  8. 2016 Medium

    Defined CD44 as a functional receptor for soluble GPNMB driving ERK/AKT-mediated survival and migration, and extended GPNMB signaling to additional receptors (Na+/K+-ATPase) and tissues (bone).

    Evidence Macrophage-MSC co-culture with CD44 blocking and rescue; Co-IP with Na+/K+-ATPase in glioma; transgenic bone-formation phenotyping

    PMID:25899717 PMID:26442636 PMID:27836549

    Open questions at the time
    • Whether single ligand engages multiple receptors simultaneously unknown
    • Stoichiometry and affinity of receptor interactions not measured
  9. 2017 High

    Uncovered a non-canonical nuclear function in which GPNMB enhances BiP pre-mRNA splicing during ER stress, independent of IRE1/PERK/ATF6, linking GPNMB to UPR and neuroprotection.

    Evidence Thapsigargin ER stress with nuclear fractionation, BiP splicing assay, UPR-pathway inhibitor controls, and transgenic MCAO mice

    PMID:28939899

    Open questions at the time
    • How a transmembrane protein reaches the nucleus mechanistically unresolved
    • Splicing machinery partners not identified
  10. 2018 High

    Confirmed CD44 as the receptor for the anti-inflammatory action of soluble GPNMB using clean genetic loss-of-function, generalizing this axis to CNS glia.

    Evidence Recombinant GPNMB on wild-type vs CD44-KO astrocytes with iNOS/NO/ROS/IL-6 readouts

    PMID:29519253

    Open questions at the time
    • Downstream NF-κB step not yet directly tied in this study
    • Co-receptors of CD44 not examined
  11. 2019 High

    Integrated GPNMB into multiple transcriptional and metabolic programs—MiT/TFE downstream of TSC2/mTORC1, TFE3 fusions in RCC, hepatic SREBP-controlled secretion driving adipose lipogenesis, and EGFR-glycosylation-dependent signaling in NSCLC.

    Evidence CRISPR TSC2/TFE3/TFEB knockouts; PRCC-TFE3 transgenic model; liver-specific knockdown/neutralizing antibody with metabolic phenotyping; N134A glycosylation mutant with EGFR Co-IP

    PMID:31043488 PMID:32694855 PMID:33706413 PMID:35072947

    Open questions at the time
    • Tissue-specific balance between secreted ligand and surface signaling unclear
    • Whether EGFR and integrin functions share a common pool of GPNMB unknown
  12. 2019 High

    Showed long-range chromatin regulation of GPNMB, with a Takayasu-associated IL6 variant recruiting a MEF2-HDAC repressive complex to suppress GPNMB ~520 kb away.

    Evidence EMSA, DNA affinity precipitation/MS, luciferase reporters, 3C chromatin looping, and HDAC inhibition in primary macrophages

    PMID:31315839

    Open questions at the time
    • Functional consequence of macrophage GPNMB loss in disease not fully traced here
    • Other distal regulatory elements not catalogued
  13. 2021 High

    Established GPNMB as a determinant of macrophage lysosome function and confirmed CD44-dependent suppression of NF-κB inflammation, tying a degradative-organelle role to metabolic and immune phenotypes.

    Evidence QTL mapping with siRNA, CRISPR-KO, and natural-null rescue for lysosome function; GPNMB-KO mouse HFD model with recombinant rescue, macrophage depletion, CD44 blocking, and NF-κB readout

    PMID:33986446 PMID:34582891

    Open questions at the time
    • Molecular link between GPNMB and lysosome machinery not yet defined in these studies
    • Relationship between surface signaling and intracellular lysosomal role unresolved
  14. 2022 High

    Identified GPNMB as a direct α-synuclein interactor required for fibril internalization and as an integrin αVβ1 ligand driving fibrosis, expanding its roles into neurodegeneration uptake and pathological ECM production.

    Evidence Co-IP and co-localization with α-synuclein plus iPSC-neuron loss-of-function fibril-uptake assay; Co-IP, siRNA, and inhibitor studies for αVβ1 in fibroblasts

    PMID:35981040 PMID:36566014

    Open questions at the time
    • Whether GPNMB acts as a fibril receptor or co-factor not fully defined
    • Mechanism coupling fibril binding to internalization route unknown
  15. 2024 High

    Identified GPR39 as a receptor for circulating GPNMB mediating cardiac repair, and resolved the cell-of-origin (bone-marrow-derived macrophages) for injury-induced GPNMB.

    Evidence Lineage tracing, bone-marrow transplantation, genetic loss-of-function, viral gain-of-function, scRNA-seq, and GPR39-KO rescue in myocardial infarction

    PMID:39455836

    Open questions at the time
    • GPR39 vs CD44 receptor selection by tissue not explained
    • Direct GPNMB-GPR39 binding interface not mapped
  16. 2025 High

    Defined a mechanistic link between GPNMB and the degradative apparatus, showing GPNMB binds the V-ATPase subunit ATP6V1A to present engulfed particles to lysosomes during microglial phagocytosis, and connected GPNMB to PPARγ-driven remyelination.

    Evidence Co-IP of GPNMB-ATP6V1A with KO phagocytosis assay and ATP6V1A activation rescue; PPARγ oligodendrocyte-specific KO, ChIP target validation, and demyelination models

    PMID:39756479 PMID:39992792

    Open questions at the time
    • How GPNMB couples particle wrapping to V-ATPase function structurally unknown
    • Whether ATP6V1A interaction underlies earlier lysosome-function QTL effect not directly tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how GPNMB partitions among its diverse receptors (CD44, GPR39, integrins α5β1/αVβ1, syndecan-4) and intracellular partners (ATP6V1A, α-synuclein, calnexin) in a tissue- and context-specific manner, and what governs the choice between membrane signaling, ectodomain shedding, and nuclear translocation.
  • No unifying model linking receptor selection to ligand processing
  • Structural basis of multi-receptor engagement undefined
  • Relative in vivo contribution of each axis to physiology not quantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0048018 receptor ligand activity 3 GO:0098631 cell adhesion mediator activity 2 GO:0008289 lipid binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005576 extracellular region 4 GO:0005764 lysosome 4 GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 2 GO:0005634 nucleus 1 GO:0005768 endosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-1430728 Metabolism 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-9612973 Autophagy 2 R-HSA-8953897 Cellular responses to stimuli 1
Partners
ATP6V1ACD44EGFRGPR39ITGAVITGB1SDC4SNCA

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 GPNMB translocates from the Golgi apparatus to peripheral vesicular compartments upon macrophage activation with IFN-γ and LPS. Overexpression reduces IL-6, IL-12p40, and NO production in response to LPS, establishing GPNMB as a negative regulator of macrophage inflammatory responses. Epitope-tagged GPNMB overexpression in RAW264.7 cells, fluorescence microscopy co-localization with Golgi marker (coat protein beta), cytokine/NO measurement; DBA/2J mice with inactivating Gpnmb mutation as loss-of-function model Journal of immunology High 17475886
2009 GPNMB localizes predominantly to melanosomes (and to a lesser degree lysosomes) in melanocytes, with lesser surface expression. Keratinocytes adhere to immobilized GPNMB in an RGD-dependent manner, establishing GPNMB as a melanosome-associated glycoprotein mediating melanocyte–keratinocyte adhesion via its RGD motif. Immunofluorescence, subcellular fractionation, newly developed monoclonal antibody for surface staining, RGD-dependent adhesion assay with PAM212 keratinocytes Experimental dermatology High 19320736
2002 EGFP-tagged GPNMB localizes to vesicular, endosomal-like structures in non-pigmented COS7 and HEK293 cells, consistent with an endosomal/melanosomal sorting signal (ExxPLL di-leucine motif) in its cytoplasmic domain. EGFP-GPNMB transfection in COS7 and HEK293 cells with fluorescence microscopy; sequence analysis identifying ExxPLL motif Brain research. Gene expression patterns Medium 12638126
2008 Gpnmb expression in melanoblasts is directly regulated by the transcription factor MITF. A conserved element (GPNMB-MCS3) containing two MITF consensus binding sites drives Gpnmb expression in melanoblasts in vivo; deletion of the 5'-most MITF site dramatically reduces enhancer activity. Luciferase reporter assay in melanocytes, in vivo enhancer-driven expression in melanoblasts, MITF mutant mouse analysis, whole-genome annotation of MITF binding sites Pigment cell & melanoma research High 18983539
2012 Silencing GPNMB by siRNA in PIG1 melanocytes sharply reduces the total number of melanosomes and decreases expression of melanosome structural proteins (tyrosinase, TRP1, Pmel17/gp100, OA1), demonstrating that GPNMB is required for melanosome formation in a MITF-independent fashion. siRNA knockdown of GPNMB in PIG1 melanocytes; transmission electron microscopy, qPCR, Western blot, immunofluorescence PloS one High 22912767
2013 The PKD domain of GPNMB lacks the sorting function present in the homologous PKD domain of PMEL. The difference is attributed to extensive N-glycosylation of the GPNMB PKD domain, which nullifies its sorting function. As a result, GPNMB localizes to compartments distinct from PMEL-containing multivesicular premelanosomes and is absent from amyloid fibrils. Domain-swapping experiments between PMEL and GPNMB in melanocytes and HeLa cells; fluorescence microscopy; glycosylation analysis Pigment cell & melanoma research High 23452376
2013 ET-1 induces melanogenesis via a MITF-regulated GPNMB pathway: ET-1 upregulates MITF, which in turn increases GPNMB expression; GPNMB silencing abolishes ET-1-induced melanosome formation and melanin synthesis, and MITF siRNA suppresses GPNMB expression and prevents ET-1-mediated pigmentation. siRNA knockdown of GPNMB and MITF in melanocytes, melanin quantification, melanosome counting, Western blot BMB reports Medium 23884103
2015 GPNMB engages α5β1 integrin through its RGD motif to promote breast cancer cell adhesion to fibronectin and activate Src and FAK signaling. Both the RGD motif and cytoplasmic tail are required for primary tumor growth, but only the RGD motif is required for lung metastasis. GPNMB also increases NRP-1 expression to potentiate VEGF signaling required for tumor growth but not metastasis. RGD-motif mutagenesis, cytoplasmic tail deletion, integrin co-immunoprecipitation, in vivo breast cancer mouse models, RNAseq correlation Oncogene High 25772243
2016 M2 macrophage-secreted GPNMB promotes MSC survival, proliferation, and migration via CD44 receptor, activating ERK and AKT signaling pathways in MSCs. Loss-of-function and rescue experiments confirmed CD44-dependence. Loss-of-function (GPNMB knockdown) and rescue studies in macrophage–MSC co-culture system; ERK/AKT phosphorylation assays; CD44 blocking Journal of cellular biochemistry Medium 26442636
2016 GPNMB transgenic overexpression in mice enhances bone formation, increases osteoblast numbers and bone formation rates, and is associated with upregulated TGF-β1 and TGF-β receptor I/II expression in osteoblasts, indicating an osteoinductive effect. Transgenic mouse (CMV-promoter GPNMB overexpression): micro-CT, histomorphometry, biomechanical testing, ELISA, qRT-PCR Journal of cellular physiology Medium 25899717
2016 GPNMB interacts with Na+/K+-ATPase α subunits to activate PI3K/Akt and MEK/ERK pathways in glioblastoma. Ouabain (a Na+/K+-ATPase inhibitor) suppresses GPNMB-driven glioma growth and blocks GPNMB-induced glioma cell migration. This interaction was confirmed in both a murine glioma model and human glioblastoma tumors. Co-immunoprecipitation (GPNMB–Na+/K+-ATPase), transgenic GPNMB mice with in vivo glioma implantation, ouabain pharmacological inhibition, migration assay Biochemical and biophysical research communications Medium 27836549
2016 Recombinant GPNMB protects motor neurons from mutant TDP-43-induced cell death by activating ERK1/2 and Akt signaling pathways. GPNMB co-localizes with TDP-43 aggregates in neurons (but not astrocytes or microglia) of ALS patient spinal cord. Recombinant GPNMB treatment of NSC34 motor neuron cells transfected with mutant TDP-43; Western blot for p-ERK1/2, p-Akt; immunohistochemistry of ALS patient spinal cord Journal of neuroscience research Medium 27935101
2017 GPNMB neuroprotection during ischemia-reperfusion involves activation of ERK1/2 and Akt. Transgenic GPNMB overexpression significantly reduces infarct volume and increases phospho-ERK1/2 and phospho-Akt. Recombinant extracellular GPNMB fragment alone is sufficient to reduce infarction, mapping the neuroprotective activity to the extracellular domain. GPNMB transgenic mice with MCAO model; recombinant GPNMB treatment; Western blot for p-ERK1/2 and p-Akt; infarct volume measurement Neuroscience Medium 25010402
2017 GPNMB induces BiP (GRP78) expression during ER stress by translocating to the nucleus and promoting BiP pre-mRNA splicing through a mechanism independent of the three canonical UPR transducers (IRE1, PERK, ATF6). GPNMB transgenic mice exhibit elevated BiP and reduced infarct size after cerebral artery occlusion. Thapsigargin-induced ER stress, nuclear fractionation showing GPNMB nuclear translocation, BiP mRNA/pre-mRNA splicing assay, IRE1/PERK/ATF6 pathway inhibitor controls, GPNMB transgenic mouse MCAO model Scientific reports High 28939899
2018 The anti-inflammatory effects of soluble GPNMB on astrocytes are mediated through the CD44 receptor. Recombinant GPNMB attenuates cytokine-induced iNOS, NO, ROS, and IL-6 in astrocytes; this effect is lost in CD44 knockout astrocytes. Recombinant GPNMB treatment of wild-type and CD44-KO primary mouse astrocytes; measurement of iNOS, NO, ROS, IL-6 Journal of neuroinflammation High 29519253
2019 Soluble macrophage-derived GPNMB activates cancer cells to express IL-33 and its receptor IL-1RL1 through the CD44 receptor, driving cancer stem cell formation (spheroids), prolonged survival, and metastatic phenotype. IL-33 binding to IL-1RL1 is sufficient to induce tumor spheroid formation. Mouse tumor models with Gpnmb-mutant DBA/2J mice, GPNMB receptor blocking with anti-CD44, IL-33/IL-1RL1 functional reconstitution, spheroid formation assay Cellular & molecular immunology High 32728200
2019 Gpnmb is a liver-secreted factor that stimulates lipogenesis in white adipose tissue (WAT). Hepatic SREBP pathway inhibition increases Gpnmb transcription and promotes its processing to a secreted form. Liver-specific knockdown or neutralizing antibody against Gpnmb improves metabolic parameters and promotes WAT beiging. Liver-specific Gpnmb knockdown, neutralizing antibody treatment, Gpnmb transgenic mice, SREBP pathway manipulation, metabolic phenotyping (weight, insulin sensitivity) Nature metabolism High 32694855
2019 GPNMB is a direct transcriptional target of TFE3 fusion proteins. In a TFE3-RCC mouse model, GPNMB expression was elevated in TFE3-driven renal tumors, and TFE3 fusion was confirmed to directly transactivate GPNMB. PRCC-TFE3 transgenic mouse model; GPNMB IHC; confirmed TFE3 direct transcriptional target by reporter/functional analysis Molecular cancer research : MCR Medium 31043488
2019 GPNMB upregulation is downstream of TSC2 loss and is dependent on MiT/TFE transcription factors and mTORC1 activity. In AML/kidney cell lines with CRISPR-mediated TSC2 loss, GPNMB is upregulated in a TFE3/TFEB- and mTORC1-dependent fashion. CRISPR-Cas9 TSC2/TFE3/TFEB knockout in AML and kidney cell lines; GPNMB immunohistochemistry; Tsc2+/- mouse model The Journal of pathology High 35072947
2019 GPNMB regulates EGFR activation and downstream STAT3 signaling in NSCLC. N-glycosylation at Asn134 of GPNMB is essential for its binding to the C-terminus of mutated EGFR and for ligand-independent EGFR phosphorylation at Y845. Depleting N134 glycosylation abolishes GPNMB–EGFR binding and downstream signaling. Membrane proteomics, Co-IP of GPNMB–EGFR, N134A glycosylation mutant, phospho-EGFR (Y845) and STAT3 assays, in vivo metastasis model Cancer science High 33706413
2019 The Takayasu arteritis risk allele in IL6 (rs2069837 A) represses GPNMB expression ~520 kb away by recruiting a MEF2-HDAC repressive complex through long-range intrachromatin looping. HDAC inhibition reverses GPNMB suppression in macrophages from AA genotype individuals. EMSA, DNA affinity precipitation + mass spectrometry, luciferase reporter assay, chromosome conformation capture (3C), primary macrophage experiments with HDAC inhibition Annals of the rheumatic diseases High 31315839
2021 GPNMB reduces macrophage inflammatory capacity by inhibiting NF-κB signaling largely through binding to CD44. In GPNMB-KO mice, macrophages produce more inflammatory cytokines; supplementation with recombinant soluble GPNMB extracellular domain abolishes this difference. Macrophage depletion abrogates the worsened metabolic phenotype of GPNMB-KO mice. GPNMB-KO mouse (CRISPR), HFD metabolic phenotyping, macrophage isolation and cytokine measurement, recombinant GPNMB rescue, clodronate liposome macrophage depletion, NF-κB signaling assay, CD44 blocking The Journal of biological chemistry High 34582891
2021 Gpnmb is required for normal macrophage lysosome function. Gpnmb is the causal gene at the strongest QTL for lysosome function (Mlfm1). siRNA knockdown of Gpnmb in AKR/J macrophages and CRISPR-Cas9 deletion in RAW264.7 cells both decrease lysosome function; restoration of wild-type Gpnmb in a DBA/2 substrain recovers lysosome function. QTL mapping, siRNA knockdown, CRISPR-Cas9 knockout in RAW264.7 cells, dual-labeled lysosome function assay, DBA/2J-Gpnmb+/SjJ substrain comparison Scientific reports High 33986446
2021 GPNMB reduces Aβ deposition and improves Alzheimer's-like behaviors in APP/PS1 mice by enhancing autophagy through suppression of mTOR signaling. Autophagy inhibitor 3-MA abolishes the beneficial effect of GPNMB on Aβ clearance, placing GPNMB upstream of mTOR-dependent autophagy. GPNMB overexpression in APP/PS1 mice; TEM and immunofluorescence for autophagy (beclin-1); 3-MA autophagy inhibition; Aβ quantification; mTOR pathway Western blot Neuroscience letters Medium 34695452
2022 GPNMB co-immunoprecipitates and co-localizes with α-synuclein (aSyn) in cells. In iPSC-derived neurons, loss of GPNMB results in loss of ability to internalize aSyn fibrils and develop aSyn pathology. Co-immunoprecipitation, co-localization immunofluorescence, GPNMB loss-of-function in iPSC-derived neurons with aSyn fibril uptake assay Science High 35981040
2022 GPNMB binds to integrin αVβ1 receptor on adventitial fibroblasts and activates downstream Akt and Erk signaling, promoting extracellular matrix production. This was established by Co-IP, siRNA, and inhibitor intervention studies in Takayasu arteritis vascular fibrosis. Co-IP assay (GPNMB–integrin αVβ1), siRNA knockdown of integrin αVβ1, pharmacological pathway inhibitors (Akt/Erk), ECM gene expression assays in adventitial fibroblasts Translational research Medium 36566014
2022 HSP90 inhibition increases GPNMB cell-surface localization by inducing lysosomal dispersion toward the cell periphery and lysosome–plasma membrane fusion, delivering GPNMB to the cell surface. This is distinct from transcriptional induction and requires lysosomal repositioning. FACS-based genetic screen, live-cell imaging of lysosomal positioning, lysosome–plasma membrane fusion assay, GPNMB surface FACS after HSP90 inhibitor treatment Oncogene High 35110681
2023 Macrophage-derived GPNMB is trapped by fibrotic ECM and activates resident fibroblasts via the CD44/Serpinb2 pathway, driving pulmonary fibrosis progression. Neutralizing antibodies against GPNMB or macrophage depletion attenuates fibroblast activation in fibrotic ECM. Silica-instilled mouse PF model, fibroblast activation assay with fibrotic ECM, GPNMB-neutralizing antibody treatment, macrophage depletion, Western blot for CD44/Serpinb2 Communications biology Medium 36732560
2023 Lactic acid-induced M2-like macrophage-derived GPNMB promotes OSCC cell migration, invasion, and EMT by binding to the CD44 receptor and activating the PI3K/AKT/mTOR signaling cascade. CD44 silencing abrogates these tumor-promoting effects. Co-culture system, GPNMB-CD44 binding assay, CD44 siRNA knockdown, PI3K/AKT/mTOR inhibition, migration/invasion assays International immunopharmacology Medium 37806107
2024 Bone-marrow-derived macrophages are the primary source of GPNMB in injured hearts after myocardial infarction. GPNMB deficiency leads to increased mortality, cardiac rupture, and left ventricular dysfunction. GPR39 is identified as a receptor for circulating GPNMB; GPR39 absence negates the beneficial cardiac effects of GPNMB. Single-cell transcriptomics showed GPNMB enhances cardiomyocyte contraction and reduces fibroblast activation. Lineage tracing, bone-marrow transplantation, GPNMB loss-of-function (genetic), viral GPNMB delivery for gain-of-function, single-cell RNA sequencing, GPR39 KO rescue experiment Nature cardiovascular research High 39455836
2025 GPNMB interacts with lysosomal vacuolar-type proton ATPase catalytic subunit A (ATP6V1A) to mediate microglial phagocytosis of pathological particles including neuronal debris and β-amyloid. GPNMB is internalized into cells, wraps engulfed particles, and presents them to lysosomes via ATP6V1A interaction. Activating ATP6V1A rescues GPNMB-deficiency-caused phagocytosis impairment. Co-immunoprecipitation (GPNMB–ATP6V1A), GPNMB genetic ablation, phagocytosis assay (engulfment and degradation), ATP6V1A activation rescue experiment, live-cell imaging of GPNMB trafficking Cell reports High 39992792
2025 PPARγ directly targets GPNMB to promote oligodendrocyte precursor cell (OPC) differentiation and CNS remyelination. PPARγ agonists increase GPNMB expression and enhance remyelination; oligodendrocyte-specific PPARγ KO decreases OPC maturation. GPNMB itself drives OPC-to-oligodendrocyte differentiation and promotes myelinogenesis. PPARγ oligodendrocyte-specific KO, PPARγ agonist treatment, ChIP/transcriptional target validation of GPNMB, cuprizone and lysophosphatidylcholine demyelination models, GPNMB overexpression/knockdown in OPCs Brain High 39756479
2012 Glycosylation of GPNMB is inhibited by interaction with mutant SOD1(G93A) in NSC34 cells, increasing motor neuron vulnerability. Extracellular fragments of GPNMB secreted from activated astrocytes attenuate SOD1(G93A) neurotoxicity in neural cells, establishing a neuroprotective paracrine role. Co-culture of NSC34 cells and astrocytes, glycosylation assay, SOD1(G93A) interaction, neurotoxicity rescue with extracellular GPNMB fragments Scientific reports Medium 22891158
2015 Soluble Gpnmb in NAFLD interacts with calnexin in hepatic macrophages and stellate cells, and this interaction is associated with reduced oxidative stress. Gpnmb transgenic overexpression ameliorates fat accumulation and liver fibrosis in diet-induced obesity. Gpnmb transgenic mice (aP2-driven), co-immunoprecipitation (Gpnmb–calnexin), oxidative stress markers, histological analysis Scientific reports Medium 26581806
2017 p53 cooperates with cytokine-mediated transcription factors to regulate HGFIN/GPNMB expression. EMSA demonstrated that p53 can interact with HGFIN promoter fragments containing p53 consensus sites. Reporter gene analyses showed p53 level correlates with HGFIN promoter activity; the untranslated exon 1 acts as a negative regulator of upstream enhancing effects. EMSA with Cy3-labeled PCR fragments, luciferase reporter assays in cells with varying p53 levels, modified cell lines with reduced cytokine production Cell cycle Medium 15684612
2021 Soluble DC-HIL (GPNMB) binds syndecan-4 on both T cells and endothelial cells. In an allergic contact dermatitis model, sDC-HIL downregulates the allergic reaction by reducing transendothelial T-cell migration (but not neutrophil or mast cell migration). This requires syndecan-4 expression on both endothelial cells and T cells. Allergic contact dermatitis mouse model, intravital microscopy, syndecan-4-deficient mice, intravenous sDC-HIL infusion, flow cytometry of immune cell infiltration The Journal of investigative dermatology High 34695414
2021 GPNMB extracellular soluble fragment protects melanocytes from oxidative stress-induced cytotoxicity and melanogenesis impairment through suppression of AKT phosphorylation, independently of CD44 (CD44 knockdown did not affect the protective effect). siRNA knockdown of CD44, recombinant soluble GPNMB treatment, AKT/ERK/p38/JNK phosphorylation assays, melanocyte viability assay International journal of molecular sciences Medium 34639184

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Gpnmb is induced in macrophages by IFN-gamma and lipopolysaccharide and acts as a feedback regulator of proinflammatory responses. Journal of immunology (Baltimore, Md. : 1950) 195 17475886
2018 The glycoprotein GPNMB attenuates astrocyte inflammatory responses through the CD44 receptor. Journal of neuroinflammation 138 29519253
2022 GPNMB confers risk for Parkinson's disease through interaction with α-synuclein. Science (New York, N.Y.) 123 35981040
2012 The potential of GPNMB as novel neuroprotective factor in amyotrophic lateral sclerosis. Scientific reports 113 22891158
2020 The soluble glycoprotein NMB (GPNMB) produced by macrophages induces cancer stemness and metastasis via CD44 and IL-33. Cellular & molecular immunology 106 32728200
2022 GPNMB expression identifies TSC1/2/mTOR-associated and MiT family translocation-driven renal neoplasms. The Journal of pathology 95 35072947
2019 Proteomics in cerebrospinal fluid and spinal cord suggests UCHL1, MAP2 and GPNMB as biomarkers and underpins importance of transcriptional pathways in amyotrophic lateral sclerosis. Acta neuropathologica 95 31701227
2017 Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) and Cancer: A Novel Potential Therapeutic Target. Steroids 89 29097143
2019 Gpnmb secreted from liver promotes lipogenesis in white adipose tissue and aggravates obesity and insulin resistance. Nature metabolism 84 32694855
2019 TFE3 Xp11.2 Translocation Renal Cell Carcinoma Mouse Model Reveals Novel Therapeutic Targets and Identifies GPNMB as a Diagnostic Marker for Human Disease. Molecular cancer research : MCR 76 31043488
2022 Integrated single-cell transcriptomic analyses reveal that GPNMB-high macrophages promote PN-MES transition and impede T cell activation in GBM. EBioMedicine 75 36054938
2016 Macrophage-Associated Osteoactivin/GPNMB Mediates Mesenchymal Stem Cell Survival, Proliferation, and Migration Via a CD44-Dependent Mechanism. Journal of cellular biochemistry 74 26442636
2009 Gpnmb is a melanosome-associated glycoprotein that contributes to melanocyte/keratinocyte adhesion in a RGD-dependent fashion. Experimental dermatology 74 19320736
2017 Targeting GPNMB with glembatumumab vedotin: Current developments and future opportunities for the treatment of cancer. Pharmacology & therapeutics 73 28546082
2015 Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis. Scientific reports 72 26581806
2015 GPNMB cooperates with neuropilin-1 to promote mammary tumor growth and engages integrin α5β1 for efficient breast cancer metastasis. Oncogene 65 25772243
2014 GPNMB/OA protein increases the invasiveness of human metastatic prostate cancer cell lines DU145 and PC3 through MMP-2 and MMP-9 activity. Experimental cell research 64 24589892
2017 Increased brain expression of GPNMB is associated with genome wide significant risk for Parkinson's disease on chromosome 7p15.3. Neurogenetics 61 28391543
2008 Gpnmb is a melanoblast-expressed, MITF-dependent gene. Pigment cell & melanoma research 61 18983539
2012 Expression and immunolocalization of Gpnmb, a glioma-associated glycoprotein, in normal and inflamed central nervous systems of adult rats. Brain and behavior 59 22574278
2022 GPNMB: a potent inducer of immunosuppression in cancer. Oncogene 57 36050467
2014 Glycoprotein nonmetastatic melanoma protein B (GPNMB) as a novel neuroprotective factor in cerebral ischemia-reperfusion injury. Neuroscience 57 25010402
2016 Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease. PloS one 54 26771826
2009 Upregulation of monocyte/macrophage HGFIN (Gpnmb/Osteoactivin) expression in end-stage renal disease. Clinical journal of the American Society of Nephrology : CJASN 47 19833906
2012 Gpnmb/osteoactivin, an attractive target in cancer immunotherapy. Neoplasma 46 22017590
2010 GPNMB expression in uveal melanoma: a potential for targeted therapy. Melanoma research 44 20375921
2018 Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans. American journal of human genetics 43 29336782
2016 Transgenic Expression of Osteoactivin/gpnmb Enhances Bone Formation In Vivo and Osteoprogenitor Differentiation Ex Vivo. Journal of cellular physiology 43 25899717
2022 Tumor endothelial cell-induced CD8+ T-cell exhaustion via GPNMB in hepatocellular carcinoma. Cancer science 42 35289033
2016 MAPK Pathway Inhibitors Sensitize BRAF-Mutant Melanoma to an Antibody-Drug Conjugate Targeting GPNMB. Clinical cancer research : an official journal of the American Association for Cancer Research 42 27515299
2019 Microglia express GPNMB in the brains of Alzheimer's disease and Nasu-Hakola disease. Intractable & rare diseases research 40 31218162
2002 mRNA expression of the murine glycoprotein (transmembrane) nmb (Gpnmb) gene is linked to the developing retinal pigment epithelium and iris. Brain research. Gene expression patterns 38 12638126
2012 Silencing of GPNMB by siRNA inhibits the formation of melanosomes in melanocytes in a MITF-independent fashion. PloS one 37 22912767
2021 GPNMB plays a protective role against obesity-related metabolic disorders by reducing macrophage inflammatory capacity. The Journal of biological chemistry 35 34582891
2019 GPNMB augments Wnt-1 mediated breast tumor initiation and growth by enhancing PI3K/AKT/mTOR pathway signaling and β-catenin activity. Oncogene 35 30914799
2023 Positive GPNMB Immunostaining Differentiates Renal Cell Carcinoma With Fibromyomatous Stroma Associated With TSC1/2/MTOR Alterations From Others. The American journal of surgical pathology 34 37661807
2016 Osteoactivin (GPNMB) ectodomain protein promotes growth and invasive behavior of human lung cancer cells. Oncotarget 34 26883195
2023 Macrophage-derived GPNMB trapped by fibrotic extracellular matrix promotes pulmonary fibrosis. Communications biology 33 36732560
2021 GPNMB mitigates Alzheimer's disease and enhances autophagy via suppressing the mTOR signal. Neuroscience letters 33 34695452
2018 GPNMB silencing suppresses the proliferation and metastasis of osteosarcoma cells by blocking the PI3K/Akt/mTOR signaling pathway. Oncology reports 33 29620278
2024 Gpnmb and Spp1 mark a conserved macrophage injury response masking fibrosis-specific programming in the lung. JCI insight 32 39509324
2021 Long non-coding RNA MALAT1 regulates cell proliferation and apoptosis via miR-135b-5p/GPNMB axis in Parkinson's disease cell model. Biological research 32 33726823
2020 Transgenic Overexpression of GPNMB Protects Against MPTP-Induced Neurodegeneration. Molecular neurobiology 32 32436108
2016 GPNMB ameliorates mutant TDP-43-induced motor neuron cell death. Journal of neuroscience research 32 27935101
2013 Endothelin-1 enhances the melanogenesis via MITF-GPNMB pathway. BMB reports 32 23884103
2021 Intracerebroventricular Treatment with 2-Hydroxypropyl-β-Cyclodextrin Decreased Cerebellar and Hepatic Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB) Expression in Niemann-Pick Disease Type C Model Mice. International journal of molecular sciences 31 33466390
2020 GPNMB is expressed in human epidermal keratinocytes but disappears in the vitiligo lesional skin. Scientific reports 31 32188902
2023 Lactic acid-induced M2-like macrophages facilitate tumor cell migration and invasion via the GPNMB/CD44 axis in oral squamous cell carcinoma. International immunopharmacology 30 37806107
2021 Anti-inflammatory role of Gpnmb in adipose tissue of mice. Scientific reports 29 34608215
2007 Role of human HGFIN/nmb in breast cancer. Breast cancer research : BCR 29 17845721
2019 DC-HIL/Gpnmb Is a Negative Regulator of Tumor Response to Immune Checkpoint Inhibitors. Clinical cancer research : an official journal of the American Association for Cancer Research 25 31822499
2013 The PKD domain distinguishes the trafficking and amyloidogenic properties of the pigment cell protein PMEL and its homologue GPNMB. Pigment cell & melanoma research 25 23452376
2023 CCN3/NOV promotes metastasis and tumor progression via GPNMB-induced EGFR activation in triple-negative breast cancer. Cell death & disease 23 36737605
2019 Takayasu arteritis risk locus in IL6 represses the anti-inflammatory gene GPNMB through chromatin looping and recruiting MEF2-HDAC complex. Annals of the rheumatic diseases 23 31315839
2011 Hematopoietic growth factor inducible neurokinin-1 (Gpnmb/Osteoactivin) is a biomarker of progressive renal injury across species. Kidney international 22 21389974
2016 Glycoprotein nonmetastatic melanoma protein B (GPNMB) promotes the progression of brain glioblastoma via Na+/K+-ATPase. Biochemical and biophysical research communications 21 27836549
2011 Genetic dissection of the Gpnmb network in the eye. Investigative ophthalmology & visual science 21 21398278
2022 miR-532-3p suppresses proliferation and invasion of ovarian cancer cells via GPNMB/HIF-1α/HK2 axis. Pathology, research and practice 20 35914373
2021 N-glycosylated GPNMB ligand independently activates mutated EGFR signaling and promotes metastasis in NSCLC. Cancer science 20 33706413
2017 DLG2, but not TMEM229B, GPNMB, and ITGA8 polymorphism, is associated with Parkinson's disease in a Taiwanese population. Neurobiology of aging 19 29290481
2024 Bone-marrow macrophage-derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair. Nature cardiovascular research 18 39455836
2023 Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease. Journal of neuroinflammation 18 38037070
2019 Transcriptome analysis reveals GPNMB as a potential therapeutic target for gastric cancer. Journal of cellular physiology 18 31498430
2024 Tumor associated microglia/macrophages utilize GPNMB to promote tumor growth and alter immune cell infiltration in glioma. Acta neuropathologica communications 17 38566120
2023 GPNMB Ameliorates Neuroinflammation Via the Modulation of AMPK/NFκB Signaling Pathway After SAH in Mice. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 17 37919457
2023 PCSK9 inhibitor protects against ischemic cerebral injury by attenuating inflammation via the GPNMB/CD44 pathway. International immunopharmacology 17 38048667
2019 Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB) Ameliorates the Inflammatory Response in Periodontal Disease. Inflammation 17 30793225
2022 A novel molecular mechanism of vascular fibrosis in Takayasu arteritis: macrophage-derived GPNMB promoting adventitial fibroblast extracellular matrix production in the aorta. Translational research : the journal of laboratory and clinical medicine 16 36566014
2005 Cloning and characterization of the 5' flanking region of the HGFIN gene indicate a cooperative role among p53 and cytokine-mediated transcription factors: relevance to cell cycle regulation. Cell cycle (Georgetown, Tex.) 16 15684612
2024 Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB) Immunohistochemistry Can Be a Useful Ancillary Tool to Identify Perivascular Epithelioid Cell Tumor. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 15 38219952
2025 Evaluation of 3,606 renal cell tumors for TFE3 rearrangements and TFEB alterations via fluorescence in situ hybridization, next generation sequencing, and GPNMB immunohistochemistry. Human pathology 14 40381702
2022 HSP90 inhibitors induce GPNMB cell-surface expression by modulating lysosomal positioning and sensitize breast cancer cells to glembatumumab vedotin. Oncogene 14 35110681
2022 TROP-2, Nectin-4, GPNMB, and B7-H3 Are Potentially Therapeutic Targets for Anaplastic Thyroid Carcinoma. Cancers 14 35158847
2021 Quantitative trait locus mapping identifies the Gpnmb gene as a modifier of mouse macrophage lysosome function. Scientific reports 14 33986446
2017 GPNMB Induces BiP Expression by Enhancing Splicing of BiP Pre-mRNA during the Endoplasmic Reticulum Stress Response. Scientific reports 14 28939899
2025 GPNMB and ATP6V1A interact to mediate microglia phagocytosis of multiple types of pathological particles. Cell reports 13 39992792
2024 Roles of Activin A and Gpnmb in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Diabetes 13 37934943
2021 Genetic ablation of Gpnmb does not alter synuclein-related pathology. Neurobiology of disease 13 34464706
2021 GPNMB plays an active role in the M1/M2 balance. Tissue & cell 13 34800878
2021 Proteomic analysis of alcohol-associated hepatitis reveals glycoprotein NMB (GPNMB) as a novel hepatic and serum biomarker. Alcohol (Fayetteville, N.Y.) 13 34923085
2019 A Host Factor GPNMB Restricts Porcine Circovirus Type 2 (PCV2) Replication and Interacts With PCV2 ORF5 Protein. Frontiers in microbiology 13 30671053
2018 Overexpression of GPNMB predicts an unfavorable outcome of epithelial ovarian cancer. Archives of gynecology and obstetrics 13 29428978
2014 Differential expression of glycoprotein non-metastatic melanoma protein B (GPNMB) involved in trichostatin A-induced apoptosis in gastric cancer. International journal of clinical and experimental medicine 13 25663982
2021 GPNMB Extracellular Fragment Protects Melanocytes from Oxidative Stress by Inhibiting AKT Phosphorylation Independent of CD44. International journal of molecular sciences 12 34639184
2025 CD206+ macrophages facilitate wound healing through interactions with Gpnmbhi fibroblasts. EMBO reports 11 40495034
2023 Serum glycoprotein non-metastatic melanoma protein B (GPNMB) level as a potential biomarker for diabetes mellitus-related cataract: A cross-sectional study. Frontiers in endocrinology 11 36875463
2023 Effects of SLC45A2 and GPNMB on Melanin Deposition Based on Transcriptome Sequencing in Chicken Feather Follicles. Animals : an open access journal from MDPI 11 37627399
2023 GPNMB+ Gal-3+ hepatic parenchymal cells promote immunosuppression and hepatocellular carcinogenesis. The EMBO journal 11 38009297
2021 Functional Domains and Evolutionary History of the PMEL and GPNMB Family Proteins. Molecules (Basel, Switzerland) 11 34207849
2021 GPNMB promotes the progression of diffuse large B cell lymphoma via YAP1-mediated activation of the Wnt/β-catenin signaling pathway. Archives of biochemistry and biophysics 11 34280359
2018 Increased GPNMB, phospho-ERK1/2, and MMP-9 in cystic fibrosis in association with reduced arylsulfatase B. Molecular genetics and metabolism 11 29703589
2017 The laminin-derived peptide C16 regulates GPNMB expression and function in breast cancer. Experimental cell research 11 28689015
2015 Aqueous humor phospholipids of DBA/2J and DBA/2J-Gpnmb(+)/SjJ mice. Biochimie 11 25843665
2025 Unlocking diagnostic potential: A retrospective analysis of GPNMB immunohistochemistry in nearly 1000 surgical pathology specimens. Human pathology 10 40389121
2023 MDSC suppresses T cell antitumor immunity in CAC via GPNMB in a MyD88-dependent manner. Cancer medicine 10 38140790
2025 Nuclear receptor PPARγ targets GPNMB to promote oligodendrocyte development and remyelination. Brain : a journal of neurology 9 39756479
2023 Glycoprotein Non-Metastatic Protein B (GPNMB): The Missing Link Between Lysosomes and Obesity. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 9 37956971
2022 Role of Gpnmb in atherosclerosis of female mice. Biochemical and biophysical research communications 9 35809343
2021 Soluble DC-HIL/Gpnmb Modulates T-Lymphocyte Extravasation to Inflamed Skin. The Journal of investigative dermatology 9 34695414
2015 Effects of GPNMB on proliferation and odontoblastic differentiation of human dental pulp cells. International journal of clinical and experimental pathology 9 26261527

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