Affinage

GRN

Progranulin · UniProt P28799

Length
593 aa
Mass
63.5 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Progranulin (GRN/PGRN) is a secreted glycoprotein with a dual life as a lysosomal cofactor and an extracellular growth/immunomodulatory factor (PMID:11134521, PMID:34450028). In the endolysosomal compartment, PGRN is a pH-dependent interactor of the phospholipid bis(monoacylglycero)phosphate (BMP), and its loss causes global BMP deficiency that cripples sphingolipid catabolism—producing ganglioside and glucosylsphingosine accumulation despite intact catabolic enzymes—and impairs proteolysis, lipolysis, and redox homeostasis (PMID:34450028, PMID:36207292). This lysosomal failure manifests in vivo as defective microglial clearance of myelin debris downstream of cathepsin D, with PGRN acting genetically upstream of cathepsin D-dependent clearance and interacting with TMEM106B such that combined loss produces accelerated lysosomal vacuolation and neuronal loss (PMID:34433069, PMID:32852886). PGRN deficiency also functions as a disease modifier of glucocerebrosidase (GBA1), exacerbating Gaucher- and Parkinson-like neuropathology (PMID:36574647). Loss of PGRN drives frontotemporal dementia with TDP-43 pathology through multiple effector arms: disinhibited Gas6-Tyro3 signaling activates PKCα to phosphorylate tau at Ser203 and cause dendritic spine loss (PMID:29382817), PGRN-deficient astrocytes acquire a reactive transcriptional state (GJA1/AQP4/APOE up, SLC1A2 down) that directly induces synaptic degeneration and TDP-43 proteinopathy (PMID:36602862), and patient cells show noncanonical Wnt5a/CaMKII/ERK dysregulation and parkin downregulation (PMID:24139281, PMID:34054428). Extracellularly, PGRN binds cell-surface receptors and acts as an autocrine mitogen, mediating estrogen-dependent proliferation and tumorigenesis via cyclin D1/CDK4 and MAPK activation (PMID:11134521, PMID:9826678, PMID:10760271, PMID:17261172). As an immune regulator, PGRN dampens type I interferon production by binding NF-κB essential modulator (NEMO) through its granulin CDE domains and recruiting A20 to deubiquitinate K63-linked chains on NEMO (PMID:31585000), and it promotes anti-inflammatory M2 macrophage polarization through direct TNFR2 binding (PMID:25387791, PMID:38689292). PGRN levels are controlled post-transcriptionally by TMEM106B and by miR-29b binding within the GRN 3' UTR, the latter being a therapeutic target for translational upregulation (PMID:21178100, PMID:37981208). Haploinsufficiency from loss-of-function GRN mutations underlies frontotemporal dementia with TDP-43 pathology (PMID:24139281, PMID:21232819).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1998 High

    Established that PGRN is a secreted autocrine growth factor whose expression is required for tumorigenicity and that it engages specific cell-surface receptors, defining its extracellular signaling identity.

    Evidence Antisense inhibition with in vivo tumor formation in syngeneic mice; radiolabeled ligand binding with Scatchard analysis and crosslinking on epithelial and fibroblast cells

    PMID:10760271 PMID:9571191 PMID:9826678

    Open questions at the time
    • The molecular identity of the ~120 kDa crosslinked receptor species was not determined
    • No reciprocal validation of receptor binding partners
  2. 2001 High

    Defined the downstream mitogenic mechanism by showing PGRN mediates estrogen-driven proliferation via cyclin D1 induction and MAP kinase activation, linking it to hormone-dependent breast cancer growth.

    Evidence Neutralizing antibody, antisense, and overexpression in MCF-7 cells with MAP kinase and cyclin D1 readouts

    PMID:11134521

    Open questions at the time
    • Receptor mediating the estrogen-PGRN-cyclin D1 axis not identified
    • Did not address PGRN's lysosomal/neuronal roles
  3. 2007 Medium

    Generalized PGRN's proliferative role to ovarian cancer and placed it upstream of cell-cycle entry (cyclin D1/CDK4) and matrix remodeling (MMP-2/MMP-9, VEGF), connecting mitogenesis to invasion.

    Evidence Antisense loss-of-function in ovarian cancer cells with proliferation, invasion, and zymography readouts; overexpression with MMP-9/VEGF assays

    PMID:15117809 PMID:17261172

    Open questions at the time
    • Mechanism linking PGRN to MMP/VEGF transcription unresolved
    • Single-lab functional data
  4. 2010 Medium

    Identified TMEM106B as a post-transcriptional modulator of circulating PGRN levels, introducing a genetic axis governing PGRN dosage relevant to neurodegeneration risk.

    Evidence Genetic association with plasma PGRN ELISA and inverse mRNA correlation in peripheral blood cohorts

    PMID:21178100

    Open questions at the time
    • Observational correlation without direct mechanistic experiment
    • Did not define the molecular mode of TMEM106B regulation
  5. 2013 Medium

    Connected PGRN haploinsufficiency in FTLD patient cells to aberrant cell cycle re-entry and noncanonical Wnt5a/CaMKII/ERK signaling, offering candidate effectors of neuronal dysfunction.

    Evidence FTLD-TDP patient lymphoblasts and SH-SY5Y knockdown with cell cycle analysis, CDK6/phospho-Rb blots, Wnt5a/CaMKII/ERK readouts, conditioned medium rescue

    PMID:21232819 PMID:24139281

    Open questions at the time
    • Link from PGRN loss to CDK6 via TDP-43 partially inferred
    • Patient-cell findings from single lab
  6. 2014 High

    Defined PGRN as an anti-inflammatory mediator acting through IL-10- and TNFR2-dependent pathways in colitis, establishing its protective immunoregulatory function in vivo.

    Evidence PGRN-/-, IL-10-/-, TNFR2-/- mice in DSS/TNBS colitis with recombinant PGRN rescue and bone marrow chimeras

    PMID:25387791

    Open questions at the time
    • Did not directly demonstrate PGRN-TNFR2 physical binding (resolved later)
    • Cell type executing protection not fully resolved
  7. 2015 Medium

    Showed that excess PGRN impairs hepatic and adipose insulin sensitivity through TNFR1/NF-κB and PERK-eIF2α ER stress signaling, revealing a context-dependent metabolic role distinct from its anti-inflammatory actions.

    Evidence PGRN treatment of mice with TNFR1 blocking peptide/siRNA, PERK inhibitor, and chemical chaperone PBA, plus insulin/autophagy/ER stress readouts

    PMID:25664864 PMID:26039714

    Open questions at the time
    • Reconciliation with PGRN's protective TNFR2 signaling not addressed
    • Single-lab pharmacological epistasis
  8. 2018 High

    Identified a specific neurodegenerative mechanism whereby PGRN reduction disinhibits Gas6-Tyro3 signaling, activating PKCα to phosphorylate tau at Ser203 and drive spine loss, providing a druggable pathway.

    Evidence PGRN-R504X knock-in mice, phosphoproteomics, PKCα kinase assay, pharmacological and siRNA rescue of spine loss and cognition

    PMID:29382817

    Open questions at the time
    • How PGRN normally restrains Gas6-Tyro3 binding mechanistically unresolved
    • Relationship to TDP-43 pathology not directly tested
  9. 2019 High

    Resolved the molecular mechanism of PGRN's interferon suppression by showing direct NEMO binding via granulin CDE domains and A20 recruitment to deubiquitinate K63 chains on NEMO at K264.

    Evidence Reciprocal Co-IP, domain mapping, deubiquitination assays, PGRN-deficient mice, and neutralizing antibody with type I IFN quantification

    PMID:31585000

    Open questions at the time
    • Subcellular site of PGRN-NEMO interaction not defined
    • Stoichiometry of the PGRN-NEMO-A20 assembly unknown
  10. 2021 High

    Reframed PGRN as a lysosomal cofactor by identifying pH-dependent BMP binding, with deficiency causing global BMP loss, sphingolipid storage, microglial myelin-clearance failure, and TMEM106B genetic interaction—unifying its neurodegenerative phenotypes around lysosomal dysfunction.

    Evidence Grn-/- mice, lipidomics, pH-dependent binding assays, iPSC-microglia, PTV:PGRN replacement, Ctsd/Grn and Tmem106b/Pgrn double-KO epistasis, EM

    PMID:32852886 PMID:34433069 PMID:34450028

    Open questions at the time
    • The structural basis of granulin-BMP interaction not resolved
    • How BMP maintenance mechanistically couples to enzyme function unclear
  11. 2022 Medium

    Extended the lysosomal model by demonstrating PGRN-dependent BMP maintenance is required for ganglioside catabolism and that PGRN modifies glucocerebrosidase function in vivo, linking PGRN to multiple sphingolipidoses.

    Evidence Ganglioside mass spectrometry and enzyme assays in human/mouse PGRN-deficient tissue; Grn/Gba1 double-mutant mice with ND7 peptide rescue

    PMID:36207292 PMID:36574647

    Open questions at the time
    • Direct biochemical reconstitution of granulin enhancement of catabolism not shown
    • GBA1 modifier mechanism in part inferred
  12. 2023 High

    Demonstrated a non-cell-autonomous neurodegenerative mechanism in which PGRN-deficient reactive astrocytes directly induce synaptic degeneration and TDP-43 proteinopathy, identifying astrocytes as drivers rather than bystanders.

    Evidence Single-nucleus RNA-seq in Grn-/- mice and FTD-GRN tissue, astrocyte-neuron cocultures, and iPSC-astrocyte organoid transplantation

    PMID:36602862

    Open questions at the time
    • Astrocyte-secreted factor mediating synaptic toxicity not identified
    • Interplay with microglial lysosomal defects not resolved
  13. 2024 Medium

    Confirmed direct PGRN-TNFR2 binding driving M2 macrophage polarization and revealed a PGRN-EGFR axis recruiting macrophages in interferon-driven liver pathology, broadening PGRN's immunoreceptor repertoire.

    Evidence Co-IP and TNFR2 neutralizing antibody with M2 markers; liver-specific Adar KO mice with PGRN depletion and EGFR+ macrophage profiling

    PMID:38689292 PMID:38935501

    Open questions at the time
    • Single-lab Co-IP for TNFR2 without reciprocal/structural validation
    • Whether PGRN binds EGFR directly not established
  14. 2023 High

    Established miR-29b-mediated translational repression of GRN as a therapeutically actionable lever, with steric-block ASOs raising progranulin protein without changing mRNA.

    Evidence ASO screen, FRET binding competition, polysome profiling, iPSC-neurons, and humanized GRN mouse model

    PMID:37981208

    Open questions at the time
    • Endogenous physiological regulation of miR-29b on GRN not characterized
    • Other 3' UTR regulators not surveyed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity and signaling logic of the cell-surface PGRN receptor(s) mediating its extracellular growth-factor activity, and how the lysosomal BMP-cofactor role mechanistically couples to the extracellular receptor signaling, remain unresolved.
  • The ~120 kDa receptor species remains molecularly unidentified
  • No unified model linking lysosomal granulin function to extracellular MAPK/PI3K signaling
  • Structural basis of granulin domain-specific functions not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 3 GO:0060089 molecular transducer activity 2 GO:0008289 lipid binding 1
Localization
GO:0005576 extracellular region 3 GO:0005764 lysosome 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-1430728 Metabolism 2
Partners
A20/TNFAIP3FAM135BGBA1NEMO/IKBKGTMEM106BTNFR1/TNFRSF1ATNFR2/TNFRSF1BTYRO3

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 PCDGF/progranulin mediates the mitogenic effect of estrogen (17β-estradiol) in MCF-7 breast cancer cells via stimulation of cyclin D1 expression and MAP kinase activation; anti-PCDGF neutralizing antibody and antisense inhibition of PCDGF both blocked E2-dependent proliferation, while PCDGF overexpression conferred estrogen-independent growth and tamoxifen resistance. Neutralizing antibody, antisense transfection, PCDGF overexpression, MAP kinase assay, cyclin D1 immunoblot, DNA synthesis assay Proceedings of the National Academy of Sciences of the United States of America High 11134521
1998 PCDGF/progranulin expression is required for tumorigenicity of PC teratoma cells; antisense-mediated inhibition of PCDGF expression dramatically reduced tumor formation in syngeneic mice, demonstrating that autocrine PCDGF production drives tumorigenesis. Antisense PCDGF cDNA transfection, in vivo tumor formation assay in syngeneic mice, Northern/Western blot Proceedings of the National Academy of Sciences of the United States of America High 10760271 9826678
1998 PCDGF/progranulin binds to two classes of cell-surface receptors on mink lung epithelial cells (CCL64): high-affinity sites (Kd ~43 pM, ~560 sites/cell) and low-affinity sites (Kd ~3.9 nM, ~16,350 sites/cell); chemical crosslinking identified a ~120 kDa receptor species; similar binding sites were detected on 3T3 fibroblasts and PC cells. Radiolabeled ligand binding (125I-PCDGF), Scatchard analysis, chemical crosslinking with disuccinimidyl suberate, SDS-PAGE Biochemical and biophysical research communications Medium 9571191
2004 Progranulin/PCDGF overexpression in MCF-7 breast cancer cells stimulates anchorage-independent growth, cell migration through Matrigel, upregulation of matrix metalloprotease-9 (by gelatin zymography and immunoblot), and VEGF expression, implicating progranulin in invasion and angiogenesis. Stable overexpression, exogenous protein treatment, gelatin zymography, immunoblot for MMP-9 and VEGF, transwell migration assay Carcinogenesis Medium 15117809
2007 Antisense-mediated inhibition of PCDGF/progranulin in ovarian cancer cells (SW626, A2780) reduced proliferation and invasion, and decreased cyclin D1 and CDK4 expression while inactivating MMP-2, placing progranulin upstream of cell cycle entry and extracellular matrix remodeling. Antisense PCDGF cDNA transfection, MTT proliferation assay, Boyden chamber invasion assay, RT-PCR and Western blot for cyclin D1/CDK4, gelatin zymography for MMP-2 BMC cancer Medium 17261172
2010 TMEM106B SNPs are significantly associated with plasma progranulin (GRN) levels in controls, and TMEM106B and GRN mRNA expression are inversely correlated in peripheral blood, indicating TMEM106B modulates progranulin levels post-transcriptionally. Genetic association study with plasma PGRN ELISA, correlation of TMEM106B and GRN mRNA expression in blood samples Neurology Medium 21178100
2021 Progranulin (PGRN) is a pH-dependent interactor of bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid; PGRN deficiency causes global BMP deficiency and impairs lysosomal proteolysis, lipolysis, and redox homeostasis. Secondary glucosylsphingosine storage occurs in aged Grn-/- brains. A brain-penetrant PTV:PGRN biologic rescued BMP levels, glucosylsphingosine accumulation, oxidative stress, lysosomal dysfunction, microgliosis, and lipofuscinosis in Grn-/- mice and human iPSC-derived microglia. Grn-/- mouse model, lipidomic profiling of BMP, pH-dependent binding assays, iPSC-derived microglia, protein replacement therapy, mass spectrometry, lysosomal functional assays Cell High 34450028
2022 PGRN deficiency causes gangliosidosis: PGRN-deficient human cells, murine brains, and human FTD-GRN frontal lobes accumulate gangliosides. Lysosomal enzymes that catabolize gangliosides are present at normal levels, but BMP levels are reduced, implicating PGRN-derived granulins in maintaining BMP levels required for ganglioside catabolism. PGRN-deficient human cells and Grn-/- mouse brains, human FTD-GRN tissue, ganglioside mass spectrometry, lysosomal enzyme activity assays, BMP lipid profiling Nature communications High 36207292
2021 In Grn knockout mice, microglia accumulate myelin debris in lysosomes in white matter regions. PGRN insufficiency in microglia leads to impaired lysosomal-mediated clearance of myelin debris. Grn KO mice deficient in cathepsin D have augmented myelin debris and increased neuronal TDP-43 pathology, placing PGRN upstream of cathepsin D-dependent lysosomal clearance of myelin. Grn-/- mouse model, electron microscopy, immunofluorescence, Ctsd/Grn double-KO genetic epistasis, human FTD-GRN tissue immunostaining Cell reports High 34433069
2020 Simultaneous loss of both PGRN and TMEM106B in mice results in severe neuronal loss, glial activation, enlarged lysosomes in microglia and astrocytes, and enhanced accumulation of lysosomal vacuoles at the axon initial segment of motor neurons, with much earlier onset than single knockouts, demonstrating genetic interaction between TMEM106B and PGRN in lysosomal function and neurodegeneration. Pgrn/Tmem106b double-knockout mouse model, neuropathology, immunohistochemistry, electron microscopy EMBO reports High 32852886
2018 In a PGRN-R504X knock-in mouse model, PGRN reduction leads to disinhibition of Gas6 binding to Tyro3, activating PKCα via PLCγ, which phosphorylates tau at Ser203, causing tau mislocalization to dendritic spines and spine loss. PKC inhibitor, B-Raf inhibitor, or knockdown of Gas6-Tyro3-tau pathway members rescued spine loss and cognitive impairment. Phosphoproteomic analysis, PGRN-R504X knock-in mice, PKCα kinase assay, pharmacological inhibition (PKC inhibitor, B-Raf inhibitor), siRNA knockdown, dendritic spine imaging, behavioral testing Nature communications High 29382817
2023 Progranulin-deficient astrocytes drive synaptic degeneration in the thalamocortical circuit: single-cell transcriptomics in Grn-/- mice and FTD-GRN patients revealed conserved upregulation of GJA1, AQP4, and APOE and downregulation of glutamate transporter SLC1A2. Progranulin-deficient astrocytes in cocultures and cortical organoid transplant experiments directly induced synaptic degeneration, neuronal stress, and TDP-43 proteinopathy. Single-nucleus RNA-seq, Grn-/- mice, FTD-GRN human tissue, iPSC-derived astrocyte transplantation into cortical organoids, astrocyte-neuron cocultures, immunostaining for TDP-43 and synaptic markers The Journal of clinical investigation High 36602862
2019 Influenza virus-induced progranulin (PGRN) negatively regulates type I interferon production by inhibiting NF-κB and IRF3 signaling. Mechanistically, PGRN directly interacts with NF-κB essential modulator (NEMO) via its Grn CDE domains and recruits A20 to deubiquitinate K63-linked polyubiquitin chains on NEMO at K264. PGRN knockdown, PGRN-deficient mice, co-immunoprecipitation of PGRN with NEMO, domain mapping (Grn CDE), deubiquitination assay showing A20 recruitment, PGRN neutralizing antibody in vivo, type I IFN quantification PLoS pathogens High 31585000
2014 Progranulin exerts anti-inflammatory protection in colitis in an IL-10- and TNFR2-dependent manner: PGRN-deficient mice show heightened susceptibility to colitis, and recombinant PGRN is protective. The protective effect was largely absent in IL-10-deficient and TNFR2-deficient colitis models, placing PGRN's action downstream of or in the same pathway as both IL-10 and TNFR2. PGRN-/-, IL-10-/-, and TNFR2-/- mice, DSS and TNBS colitis models, bone marrow chimera, CD4+ T cell transfer, recombinant PGRN treatment, histological scoring Scientific reports High 25387791
2024 PGRN directly binds TNFR2 (confirmed by co-immunoprecipitation), co-localizes with TNFR2 on M2 macrophages, and promotes macrophage M2 polarization through TNFR2; TNFR2-blocking antibody inhibits PGRN-mediated M2 polarization. Co-immunoprecipitation, multiplex immunohistochemistry, TNFR2 neutralizing antibody, flow cytometry, ELISA for M1/M2 markers Journal of translational medicine Medium 38689292
2015 PGRN impairs hepatic insulin sensitivity via TNFR1/NF-κB signaling: in vivo PGRN treatment impairs glucose and insulin tolerance with hepatic autophagy imbalance; TNFR1 blocking peptide-Fc restores insulin sensitivity and autophagy. In hepatocytes, PGRN-induced insulin resistance and autophagy defects are nullified by TNFR1 siRNA via TNFR1-NF-κB-dependent manner. PGRN treatment of mice for 21 days, TNFR1 blocking peptide-Fc, TNFR1 siRNA in hepatocytes, glucose/insulin tolerance tests, autophagy markers (LC3, p62), insulin signaling (Akt phosphorylation) Molecular endocrinology (Baltimore, Md.) Medium 25664864
2015 PGRN triggers ER stress and impairs insulin sensitivity via the PERK-eIF2α axis: PGRN treatment in mice induces ER stress and attenuated insulin signaling in liver and adipose tissue (not skeletal muscle); chemical chaperone PBA restores insulin sensitivity; PERK blockade partially nullifies PGRN-induced insulin resistance in hepatocytes and adipocytes. PGRN treatment of mice, PBA (ER stress inhibitor), PERK inhibitor in cell culture, glucose/insulin tolerance, insulin signaling markers, ER stress markers Cell cycle (Georgetown, Tex.) Medium 26039714
2013 PGRN haploinsufficiency activates noncanonical Wnt5a signaling: lymphoblasts from c.709-1G>A PGRN mutation carriers show increased Wnt5a protein (cellular and secreted), enhanced CaMKII phosphorylation, and activated ERK1/2 in a Ca2+/PKC/pertussis toxin-sensitive manner. Exogenous PGRN or control-conditioned medium normalized ERK1/2. PGRN knockdown in SH-SY5Y cells recapitulated increased Wnt5a. Lymphoblasts from FTLD-TDP PGRN mutation carriers, exogenous PGRN treatment, conditioned medium, ERK1/2 kinase assay, CaMKII phosphorylation, PGRN siRNA in SH-SY5Y, pertussis toxin, PKC inhibition Neurobiology of aging Medium 24139281
2011 PGRN haploinsufficiency in lymphoblasts from c.709-1G>A FTLD-TDP patients increases cell cycle activity with elevated CDK6 and phospho-Rb, leading to G1/S regulatory failure; altered TDP-43 subcellular distribution may underlie CDK6 upregulation via loss of TDP-43 repression of CDK6. Patient lymphoblasts, cell cycle analysis, Western blot for CDK6, phospho-Rb, TDP-43 localization by immunofluorescence Neurobiology of aging Medium 21232819
2018 Transcription factor REST represses PGRN expression by directly binding the PGRN promoter, and PGRN promotes microglia-like BV2 cell migration. REST knockdown increases PGRN expression and BV2 migration; REST overexpression suppresses both; siRNA targeting PGRN blocks the migration-promoting effect. siRNA knockdown of PGRN and REST, REST overexpression, dual luciferase reporter for PGRN promoter activity, transwell migration assay Neural plasticity Medium 33299399
2023 Antisense oligonucleotides (ASOs) that sterically block the miR-29b binding site in the 3' UTR of human GRN mRNA increase progranulin protein translation (not mRNA levels), as demonstrated by polysome profiling; ASOs competed with miR-29b for GRN 3' UTR binding in FRET assays and increased progranulin in iPSC-derived neurons and a humanized GRN mouse model. ASO screen in neuroglioma cells, FRET-based binding competition, polysome profiling, iPSC-derived neurons, humanized GRN mouse model, progranulin ELISA/Western blot The Journal of biological chemistry High 37981208
2022 PGRN is a modifier of glucocerebrosidase (GCase/GBA1) function in vivo: PGRN-deficient mice crossed with Gba1-D409V knock-in mice exhibit exacerbated neurobehavioral deficits, earlier onset, more severe Gaucher disease phenotypes, and PD-like pathology compared to single mutants, with severe neuroinflammation (microgliosis, astrogliosis) and impaired autophagy. A PGRN-derived peptide (ND7) crosses the blood-brain barrier and rescues disease phenotypes in nGD and PD models. Grn/Gba1 double-mutant mice, neuropathology, behavior, PGRN peptide ND7 BBB penetration and treatment, GD patient fibroblasts ex vivo Proceedings of the National Academy of Sciences of the United States of America Medium 36574647
2020 PGRN-/- tumor-associated macrophages (TAMs) inhibit breast cancer cell invasion, migration, and EMT through their exosomes; miR-5100 is upregulated in PGRN-/- TAM-derived exosomes and targets CXCL12, thereby inhibiting the CXCL12/CXCR4 axis. PGRN-/- mouse xenograft model, flow cytometry, transwell/wound healing assays, Western blot, miRNA profiling, qPCR, luciferase reporter assay for miR-5100 target (CXCL12) Life sciences Medium 33181174
2020 FAM135B directly interacts with progranulin (GRN) in esophageal squamous cell carcinoma cells, forming a feedforward loop with AKT/mTOR signaling to promote tumor proliferation; this interaction was identified by co-immunoprecipitation and mass spectrometry. Co-immunoprecipitation and mass spectrometry, ectopic FAM135B expression, in vitro proliferation, in vivo xenograft, serum GRN ELISA in FAM135B transgenic mice Cancer research Medium 33323378
2024 Progranulin mediates ADAR1 deficiency-induced liver pathology by promoting interferon signaling and recruiting EGFR+ macrophages into the liver; PGRN-EGFR crosstalk exacerbates hepatic inflammation in liver-specific Adar KO mice, and this communication is repressed in ADAR1-high tumors. Liver-specific Adar KO mice, Ifih1;Adar double KO, macrophage recruitment assays, PGRN neutralization/depletion, EGFR+ macrophage flow cytometry, interferon signaling assays Cell reports Medium 38935501
2021 PGRN deficiency causes parkin (PRKN) downregulation in fibroblasts from FTLD patients with four different PGRN pathogenic variants, as well as in control fibroblasts upon PGRN silencing; PGRN knockdown also decreased parkin downstream targets MFN2 and VDAC1. TDP-43 overexpression rescued PRKN levels upon transient PGRN silencing but not in FTLD patient fibroblasts, and TDP-43 silencing itself caused PRKN decrease. Patient-derived fibroblasts, siRNA PGRN knockdown, TDP-43 overexpression/knockdown, Western blot for PRKN, MFN2, VDAC1 Frontiers in molecular neuroscience Medium 34054428
2018 TSH upregulates PGRN expression in endothelial cells, and PGRN in turn upregulates Akt and eNOS expression; siRNA knockdown of PGRN in HUVECs suppresses both Akt and eNOS, placing PGRN downstream of TSH and upstream of the Akt/eNOS axis. HUVECs, TSH stimulation, PGRN siRNA knockdown, Western blot for eNOS, p-Akt, PGRN; NO and superoxide assays; SCH rat model Frontiers in endocrinology Low 30026730
2020 PGRN suppresses inflammation and promotes autophagy in keratinocytes (HaCaT cells) through the Wnt/β-catenin signaling pathway: PGRN siRNA increases inflammatory cytokines (IL-1β, IL-6, COX-2, iNOS, MCP-1), suppresses autophagy markers (LC3II, Atg7), and upregulates β-catenin/cyclin D1/c-myc; these effects are reversed by the Wnt/β-catenin inhibitor IWP-2. PGRN siRNA and overexpression in HaCaT cells, Wnt/β-catenin inhibitor (IWP-2), cytokine ELISA, autophagy marker Western blot, β-catenin signaling reporter Inflammation Low 27239673
2018 Reduction of PGRN by siRNA in wound healing mouse model augments fibrosis, skin thickness, and collagen I deposition, and increases TGF-β1, TGF-β receptor I, Smad3, and phospho-Smad3 expression, indicating PGRN normally suppresses TGF-β/Smad fibrotic signaling. Excisional wound model in mice, si-m-PGRN injection, histology (H&E, Masson's trichrome), RT-qPCR and Western blot for TGF-β1, TβRI, Smad3, P-Smad3, Col I Histology and histopathology Low 30561754

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology 219 21178100
2008 Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia. The Lancet. Neurology 189 18771956
2021 Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic. Cell 184 34450028
2018 LncRNA H19/miR-29b-3p/PGRN Axis Promoted Epithelial-Mesenchymal Transition of Colorectal Cancer Cells by Acting on Wnt Signaling. Molecules and cells 161 29754471
2001 Mediation of estrogen mitogenic effect in human breast cancer MCF-7 cells by PC-cell-derived growth factor (PCDGF/granulin precursor). Proceedings of the National Academy of Sciences of the United States of America 124 11134521
2008 Refining frontotemporal dementia with parkinsonism linked to chromosome 17: introducing FTDP-17 (MAPT) and FTDP-17 (PGRN). Archives of neurology 122 18413467
2000 Inhibition of PC cell-derived growth factor (PCDGF, epithelin/granulin precursor) expression by antisense PCDGF cDNA transfection inhibits tumorigenicity of the human breast carcinoma cell line MDA-MB-468. Proceedings of the National Academy of Sciences of the United States of America 118 10760271
2004 PC cell-derived growth factor (PCDGF/GP88, progranulin) stimulates migration, invasiveness and VEGF expression in breast cancer cells. Carcinogenesis 116 15117809
2017 MiR-29b-3p promotes chondrocyte apoptosis and facilitates the occurrence and development of osteoarthritis by targeting PGRN. Journal of cellular and molecular medicine 109 28609022
2020 Loss of TMEM106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice. EMBO reports 86 32852886
2012 Analyses of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, and CBS. Parkinsonism & related disorders 82 22818528
2022 Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis. Nature communications 76 36207292
2015 Distinct clinical and pathological phenotypes in frontotemporal dementia associated with MAPT, PGRN and C9orf72 mutations. Amyotrophic lateral sclerosis & frontotemporal degeneration 76 26473392
1998 Inhibition of tumorigenicity of the teratoma PC cell line by transfection with antisense cDNA for PC cell-derived growth factor (PCDGF, epithelin/granulin precursor). Proceedings of the National Academy of Sciences of the United States of America 73 9826678
2020 Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms. Brain : a journal of neurology 71 31855245
2014 PGRN protects against colitis progression in mice in an IL-10 and TNFR2 dependent manner. Scientific reports 68 25387791
2021 Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD. Cell reports 67 34433069
2009 Brain progranulin expression in GRN-associated frontotemporal lobar degeneration. Acta neuropathologica 60 19649643
2022 Neurovascular dysfunction in GRN-associated frontotemporal dementia identified by single-nucleus RNA sequencing of human cerebral cortex. Nature neuroscience 59 35879464
2016 PGRN Suppresses Inflammation and Promotes Autophagy in Keratinocytes Through the Wnt/β-Catenin Signaling Pathway. Inflammation 54 27239673
2021 Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications. Journal of neurology, neurosurgery, and psychiatry 51 34349004
2011 Trajectories of brain and hippocampal atrophy in FTD with mutations in MAPT or GRN. Neurology 48 21753165
2007 Clinicopathologic correlation in PGRN mutations. Neurology 48 17522386
2016 PGRN Is Associated with Late-Onset Alzheimer's Disease: a Case-Control Replication Study and Meta-analysis. Molecular neurobiology 47 26820675
2014 Circulating PGRN is significantly associated with systemic insulin sensitivity and autophagic activity in metabolic syndrome. Endocrinology 47 24971611
2008 Novel PSEN1 and PGRN mutations in early-onset familial frontotemporal dementia. Neurobiology of aging 47 18314228
2020 PGRN-/- TAMs-derived exosomes inhibit breast cancer cell invasion and migration and its mechanism exploration. Life sciences 45 33181174
2015 PGRN promotes migration and invasion of epithelial ovarian cancer cells through an epithelial mesenchymal transition program and the activation of cancer associated fibroblasts. Experimental and molecular pathology 45 26607602
2010 Expression of progranulin (Acrogranin/PCDGF/Granulin-Epithelin Precursor) in benign and malignant ovarian tumors and activation of MAPK signaling in ovarian cancer cell line. Cancer investigation 44 19863344
2023 Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations. Acta neuropathologica communications 43 36967384
2015 PGRN induces impaired insulin sensitivity and defective autophagy in hepatic insulin resistance. Molecular endocrinology (Baltimore, Md.) 43 25664864
2024 PGRN is involved in macrophage M2 polarization regulation through TNFR2 in periodontitis. Journal of translational medicine 42 38689292
2020 Downregulation of LncRNA OIP5-AS1 Induced by IL-1β Aggravates Osteoarthritis via Regulating miR-29b-3p/PGRN. Cartilage 42 32037864
1998 Identification of cell surface binding sites for PC-cell-derived growth factor, PCDGF, (epithelin/granulin precursor) on epithelial cells and fibroblasts. Biochemical and biophysical research communications 39 9571191
2013 Clinical and genetic analysis of MAPT, GRN, and C9orf72 genes in Korean patients with frontotemporal dementia. Neurobiology of aging 38 24387985
2008 Progranulin (PGRN) expression in ALS: an immunohistochemical study. Journal of the neurological sciences 38 18848708
2019 miR-138 activates NF-κB signaling and PGRN to promote rheumatoid arthritis via regulating HDAC4. Biochemical and biophysical research communications 37 31492495
2016 Analyses MAPT, GRN, and C9orf72 mutations in Chinese patients with frontotemporal dementia. Neurobiology of aging 37 27311648
2012 Progranulin gene (GRN) promoter methylation is increased in patients with sporadic frontotemporal lobar degeneration. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 36 22797721
2023 Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations. The Journal of clinical investigation 34 36602862
2019 NAMPT, GRN, and SERPINE1 signature as predictor of disease progression and survival in gliomas. Journal of cellular biochemistry 34 31710121
2007 Inhibition of PC cell-derived growth factor (PCDGF)/granulin-epithelin precursor (GEP) decreased cell proliferation and invasion through downregulation of cyclin D and CDK4 and inactivation of MMP-2. BMC cancer 34 17261172
2021 Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia. Journal of neurology, neurosurgery, and psychiatry 33 33452053
2021 Primary Progressive Aphasia Associated With GRN Mutations: New Insights Into the Nonamyloid Logopenic Variant. Neurology 33 33980708
2021 Evidence for GRN connecting multiple neurodegenerative diseases. Brain communications 33 34693284
2018 Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers. NeuroImage. Clinical 33 29845007
2019 A PSCA/PGRN-NF-κB-Integrin-α4 Axis Promotes Prostate Cancer Cell Adhesion to Bone Marrow Endothelium and Enhances Metastatic Potential. Molecular cancer research : MCR 32 31722969
2023 Progranulin (PGRN) as a regulator of inflammation and a critical factor in the immunopathogenesis of cardiovascular diseases. Journal of inflammation (London, England) 31 36658641
2017 Genetic Features of MAPT, GRN, C9orf72 and CHCHD10 Gene Mutations in Chinese Patients with Frontotemporal Dementia. Current Alzheimer research 31 28462717
2016 MicroRNA-588 suppresses tumor cell migration and invasion by targeting GRN in lung squamous cell carcinoma. Molecular medicine reports 31 27571908
2021 PGRN exacerbates the progression of non-small cell lung cancer via PI3K/AKT/Bcl-2 antiapoptotic signaling. Genes & diseases 30 36157487
2019 Induction of PGRN by influenza virus inhibits the antiviral immune responses through downregulation of type I interferons signaling. PLoS pathogens 29 31585000
2018 Targeting Tyro3 ameliorates a model of PGRN-mutant FTLD-TDP via tau-mediated synaptic pathology. Nature communications 27 29382817
2017 Modifiers of GRN-Associated Frontotemporal Lobar Degeneration. Trends in molecular medicine 27 28890134
2020 Premature termination codon readthrough upregulates progranulin expression and improves lysosomal function in preclinical models of GRN deficiency. Molecular neurodegeneration 26 32178712
2020 A GRN Autocrine-Dependent FAM135B/AKT/mTOR Feedforward Loop Promotes Esophageal Squamous Cell Carcinoma Progression. Cancer research 26 33323378
2011 Expression, refolding and purification of Ov-GRN-1, a granulin-like growth factor from the carcinogenic liver fluke, that causes proliferation of mammalian host cells. Protein expression and purification 25 21757010
2016 GRN and MAPT Mutations in 2 Frontotemporal Dementia Research Centers in Brazil. Alzheimer disease and associated disorders 24 27082848
2022 Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia. Acta neuropathologica communications 23 35799292
2022 Knockout of liver fluke granulin, Ov-grn-1, impedes malignant transformation during chronic infection with Opisthorchis viverrini. PLoS pathogens 23 36137145
2015 Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner. Cell cycle (Georgetown, Tex.) 23 26039714
2013 PGRN haploinsufficiency increased Wnt5a signaling in peripheral cells from frontotemporal lobar degeneration-progranulin mutation carriers. Neurobiology of aging 23 24139281
2021 Neuropathological and behavioral characterization of aged Grn R493X progranulin-deficient frontotemporal dementia knockin mice. Acta neuropathologica communications 22 33795008
2015 The Role of PGRN in Alzheimer's Disease. Molecular neurobiology 22 26215834
2011 Alteration in cell cycle-related proteins in lymphoblasts from carriers of the c.709-1G>A PGRN mutation associated with FTLD-TDP dementia. Neurobiology of aging 22 21232819
2021 Circ_GRN Promotes the Proliferation, Migration, and Inflammation of Vascular Smooth Muscle Cells in Atherosclerosis Through miR-214-3p/FOXO1 Axis. Journal of cardiovascular pharmacology 21 33818550
2024 GRouNdGAN: GRN-guided simulation of single-cell RNA-seq data using causal generative adversarial networks. Nature communications 20 38744843
2022 GRN Mutations Are Associated with Lewy Body Dementia. Movement disorders : official journal of the Movement Disorder Society 20 35810449
2018 Using ATAC-seq and RNA-seq to increase resolution in GRN connectivity. Methods in cell biology 20 30948003
2022 Shared brain transcriptomic signature in TDP-43 type A FTLD patients with or without GRN mutations. Brain : a journal of neurology 19 34918030
2023 The Role of Progranulin (PGRN) in the Pathogenesis of Ischemic Stroke. Cellular and molecular neurobiology 17 37561339
2020 PGRN exerts inflammatory effects via SIRT1-NF-κB in adipose insulin resistance. Journal of molecular endocrinology 17 31990656
2024 A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors. Alzheimer's research & therapy 16 38539243
2020 Isolated parkinsonism is an atypical presentation of GRN and C9orf72 gene mutations. Parkinsonism & related disorders 16 32961397
2020 GRN, NOTCH3, FN1, and PINK1 expression in eutopic endometrium - potential biomarkers in the detection of endometriosis - a pilot study. Journal of assisted reproduction and genetics 16 33029756
2020 Repressor Element 1 Silencing Transcription Factor (REST) Governs Microglia-Like BV2 Cell Migration via Progranulin (PGRN). Neural plasticity 16 33299399
2019 The role of progranulin (PGRN) in the modulation of anti-inflammatory response in asthma. Central-European journal of immunology 16 31114443
2017 C5a/C5aR pathway accelerates renal ischemia-reperfusion injury by downregulating PGRN expression. International immunopharmacology 16 29031143
2021 Elevated serum and urine levels of progranulin (PGRN) as a predictor of microglia activation in the early phase of traumatic brain injury: a further link with the development of neurodegenerative diseases. Folia neuropathologica 15 33969679
2021 Parkin Levels Decrease in Fibroblasts With Progranulin (PGRN) Pathogenic Variants and in a Cellular Model of PGRN Deficiency. Frontiers in molecular neuroscience 15 34054428
2017 Increased expression of PGRN protein in follicular fluid and mRNA in granulosa cells in overweight patients with polycystic ovary syndrome. European journal of obstetrics, gynecology, and reproductive biology 15 28964971
2016 Identification of biological pathways regulated by PGRN and GRN peptide treatments using transcriptome analysis. The European journal of neuroscience 15 27307215
2022 PGRN deficiency exacerbates, whereas a brain penetrant PGRN derivative protects, GBA1 mutation-associated pathologies and diseases. Proceedings of the National Academy of Sciences of the United States of America 14 36574647
2019 Interaction between PGRN gene and the early trauma on clinical characteristics in patients with obsessive-compulsive disorder. Journal of affective disorders 14 31818769
2019 Trajectory of lobar atrophy in asymptomatic and symptomatic GRN mutation carriers: a longitudinal MRI study. Neurobiology of aging 14 31918955
2024 Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver. Cell reports 13 38935501
2023 Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation. The Journal of biological chemistry 13 37981208
2021 CSF sTREM2 is elevated in a subset in GRN-related frontotemporal dementia. Neurobiology of aging 13 33896652
2020 Elevated levels of extracellular vesicles in progranulin-deficient mice and FTD-GRN Patients. Annals of clinical and translational neurology 13 33197149
2018 Thyrotropin Regulates eNOS Expression in the Endothelium by PGRN Through Akt Pathway. Frontiers in endocrinology 13 30026730
2024 PMF-GRN: a variational inference approach to single-cell gene regulatory network inference using probabilistic matrix factorization. Genome biology 12 38589899
2023 Plasma lysosphingolipids in GRN-related diseases: Monitoring lysosomal dysfunction to track disease progression. Neurobiology of disease 12 37003407
2022 MicroRNA-1246 suppresses the metastasis of breast cancer cells by targeting the DYRK1A/PGRN axis to prevent the epithelial-mesenchymal transition. Molecular biology reports 12 35059968
2021 Inference of dynamic spatial GRN models with multi-GPU evolutionary computation. Briefings in bioinformatics 12 33834216
2017 A novel frameshift GRN mutation results in frontotemporal lobar degeneration with a distinct clinical phenotype in two siblings: case report and literature review. BMC neurology 12 28915852
2024 The Role of Progranulin (PGRN) in the Pathogenesis of Glioblastoma Multiforme. Cells 11 38247816
2022 Application Value of Serum TK1 and PCDGF, CYFRA21-1, NSE, and CEA plus Enhanced CT Scan in the Diagnosis of Nonsmall Cell Lung Cancer and Chemotherapy Monitoring. Journal of oncology 11 35368891
2019 FTLD-TDP With and Without GRN Mutations Cause Different Patterns of CA1 Pathology. Journal of neuropathology and experimental neurology 11 31361008
2018 Extended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one family. Alzheimer's research & therapy 11 29370838
2018 Reduction of PGRN increased fibrosis during skin wound healing in mice. Histology and histopathology 11 30561754

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