Affinage

NELL1

Protein kinase C-binding protein NELL1 · UniProt Q92832

Length
810 aa
Mass
89.6 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 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

NELL1 is a secreted homotrimeric, heparin-binding glycoprotein that acts as an osteoinductive signaling molecule controlling skeletal cell fate during both intramembranous and endochondral ossification (PMID:10548494, PMID:16537572). Its expression is restricted to neural tissue and osteogenic fronts, where it is concentrated in mesenchymal/osteoblast lineages at cranial sutures (PMID:9893069). NELL1 sits downstream of the master osteoblast transcription factor axis: Runx2 directly binds OSE2 elements in the NELL1 promoter to activate transcription, while Osterix represses it through Sp1 sites, placing NELL1 under bidirectional transcriptional control (PMID:17042739, PMID:21931789). Gain- and loss-of-function mouse models establish that NELL1 dosage is sufficient and required for normal skeletogenesis, with overexpression driving craniosynostosis-like phenotypes and accelerated osteoblast differentiation and deficiency producing cranial and vertebral defects (PMID:12235118, PMID:16537572). Functionally, NELL1 engages cell-surface receptors—integrin β1 and integrin α3β1—to nucleate focal adhesions and activate FAK, and signals through MAPK (ERK1/2, JNK1) cascades that feed back to phosphorylate Runx2, while sparing the Smad pathway used by BMP2 (PMID:22807400, PMID:20939017, PMID:22728432, PMID:18082140). Downstream of receptor engagement, NELL1 promotes Wnt/β-catenin signaling to expand osteogenic progenitors and tip the osteoblast:osteoclast balance toward bone formation, with haploinsufficient mice developing age-related osteoporosis (PMID:26082355, PMID:28614787). NELL1 also acts as a checkpoint between lineages: it inhibits adipogenesis through Hedgehog signaling and, in chondrocytes, induces Nfatc2 in a Runx2-dependent manner and modulates the Ihh–PTHrP feedback loop to govern chondrocyte proliferation and differentiation (PMID:21723263, PMID:21611965, PMID:30352124). Adhesive activity requires cysteine-dependent oligomerization, and proteoglycan binding is mediated by heparin-binding sites in the N-terminal TSPN domain (PMID:24563467, PMID:26627376). Beyond skeletal biology, NELL1 is a glomerular target autoantigen in membranous nephropathy, where patient IgG co-localizes with NELL1 along the glomerular basement membrane (PMID:31901340), and in osteosarcoma NELL1 shapes the matricellular environment to sustain FAK-dependent invasion (PMID:35700263).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 Medium

    Established NELL1's molecular nature—answering what kind of protein it is—by showing it is a secreted, homotrimeric, heparin-binding glycoprotein built from TSPN, von Willebrand C, and EGF-like modules expressed selectively in neural and cranial osteogenic tissue.

    Evidence Recombinant expression in COS-7 cells with biochemical characterization, plus in situ hybridization/Northern/RT-PCR across human and rat tissues

    PMID:10548494 PMID:9893069

    Open questions at the time
    • No receptor or signaling pathway identified at this stage
    • Functional consequence of secretion not tested
  2. 2002 High

    Demonstrated NELL1 is a functional regulator of osteoblast differentiation in vivo, resolving whether its restricted expression was causal—transgenic overexpression drives craniosynostosis and accelerated mineralization while knockdown blocks differentiation.

    Evidence Transgenic mouse overexpression and in vitro calvarial osteoblast culture with overexpression/knockdown, histology and ALP assays

    PMID:12235118

    Open questions at the time
    • Signaling mechanism and receptor unknown
    • Did not distinguish direct osteoinduction from apoptosis-mediated remodeling
  3. 2006 High

    Defined NELL1's requirement and apoptotic activity in skeletal patterning—loss-of-function causes cranial/vertebral defects with reduced ECM gene expression, while excess NELL1 triggers Fas/Fas-L-dependent apoptosis of osteoblasts and chondrocytes.

    Evidence ENU-induced truncation mouse, positional cloning, qRT-PCR of 219 genes, transgenic embryo apoptosis analysis with Fas/Fas-L immunostaining

    PMID:14672347 PMID:16537572 PMID:16652108

    Open questions at the time
    • Direct molecular target driving ECM gene changes not identified
    • Apoptotic mechanism cell-type specificity not fully explained
  4. 2007 High

    Placed NELL1 within the osteoblast transcriptional hierarchy and its proximal signaling output—Runx2 directly transactivates NELL1, and NELL1 in turn activates MAPK and phosphorylates Runx2 without engaging Smad, distinguishing it from BMP2.

    Evidence Promoter-luciferase, EMSA, ChIP, rescue in Runx2-null cells; in vitro MAPK and Smad signaling assays with recombinant NELL1; C2C12 synergy with BMP2

    PMID:17042739 PMID:17352654 PMID:18082140

    Open questions at the time
    • Cell-surface receptor mediating MAPK activation not yet identified
    • Mechanism of Runx2 phosphorylation feedback unresolved
  5. 2011 High

    Identified NELL1 cell-surface receptors and downstream effectors, answering how the secreted protein transduces signal—it binds integrin β1, activates ERK1/2 and JNK1 to phosphorylate Runx2, is repressed by Osterix, and induces chondrocyte Nfatc2 in a Runx2-dependent manner.

    Evidence Co-IP and siRNA for integrin β1; genetic epistasis in Runx2+/- and Nell1-/- mice; Osterix promoter ChIP/EMSA/siRNA; microarray with Nfatc2 siRNA rescue and APR3 biopanning

    PMID:20939017 PMID:21611965 PMID:21723284 PMID:21931789 PMID:22807400

    Open questions at the time
    • Whether integrin β1 is the sole or primary receptor unresolved
    • Structural basis of receptor engagement unknown
  6. 2012 Medium

    Resolved the adhesion receptor and lineage-balancing functions—NELL1's C-terminus mediates adhesion through integrin α3β1 with FAK activation, it activates phosphate transporters Pit1/Pit2 distinct from BMP2, and inhibits adipogenesis via Hedgehog signaling.

    Evidence Domain-mapping deletion proteins and α3/β1 blocking antibodies with FAK assay; Pi influx with Pit-1/Pit-2 neutralizing antibodies; Cyclopamine reversal in adipose-derived stromal cells

    PMID:21723263 PMID:22580275 PMID:22728432

    Open questions at the time
    • Relationship between integrin α3β1 and β1 receptor reports not reconciled
    • Direct Hedgehog ligand interaction not tested
  7. 2014 High

    Defined the structural requirement for NELL1 adhesion—cysteine-dependent oligomerization producing a conformational change in the C-terminal cysteine-rich region is essential, and TSPN heparin-binding sites mediate proteoglycan engagement.

    Evidence Systematic deletion/cysteine-to-serine mutagenesis with reducing-agent and adhesion assays; TSPN domain heparin-binding site mutagenesis guided by 3D modeling

    PMID:24563467 PMID:26627376

    Open questions at the time
    • No experimental atomic structure of full-length oligomer
    • How oligomerization couples to receptor activation not shown
  8. 2015 High

    Linked NELL1 receptor binding to Wnt/β-catenin output and systemic bone homeostasis—integrin β1 binding induces Wnt/β-catenin signaling that favors osteoblasts over osteoclasts, with haploinsufficiency causing osteoporosis.

    Evidence Recombinant integrin β1 binding and Wnt/β-catenin analysis, Nell1 haploinsufficient mouse, systemic delivery in osteoporotic mice and sheep

    PMID:26082355

    Open questions at the time
    • Mechanistic link from integrin engagement to Wnt activation not detailed
    • Receptor for Wnt induction versus adhesion not separated
  9. 2017 Medium

    Connected NELL1 to progenitor pool expansion—NELL1 induces Sca-1 in mesenchymal progenitors through Wnt/β-catenin, and dosage controls the marrow MPC population.

    Evidence Haploinsufficient mouse flow cytometry, systemic rhNELL-1, Wnt/β-catenin inhibition, nonhuman primate spinal fusion

    PMID:28614787

    Open questions at the time
    • Direct transcriptional mechanism of Sca-1 induction unknown
    • Receptor mediating progenitor effect not identified
  10. 2018 High

    Established the chondrocyte-autonomous role of NELL1 in endochondral ossification—conditional deletion in cartilage impairs skeletogenesis via the Ihh–PTHrP feedback loop, with rescue blocked by Ihh inhibitors; NELL1 also signals through MAPK/ERK on osteogenic surfaces.

    Evidence Col2α1-Cre conditional knockout with micro-CT/histomorphometry and Ihh/PTHrP immunostaining, Ihh inhibitor rescue; ERK inhibitor U0126 blockade on Ti surfaces; Nell-1-ΔE/ENO-1 Co-IP/MS

    PMID:29388706 PMID:30352124 PMID:30359975

    Open questions at the time
    • How NELL1 engages the Ihh pathway molecularly unresolved
    • Function of the ΔE splice variant/ENO-1 axis in vivo unknown
  11. 2019 High

    Extended NELL1 to neural crest skeletogenesis, a candidate osteogenic receptor, autoimmune kidney disease, and tumor suppression—Wnt1-lineage deletion causes craniofacial defects via reduced β-catenin, Cntnap4 was named as an osteogenic receptor, NELL1 is a membranous nephropathy autoantigen, and it restrains lung cancer stem-like cells.

    Evidence Wnt1-Cre conditional knockout with lineage tracing and protein rescue; review citation of Cntnap4; glomerular mass spectrometry/IHC/serology; NELL1 overexpression in lung cancer stem-like cells with pathway markers

    PMID:30628703 PMID:31582804 PMID:31610747 PMID:31901340

    Open questions at the time
    • Cntnap4 receptor claim is review-level, lacking primary detail (Low confidence)
    • Lung cancer c-MET-Notch link lacks inhibitor/rescue validation (Low confidence)
    • Mechanism converting NELL1 from skeletal factor to glomerular autoantigen unknown
  12. 2022 High

    Revealed a context-dependent oncogenic role—in osteosarcoma NELL1 sustains invasion and FAK signaling by shaping the matricellular environment, with ECM rescue restoring the phenotype.

    Evidence Genetic deletion in human OS lines, xenograft and p53/Rb-driven sarcoma conditional knockout, transcriptomics/phosphoproteomics, matricellular ECM rescue

    PMID:35700263

    Open questions at the time
    • Receptor mediating OS FAK signaling not specified
    • Reconciliation of tumor-suppressive versus pro-invasive roles across cancers unresolved
  13. 2024 Medium

    Identified an immunomodulatory function—NELL1 drives macrophage M1-to-M2 polarization through JNK/MAPK signaling, linking it to resolution of inflammation in bone-associated tissue.

    Evidence LPS-stimulated RAW 264.7 macrophages with JNK inhibitor SP600125 blockade, flow cytometry, plus rat periodontitis model

    PMID:38908089

    Open questions at the time
    • Receptor on macrophages not identified
    • Single cell-line context for the polarization mechanism

Open questions

Synthesis pass · forward-looking unresolved questions
  • The unifying receptor logic remains open: how NELL1 reconciles integrin β1, integrin α3β1, and the proposed Cntnap4 into a coherent receptor system, and how the same molecule acts as osteoinductive factor, lineage gatekeeper, autoantigen, and context-dependent tumor modulator.
  • No structural model of receptor-bound NELL1
  • No single study reconciles divergent receptor identifications
  • Mechanism of autoantigen exposure in membranous nephropathy uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 3 GO:0008289 lipid binding 2
Localization
GO:0005576 extracellular region 3 GO:0005829 cytosol 1 GO:0031012 extracellular matrix 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-168256 Immune System 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
APR3CNTNAP4ENO1ITGA3ITGB1RUNX2SP7

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 NELL1 and NELL2 proteins expressed in COS-7 cells are homotrimeric glycoproteins with heparin-binding activity, contain an N-terminal thrombospondin-1-like module, five von Willebrand factor C domains, and six EGF-like domains, and are partially secreted into culture medium while showing distinct subcellular cytoplasmic localization. Recombinant protein expression in COS-7 cells, biochemical characterization (heparin-binding assay, glycoprotein analysis) Biochemical and biophysical research communications Medium 10548494
1999 NELL1 mRNA is specifically expressed in neural tissue and in mesenchymal cells/osteoblasts at osteogenic fronts of prematurely fusing cranial sutures, and is upregulated in unilateral coronal synostosis; its expression is largely absent in tibiae and fibroblast cultures but present in rat calvarial osteoprogenitor cells. In situ hybridization, Northern blot (multiorgan tissue mRNA blot), RT-PCR in rat calvarial cells Journal of bone and mineral research Medium 9893069
2002 Overexpression of Nell-1 in transgenic mice is sufficient to induce craniosynostosis-like phenotypes, accelerate calvarial osteoblast differentiation and mineralization, and promote alkaline phosphatase expression and micronodule formation in vitro; conversely, Nell-1 downregulation inhibits osteoblast differentiation in vitro. Transgenic mouse overexpression model, in vitro calvarial osteoblast culture with Nell-1 overexpression/knockdown, histology, alkaline phosphatase assay The Journal of clinical investigation High 12235118
2003 Overexpression of Nell-1 induces apoptosis specifically in osteoblastic cells (not in NIH3T3 fibroblasts), associated with modulation of apoptosis-related genes; the craniosynostosis mouse model overexpressing Nell-1 showed increased apoptosis in calvaria. Viral transduction, recombinant protein treatment, apoptosis assays, gene expression analysis in osteoblastic cells and primary fibroblasts, in vivo mouse model Journal of bone and mineral research Medium 14672347
2006 Nell-1 deficiency (ENU-induced Cys502Ter truncation) in mice results in cranial and vertebral skeletal defects and is associated with reduced expression of extracellular matrix genes critical for chondrogenesis and osteogenesis, revealing a role for Nell1 in signal transduction in both intramembranous and endochondral ossification. ENU mutagenesis, positional cloning, real-time quantitative RT-PCR of 219 genes, skeletal phenotyping Human molecular genetics High 16537572
2006 Nell-1 overexpression during embryonic development induces acrania via massive apoptosis in calvarial osteoblasts and neural cells, associated with increased Fas and Fas-L production; transgenic mice also showed premature hypertrophy and increased apoptosis of chondrocytes. Transgenic mouse embryo analysis, apoptosis assays, immunostaining for Fas/Fas-L, in vitro primary chondrocyte AdNell-1 transduction Laboratory investigation Medium 16652108
2007 NELL1 protein transiently activates the MAPK signaling cascade, induces phosphorylation of Runx2, and promotes rapid intracellular accumulation of Tyr-phosphorylated proteins in osteoblastic cells; unlike BMP2, NELL1 does not activate the Smad signaling cascade. In vitro signaling assays (MAPK activation, phospho-protein analysis, Smad pathway assay) in osteoblastic cells treated with recombinant NELL1 protein FEBS letters Medium 18082140
2007 Runx2 directly binds to three OSE2 elements in the NELL-1 promoter and transactivates NELL-1 expression; forced Runx2 expression induces NELL-1 in rat calvarial cells and rescues NELL-1 expression in Runx2-null calvarial cells. Promoter-luciferase reporter assays, gel shift/supershift with Runx2 antibodies, ChIP assay, site-directed mutagenesis, RT-PCR in Runx2 null cells Journal of bone and mineral research High 17042739
2007 Nell-1 and BMP-2 synergistically enhance osteogenic differentiation of C2C12 myoblasts and activate the JNK MAPK pathway; Nell-1 alone does not induce osteogenic differentiation of myoblasts, demonstrating osteochondral lineage specificity. Adenoviral transduction of C2C12 myoblasts, alkaline phosphatase activity, osteopontin production, MAPK signaling analysis (JNK, p38, ERK1/2), nude mouse muscle injection model Journal of bone and mineral research Medium 17352654
2011 NELL-1 directly binds to extracellular Integrinβ1, induces focal adhesion, and promotes cell adherence; siRNA knockdown of Integrinβ1 abolishes NELL-1-mediated cell surface binding and enhanced cell attachment. Co-immunoprecipitation (NELL-1 binding to Integrinβ1), siRNA knockdown, cell adhesion assays in multiple cell lines, PLGA scaffold pre-coating experiments Journal of cellular biochemistry Medium 22807400
2011 NELL-1 is a direct transcriptional target of Osterix, which suppresses NELL-1 expression by binding to Sp1 sites in the NELL-1 promoter; knockdown of Osterix increases NELL-1 transcription and osteoblastic differentiation. Promoter-luciferase reporter assays, site-directed mutagenesis (Sp1 sites), EMSA, ChIP assay in Saos-2 cells and primary human osteoblasts, siRNA knockdown of Osterix PloS one High 21931789
2011 Nell-1 is a critical downstream mediator of Runx2: Nell-1 signaling activates ERK1/2 and JNK1 MAPK pathways and enhances Runx2 phosphorylation; genetic rescue experiments showed Nell-1 can partially rescue calvarial defects in Runx2 haploinsufficient mice, but requires at least one Runx2 allele for mineralization. CMV-Nell-1 × Runx2+/- cross-mating, siRNA knockdown of Nell-1, ENU-induced Nell-1-/- calvarial cells, MAPK pathway analysis, calvarial explant bone formation assays Journal of bone and mineral research High 20939017
2011 Nfatc2 is a primary response gene of Nell-1 in chondrocytes; Nell-1 transiently induces Nfatc2 transcription and translation through a Runx2-dependent mechanism, and siRNA knockdown of Nfatc2 reverses Nell-1's inhibitory effects on chondrocyte differentiation. Microarray screen, real-time PCR validation, dominant-negative Runx2 adenoviral transduction, siRNA knockdown of Nfatc2, ATDC5 and primary mouse chondrocyte assays, immunohistochemistry in wild-type and Nell1-deficient mouse femurs Journal of bone and mineral research High 21611965
2011 NELL-1 binds to APR3 (apoptosis related protein 3), a membrane proliferation suppressor; NELL-1 and APR3 co-localize on the nuclear envelope of human osteoblasts, and NELL-1 inhibits osteoblast proliferation via APR3 through down-regulation of Cyclin D1; RNAi of APR3 significantly reduces the differentiation effect of NELL-1. Biopanning for NELL-1 binding proteins, co-localization (immunofluorescence), co-transfection experiments, RNAi of APR3, osteogenic differentiation and proliferation assays FEBS letters Medium 21723284
2012 The C-terminal region of NELL1 mediates osteoblastic cell adhesion through integrin α3β1; function-blocking antibodies against integrin α3 and β1 subunits strongly inhibit cell adhesion to NELL1, and focal adhesion kinase (FAK) activation is involved in NELL1 signaling. Series of recombinant NELL1 deletion and domain-mapping proteins, function-blocking antibody experiments, FAK activation assay FEBS letters Medium 22728432
2014 NELL1-mediated cell adhesion and spreading requires oligomerization: a cysteine-to-serine mutant NELL1 that cannot form homo-oligomers shows substantially lower cell adhesion activity; an oligomerization-induced conformational change in the C-terminal cysteine-rich region is critical for NELL1 adhesive function. Recombinant NELL1 proteins (intact, deleted, cysteine-mutant), reducing agent treatment, site-directed cysteine-to-serine mutagenesis at coiled-coil domain, cell adhesion assays The Journal of biological chemistry High 24563467
2015 NELL1 binds to cell surface proteoglycans through its N-terminal thrombospondin-1-like (TSPN) domain; mutational analysis of predicted heparin-binding sites on a 3D structural model of the TSPN domain confirmed that heparin-binding activity of this domain mediates interaction with cell surface proteoglycans. Site-directed mutagenesis of TSPN domain heparin-binding sites, 3D structural modeling, cell surface proteoglycan binding assays FEBS letters Medium 26627376
2015 Recombinant NELL-1 binds to integrin β1 and induces Wnt/β-catenin signaling, which is associated with increased osteoblast differentiation and inhibition of osteoclast-directed bone resorption; Nell-1-haploinsufficient mice develop age-related osteoporosis with a reduced osteoblast:osteoclast ratio. Recombinant protein binding assay (integrin β1), Wnt/β-catenin signaling analysis, Nell-1 haploinsufficient mouse model, systemic NELL-1 delivery in gonadectomy-induced osteoporotic mice and sheep Nature communications High 26082355
2012 NELL-1 increases pre-osteoblast mineralization through activation of both phosphate transporter Pit1 and Pit2; neutralizing antibodies against Pit-1 and Pit-2 completely abrogate NELL-1-induced Pi influx, distinguishing NELL-1 from BMP-2 which uses only Pit-1. Recombinant NELL-1 and BMP-2 treatment of MC3T3-E1 pre-osteoblasts, intracellular Pi quantification (malachite green), Pit-1/Pit-2 expression analysis, neutralizing antibodies Biochemical and biophysical research communications Medium 22580275
2013 NELL-1 suppresses BMP2-induced NF-κB transcriptional activity and generation of reactive oxygen species (ROS) in fibroblasts, attenuating BMP2-induced inflammation (TNFα, IL6) both locally and systemically in rats. In vivo rat femoral bone onlay with histology, immunohistochemistry, real-time PCR, ELISA for TNFα/IL6; in vitro NIH3T3 cell assays for NF-κB activity and ROS Tissue engineering. Part A Medium 23758588
2017 NELL-1 induces Sca-1 transcription in mesenchymal progenitor cells (MPCs) in a process requiring intact Wnt/β-catenin signaling; Nell-1 haploinsufficiency reduces Sca-1+CD45-CD31- bone marrow MPCs, while systemic rhNELL-1 administration increases this population. Nell-1 haploinsufficient mouse analysis (flow cytometry), systemic rhNELL-1 administration, Wnt/β-catenin pathway inhibition, nonhuman primate spinal fusion model JCI insight Medium 28614787
2018 Chondrocyte-specific inactivation of Nell-1 (Col2α1-Cre) impedes appendicular skeletogenesis and osteoporosis through inhibition of Ihh signaling and alteration of the Ihh-PTHrP feedback loop; exogenous Nell-1 protein partially rescues decreased proliferation/differentiation of Nell-1-deficient chondrocytes, and this rescue is diminished by Ihh signaling inhibitors (cyclopamine or GANT61). Conditional knockout mice (Nell-1flox/flox; Col2α1-Cre+), micro-CT, histomorphometry, immunohistochemistry (Ihh, Patched-1, PTHrP, PTHrP receptor, Gli-1), Ihh inhibitor rescue experiments Journal of bone and mineral research High 30352124
2019 Neural crest cell (Wnt1 lineage)-specific Nell-1 inactivation causes frontonasal and mandibular bone defects with decreased Wnt/β-catenin markers; Nell-1-deficient cranial neural crest cells (CNCCs) show reduced proliferation and osteogenic differentiation, and exogenous Nell-1 rescues active-β-catenin levels and osteogenic capacity. Nell-1flox/flox; Wnt1-Cre conditional knockout mice, lineage tracing, immunostaining (Osteocalcin, active-β-catenin), primary CNCC culture with Nell-1 protein rescue Cell death and differentiation High 31582804
2019 A specific receptor for NELL-1 in osteogenesis was identified as contactin-associated protein-like 4 (Cntnap4); NELL-1 signaling involves MAPK and Wnt/β-catenin pathways with key regulatory roles for Runx2. Cited in review as identified receptor (Cntnap4 for osteogenesis); supporting MAPK and Wnt/β-catenin pathway data from referenced primary studies Journal of dental research Low 31610747
2012 NELL-1 inhibits adipogenic differentiation and increases expression of Hedgehog signaling markers (Ihh, Gli1, Ptc1); co-application of the Smoothened antagonist Cyclopamine reverses the pro-osteogenic effect of NELL-1, indicating NELL-1's anti-adipogenic effect is partly Hedgehog-dependent. Adenoviral NELL-1 delivery and recombinant NELL-1 protein in 3T3-L1 and human adipose-derived stromal cells, hedgehog pathway inhibitor (Cyclopamine) blockade, oil red O staining, gene expression Biochemical and biophysical research communications Medium 21723263
2018 Nell-1 enhances osteogenic differentiation of pre-osteoblasts on titanium surfaces via activation of MAPK/ERK (and JNK) signaling; ERK inhibitor U0126 suppresses the promotive effect of Nell-1 on most osteogenic markers. Recombinant Nell-1 treatment of MC3T3-E1 on Ti surfaces, Western blot for MAPK pathway, ERK inhibitor U0126 blockade, ALP assay, ELISA, RT-PCR Cellular physiology and biochemistry Medium 30359975
2018 A novel NELL-1 transcript (Nell-1-ΔE) lacking one EGF-like domain, but not full-length Nell-1, inhibits cell migration by interacting with enolase-1 (ENO-1) in the extracellular space; this interaction was confirmed by co-immunoprecipitation and LC/MS-MS. Homology modeling, recombinant protein production, Co-IP/LC-MS-MS identification of ENO-1 as Nell-1-ΔE binding partner, wound healing assay in ENO-1-overexpressing cells Journal of cellular biochemistry Medium 29388706
2022 Genetic deletion of NELL1 in osteosarcoma cell lines reduces invasive behavior and FAK signaling; transcriptomic and phosphoproteomic analyses show NELL1 loss skews matricellular protein expression; culturing NELL1-knockout sarcoma cells on wild-type OS-enriched matricellular proteins reverses the phenotypic and signaling changes. NELL1 genetic deletion in human OS cell lines, xenograft mouse model, conditional Nell1 knockout in p53/Rb-driven sarcomagenesis mouse model, transcriptomics, phosphoproteomics, ECM rescue experiment Cancer research High 35700263
2024 Nell-1 promotes macrophage polarization from M1 to M2 phenotype through the JNK/MAPK signaling pathway; JNK inhibitor SP600125 reverses Nell-1's effect on macrophage polarization in LPS-stimulated RAW 264.7 cells. LPS-stimulated RAW 264.7 macrophages treated with Nell-1 protein, JNK inhibitor SP600125 blockade, RT-PCR, Western blot, flow cytometry for M1/M2 markers; rat ligation-induced periodontitis model International immunopharmacology Medium 38908089
2019 NELL1 reduces colony formation, invasion, and chemotherapeutic resistance of lung cancer stem-like cells, associated with reduced phospho-MET, Notch3, and HES1 expression, suggesting NELL1 induces differentiation by inhibiting c-MET-Notch signaling. NELL1 overexpression in 95-D lung cancer stem-like cells, soft agar colony formation, invasion assay, cell proliferation assay with carboplatin/cisplatin, Western blot for p-MET/Notch3/HES1 Oncology reports Low 30628703
2019 NELL1 is expressed in glomeruli and detected as a target antigen in membranous nephropathy; IgG co-localizes with NELL1 along the glomerular basement membrane, and patients have serum anti-NELL1 antibodies reactive by Western blot. Laser microdissection/mass spectrometry of glomeruli, immunohistochemistry, confocal microscopy co-localization, Western blot with patient sera Kidney international High 31901340

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy. Kidney international 275 31901340
2020 NELL1 is a target antigen in malignancy-associated membranous nephropathy. Kidney international 146 32828756
1999 Human NELL-1 expressed in unilateral coronal synostosis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 145 9893069
2002 Craniosynostosis in transgenic mice overexpressing Nell-1. The Journal of clinical investigation 130 12235118
1999 Biochemical characterization and expression analysis of neural thrombospondin-1-like proteins NELL1 and NELL2. Biochemical and biophysical research communications 119 10548494
1996 Cloning and characterization of two novel human cDNAs (NELL1 and NELL2) encoding proteins with six EGF-like repeats. Genomics 117 8975702
2007 Systematic association mapping identifies NELL1 as a novel IBD disease gene. PloS one 106 17684544
2010 The role of NELL-1, a growth factor associated with craniosynostosis, in promoting bone regeneration. Journal of dental research 105 20647499
2015 NELL-1 in the treatment of osteoporotic bone loss. Nature communications 99 26082355
2006 Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects. Human molecular genetics 97 16537572
2006 The osteoinductive properties of Nell-1 in a rat spinal fusion model. The spine journal : official journal of the North American Spine Society 87 17197333
2011 Nell-1, a key functional mediator of Runx2, partially rescues calvarial defects in Runx2(+/-) mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 79 20939017
2012 Additive effects of sonic hedgehog and Nell-1 signaling in osteogenic versus adipogenic differentiation of human adipose-derived stromal cells. Stem cells and development 77 22264144
2007 A study of the role of nell-1 gene modified goat bone marrow stromal cells in promoting new bone formation. Molecular therapy : the journal of the American Society of Gene Therapy 76 17653100
2013 BMP2-induced inflammation can be suppressed by the osteoinductive growth factor NELL-1. Tissue engineering. Part A 68 23758588
2007 Synergistic effects of Nell-1 and BMP-2 on the osteogenic differentiation of myoblasts. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 67 17352654
2007 Involvement of MAPK signaling molecules and Runx2 in the NELL1-induced osteoblastic differentiation. FEBS letters 67 18082140
2011 Nell-1 protein promotes bone formation in a sheep spinal fusion model. Tissue engineering. Part A 64 21128865
2007 Craniosynostosis-associated gene nell-1 is regulated by runx2. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 62 17042739
2011 Nell-1 enhances bone regeneration in a rat critical-sized femoral segmental defect model. Plastic and reconstructive surgery 55 21285762
2011 The Nell-1 growth factor stimulates bone formation by purified human perivascular cells. Tissue engineering. Part A 54 21615216
2011 A new function of Nell-1 protein in repressing adipogenic differentiation. Biochemical and biophysical research communications 53 21723263
2010 Delivery of lyophilized Nell-1 in a rat spinal fusion model. Tissue engineering. Part A 52 20528102
2003 Overexpression of Nell-1, a craniosynostosis-associated gene, induces apoptosis in osteoblasts during craniofacial development. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 48 14672347
2017 NEL-Like Molecule-1 (Nell1) Is Regulated by Bone Morphogenetic Protein 9 (BMP9) and Potentiates BMP9-Induced Osteogenic Differentiation at the Expense of Adipogenesis in Mesenchymal Stem Cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 47 28214873
2011 NELL-1 promotes cartilage regeneration in an in vivo rabbit model. Tissue engineering. Part A 42 21902605
2012 NELL-1 promotes cell adhesion and differentiation via Integrinβ1. Journal of cellular biochemistry 40 22807400
2022 Runx2 and Nell-1 in dental follicle progenitor cells regulate bone remodeling and tooth eruption. Stem cell research & therapy 39 36175952
2010 Effect of Nell-1 delivery on chondrocyte proliferation and cartilaginous extracellular matrix deposition. Tissue engineering. Part A 39 20028218
2012 NELL-1 increases pre-osteoblast mineralization using both phosphate transporter Pit1 and Pit2. Biochemical and biophysical research communications 38 22580275
2010 The effect of NELL1 and bone morphogenetic protein-2 on calvarial bone regeneration. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 38 20116699
2019 Nell-1 Is a Key Functional Modulator in Osteochondrogenesis and Beyond. Journal of dental research 36 31610747
2015 Expression and regulatory effects on cancer cell behavior of NELL1 and NELL2 in human renal cell carcinoma. Cancer science 36 25726761
2022 The Many Faces of NELL1 MN. Clinical kidney journal 35 36865014
2011 NELL-1 binds to APR3 affecting human osteoblast proliferation and differentiation. FEBS letters 34 21723284
2011 Nfatc2 is a primary response gene of Nell-1 regulating chondrogenesis in ATDC5 cells. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 33 21611965
2013 NELL-1 based demineralized bone graft promotes rat spine fusion as compared to commercially available BMP-2 product. Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 31 23686083
2010 NELL1 promotes high-quality bone regeneration in rat femoral distraction osteogenesis model. Bone 31 20959151
2011 Combined effects of recombinant human BMP-2 and Nell-1 on bone regeneration in rapid distraction osteogenesis of rabbit tibia. Injury 30 21703614
2017 Neural EGF-like protein 1 (NELL-1): Signaling crosstalk in mesenchymal stem cells and applications in regenerative medicine. Genes & diseases 28 29276737
1999 The neuronal EGF-related genes NELL1 and NELL2 are expressed in hemopoietic cells and developmentally regulated in the B lineage. Gene 28 10231576
2016 Accelerated Chondrogenic Differentiation of Human Perivascular Stem Cells with NELL-1. Tissue engineering. Part A 27 26700847
2011 Maxillary sinus floor elevation using BMP-2 and Nell-1 gene-modified bone marrow stromal cells and TCP in rabbits. Calcified tissue international 27 21584647
2006 Nell-1 induces acrania-like cranioskeletal deformities during mouse embryonic development. Laboratory investigation; a journal of technical methods and pathology 27 16652108
2018 Nell-1 Enhances Osteogenic Differentiation of Pre-Osteoblasts on Titanium Surfaces via the MAPK-ERK Signaling Pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 26 30359975
2017 NELL-1, HMGB1, and CCN2 Enhance Migration and Vasculogenesis, But Not Osteogenic Differentiation Compared to BMP2. Tissue engineering. Part A 26 28463604
2012 Calvarial cleidocraniodysplasia-like defects with ENU-induced Nell-1 deficiency. The Journal of craniofacial surgery 26 22337375
2018 Tissue engineering using 3D printed nano-bioactive glass loaded with NELL1 gene for repairing alveolar bone defects. Regenerative biomaterials 25 30094060
2015 Proliferation and osteogenic differentiation of mesenchymal stem cells induced by a short isoform of NELL-1. Stem cells (Dayton, Ohio) 25 25376942
2001 Brain specific human genes, NELL1 and NELL2, are predominantly expressed in neuroblastoma and other embryonal neuroepithelial tumors. Neurologia medico-chirurgica 25 11803583
2012 The C-terminal region of NELL1 mediates osteoblastic cell adhesion through integrin α3β1. FEBS letters 24 22728432
2014 Effect of NELL1 gene overexpression in iPSC-MSCs seeded on calcium phosphate cement. Acta biomaterialia 23 25220281
2011 NELL-1, an osteoinductive factor, is a direct transcriptional target of Osterix. PloS one 22 21931789
2017 Chitosan-stablized bovine serum albumin nanoparticles having ability to control the release of NELL-1 protein. International journal of biological macromolecules 21 29288032
2012 Expression and localization of Nell-1 during murine molar development. Journal of molecular histology 21 23264108
2017 NELL-1 induces Sca-1+ mesenchymal progenitor cell expansion in models of bone maintenance and repair. JCI insight 20 28614787
2012 Lentiviral-mediated gene transfer into human adipose-derived stem cells: role of NELL1 versus BMP2 in osteogenesis and adipogenesis in vitro. Acta biochimica et biophysica Sinica 20 23017834
2016 Vertebral Implantation of NELL-1 Enhances Bone Formation in an Osteoporotic Sheep Model. Tissue engineering. Part A 19 27113550
2015 Pharmacokinetics and osteogenic potential of PEGylated NELL-1 in vivo after systemic administration. Biomaterials 19 25913252
2021 Posttransplant nephrotic syndrome resulting from NELL1-positive membranous nephropathy. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 18 33866674
2018 DNA methylation of neural EGFL like 1 (NELL1) is associated with advanced disease and the metastatic state of renal cell cancer patients. Oncology reports 18 30272321
2022 NELL1 Regulates the Matrisome to Promote Osteosarcoma Progression. Cancer research 17 35700263
2012 Efficient production and characterization of recombinant human NELL1 protein in human embryonic kidney 293-F cells. Molecular biotechnology 17 21814724
2022 NELL1 augments osteogenesis and inhibits inflammation of human periodontal ligament stem cells induced by BMP9. Journal of periodontology 16 34647317
2021 Nell-1 attenuates lipopolysaccharide-induced inflammation in human dental pulp cells. Journal of molecular histology 16 33905072
2014 Oligomerization-induced conformational change in the C-terminal region of Nel-like molecule 1 (NELL1) protein is necessary for the efficient mediation of murine MC3T3-E1 cell adhesion and spreading. The Journal of biological chemistry 16 24563467
2014 Bioactivity and circulation time of PEGylated NELL-1 in mice and the potential for osteoporosis therapy. Biomaterials 16 24818884
2019 Cumulative inactivation of Nell-1 in Wnt1 expressing cell lineages results in craniofacial skeletal hypoplasia and postnatal hydrocephalus. Cell death and differentiation 15 31582804
2020 The synergistic effect of NELL1 and adipose-derived stem cells on promoting bone formation in osteogenesis imperfecta treatment. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 14 32454289
2019 Effect of NELL1 on lung cancer stem‑like cell differentiation. Oncology reports 14 30628703
2019 Nell-1 promotes the neural-like differentiation of dental pulp cells. Biochemical and biophysical research communications 14 30979495
2019 Synergistic Effect of NELL-1 and an Ultra-Low Dose of BMP-2 on Spinal Fusion. Tissue engineering. Part A 14 31337284
2023 Mercury-associated neural epidermal growth factor-like 1 protein (NELL-1) positive membranous nephropathy after use of skin lightening creams. Clinical toxicology (Philadelphia, Pa.) 13 37078902
2018 miR-27a protects human mitral valve interstitial cell from TNF-α-induced inflammatory injury via up-regulation of NELL-1. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 13 29694513
2017 The Effects of Systemic Therapy of PEGylated NEL-Like Protein 1 (NELL-1) on Fracture Healing in Mice. The American journal of pathology 13 29294300
2020 Activation of Nell-1 in BMSC Sheet Promotes Implant Osseointegration Through Regulating Runx2/Osterix Axis. Frontiers in cell and developmental biology 12 33072736
2018 Inactivation of Nell-1 in Chondrocytes Significantly Impedes Appendicular Skeletogenesis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 12 30352124
2017 NELL1, whose high expression correlates with negative outcomes, has different methylation patterns in alveolar and embryonal rhabdomyosarcoma. Oncotarget 12 28380437
2015 NELL-1 expression in benign and malignant bone tumors. Biochemical and biophysical research communications 12 25791475
2018 Optimizing Osteogenic Differentiation of Ovine Adipose-Derived Stem Cells by Osteogenic Induction Medium and FGFb, BMP2, or NELL1 In Vitro. Stem cells international 11 30356449
2015 MALDI-TOF Mass Array Analysis of Nell-1 Promoter Methylation Patterns in Human Gastric Cancer. BioMed research international 11 26090379
2015 Mapping the heparin-binding site of the osteoinductive protein NELL1 by site-directed mutagenesis. FEBS letters 11 26627376
2016 Controlled release of NELL-1 protein from chitosan/hydroxyapatite-modified TCP particles. International journal of pharmaceutics 9 27349789
2016 Efficacy of Intraperitoneal Administration of PEGylated NELL-1 for Bone Formation. BioResearch open access 9 27354930
2015 NELL-1 expression in tumors of cartilage. Journal of orthopaedics 9 27047227
2022 Backtracking cryptic recurrence of esophageal cancer from membranous nephropathy: the detection of glomerular NELL-1 and IgG4. Clinical kidney journal 8 37007702
2021 NELL-1 Increased the Osteogenic Differentiation and mRNA Expression of Spheroids Composed of Stem Cells. Medicina (Kaunas, Lithuania) 8 34201046
2024 Neural epidermal growth factor-like 1 protein (Nell-1) alleviates periodontal tissue destruction in periodontitis by regulating the ratio of M2/M1 macrophage phenotypes. International immunopharmacology 7 38908089
2021 Novel Molecule Nell-1 Promotes the Angiogenic Differentiation of Dental Pulp Stem Cells. Frontiers in physiology 7 34512380
2024 NELL1 membranous nephropathy: clinical associations provide mechanistic clues. Frontiers in nephrology 6 38596642
2018 Association of DFNA5, SYK, and NELL1 variants along with HPV infection in oral cancer among the prolonged tobacco-chewers. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 6 30091681
2013 Human NELL1 protein augments constructive tissue remodeling with biologic scaffolds. Cells, tissues, organs 6 24335144
2023 Anti-PLA2R Antibody Development During NELL1-Associated Membranous Glomerulonephritis Treatment: A Case Report. Kidney medicine 5 37122392
2022 NELL1-Positive HIV-Associated Lupus-Like Membranous Nephropathy with Spontaneous Remission. Glomerular diseases 5 36817287
2018 Nell-1-ΔE, a novel transcript of Nell-1, inhibits cell migration by interacting with enolase-1. Journal of cellular biochemistry 5 29388706
2016 [NELL-1: a novel highly efficient and specific growth factor]. Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 5 27080300
2012 NELL1 promotes bone regeneration in polyethylene particle-induced osteolysis. Tissue engineering. Part A 5 22404332
2009 An ectopic study of tissue-engineered bone with Nell-1 gene modified rat bone marrow stromal cells in nude mice. Chinese medical journal 5 19493425
2019 Age dependent effects of NELL-1 isoforms on bone marrow stromal cells. Journal of orthopaedics 4 30899146
2025 Detection and characterization of NELL1 autoantibodies in NELL1 positive membranous nephropathy. Kidney international 3 40541723

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