Affinage

SMOC2

SPARC-related modular calcium-binding protein 2 · UniProt Q9H3U7

Length
446 aa
Mass
49.7 kDa
Annotated
2026-06-10
53 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMOC2 is a secreted, calcium-binding modular matricellular glycoprotein of the SPARC/BM-40 family that couples the extracellular matrix to integrin- and growth-factor-driven signaling to regulate cell adhesion, proliferation, fibrosis, and skeletal development (PMID:12741954, PMID:18582461). Its EF-hand extracellular calcium-binding domain adopts a calcium-dependent conformation and mediates keratinocyte attachment, focal adhesion formation, and migration through αvβ6 and αvβ1 integrins (PMID:12741954, PMID:18582461). A central, recurring mechanism is engagement of integrin receptors to control cell-cycle progression: SMOC2 sustains integrin-linked kinase (ILK) activity to drive growth-factor-induced cyclin D1 expression and G1 progression (PMID:17989364), whereas in renal tubular cells it binds integrin β3 (ITGB3) to restrain the CCND1-CDK4/6 axis and arrest cells in G1 to permit DNA repair (PMID:41663805). Through integrin β3/FAK/paxillin signaling and ILK-dependent suppression of E-cadherin, SMOC2 drives epithelial-mesenchymal transition and tumor cell motility (PMID:25915847, PMID:35869056). SMOC2 is a major pro-fibrotic effector across kidney, lung, and heart, mediating TGFβ1/SMAD2/3- and ILK/p38-dependent fibroblast-to-myofibroblast transition (PMID:28422762, PMID:30021376, PMID:36935650). It also potentiates canonical WNT/β-catenin signaling by binding the co-receptors Fzd6 and LRP6 and enhancing WNT ligand-receptor interaction (PMID:30594556), and modulates BMP signaling: a Leu359Arg missense mutation that abolishes COL9A1/HSPG binding causes SMOC2 to competitively bind BMPR1B, inhibit BMP-SMAD1/5/9 signaling, and produce growth-plate defects and short-limbed dwarfism in knock-in mice (PMID:33059102). SMOC2 is a transcriptional target of Runx2 required for osteoblastogenesis (PMID:34667264) and is post-transcriptionally stabilized by METTL3-mediated m6A methylation (PMID:40913254). In sensory ganglia, fibroblast-secreted SMOC2 binds and inhibits the P2X7 receptor on satellite glial cells to suppress coupled nociceptive neuronal activation (PMID:35437277).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 2003 High

    Established SMOC2 as a secreted modular glycoprotein and defined its domain architecture, providing the structural basis for its matricellular function.

    Evidence Recombinant protein expression with domain mapping and calcium-binding characterization

    PMID:12741954

    Open questions at the time
    • No receptor or binding partner identified at this stage
    • Functional consequence of calcium-dependent conformation untested
  2. 2006 Medium

    Showed SMOC2 functionally potentiates growth-factor-induced endothelial proliferation and angiogenesis, moving it from a structural ECM component to a modulator of growth-factor responses.

    Evidence Adenoviral overexpression, siRNA knockdown, Matrigel angiogenesis and plug assays in mice

    PMID:16774925

    Open questions at the time
    • No receptor mediating the angiogenic effect identified
    • Mechanism linking SMOC2 to VEGF/bFGF signaling unresolved
  3. 2007 High

    Defined the SMOC2-ILK-cyclin D1 axis, explaining how SMOC2 promotes G1 cell-cycle progression downstream of growth factors.

    Evidence siRNA knockdown with ILK activity assay and epistasis rescue by hyperactive ILK and cyclin D1

    PMID:17989364

    Open questions at the time
    • How SMOC2 maintains ILK activity mechanistically unclear
    • Upstream receptor coupling SMOC2 to ILK not defined here
  4. 2008 High

    Identified the specific integrin receptors (αvβ6, αvβ1) and the calcium-binding domain as the structural determinant for SMOC2-mediated adhesion and migration, separating adhesion/migration from proliferation.

    Evidence Cell attachment, integrin blocking antibodies, focal adhesion imaging, and domain deletion in keratinocytes

    PMID:18582461

    Open questions at the time
    • Did not connect integrin engagement to the ILK/cyclin D1 axis
    • Cell-type specificity of integrin usage untested
  5. 2008 Medium

    Placed SMOC2 transcription under negative control of AHR signaling, identifying an environmental/ligand-responsive regulatory input.

    Evidence Promoter-reporter assay, AHR ligand treatment, and Ahr-knockout organ culture

    PMID:19146932

    Open questions at the time
    • Direct AHR binding to the SMOC2 promoter not shown by ChIP
    • Physiological context of AHR repression unclear
  6. 2009 Medium

    Showed Smoc2 expression in the fetal gonad/kidney is Hedgehog-dependent and sexually dimorphic, embedding SMOC2 in developmental signaling pathways.

    Evidence Organ culture with Hedgehog inhibition, in situ hybridization, transgenic mutant analysis

    PMID:19842175

    Open questions at the time
    • Direct vs indirect Hedgehog regulation not distinguished
    • Functional consequence of gonadal Smoc2 expression untested
  7. 2011 Medium

    Established SMOC2 as functionally required for tooth development, placing it upstream of odontogenic transcription factors and linking it to human dentin dysplasia.

    Evidence Morpholino knockdown in zebrafish with in situ hybridization for dlx2, bmp2, pitx2

    PMID:22152679

    Open questions at the time
    • Molecular intermediary between SMOC2 and odontogenic genes unknown
    • Morpholino approach lacks genetic confirmation
  8. 2014 Medium

    Extended SMOC2's developmental role to embryonic myelopoiesis and placed it upstream of BMP target gene transcription.

    Evidence Morpholino knockdown in zebrafish with marker and BMP target gene analysis

    PMID:25044883

    Open questions at the time
    • Mechanism linking SMOC2 to BMP signaling not biochemically defined
    • Conservation in mammalian hematopoiesis untested
  9. 2015 Medium

    Identified SMOC2 as a pro-metastatic effector in colorectal cancer that drives EMT via ILK signaling, integrating its adhesion biology with tumor progression.

    Evidence siRNA/overexpression, motility assays, liver metastasis mouse model, EMT marker western blot

    PMID:25915847

    Open questions at the time
    • Direct receptor engagement in colorectal cells not shown
    • Single-lab in vivo metastasis model
  10. 2017 High

    Established SMOC2 as a critical mediator of fibroblast-to-myofibroblast transition and kidney fibrosis downstream of TGFβ1, defining its central pro-fibrotic role.

    Evidence SMOC2 overexpression and knockdown mice, siRNA in vitro, TGFβ1 stimulation, fibrosis readouts

    PMID:28422762

    Open questions at the time
    • Receptor coupling SMOC2 to TGFβ1/SMAD response not defined here
    • Whether effect is cell-autonomous to fibroblasts unresolved
  11. 2017 Medium

    Demonstrated dose-dependent control of facial skeletal length by SMOC2 expression via a natural splice-disrupting insertion, providing in vivo evidence for SMOC2 in craniofacial morphogenesis.

    Evidence QTL mapping, splice analysis, transcript quantification in brachycephalic dogs

    PMID:28552356

    Open questions at the time
    • Molecular pathway connecting SMOC2 dosage to bone length unclear
    • Correlational genetics rather than direct mechanism
  12. 2018 Medium

    Identified direct SMOC2 binding to WNT co-receptors Fzd6 and LRP6 and potentiation of canonical WNT signaling, expanding SMOC2's receptor repertoire beyond integrins.

    Evidence Co-immunoprecipitation, luciferase reporter, sphere formation in endometrial cancer cells

    PMID:30594556

    Open questions at the time
    • Reciprocal/endogenous interaction validation limited
    • Binding interface on SMOC2 not mapped
  13. 2018 Medium

    Placed SMOC2 upstream of the TGFβ1/SMAD2/3 axis in pulmonary fibrosis, generalizing its pro-fibrotic mechanism to a second organ.

    Evidence SMOC2 knockout mice, BLM fibrosis model, siRNA in vitro, SMAD phosphorylation western blot

    PMID:30021376

    Open questions at the time
    • How SMOC2 modulates SMAD phosphorylation mechanistically unknown
    • Receptor not identified
  14. 2020 High

    Resolved a disease-causing missense mutation mechanism in which loss of COL9A1/HSPG binding redirects SMOC2 to competitively inhibit BMPR1B, linking SMOC2 to BMP-SMAD1/5/9 signaling and skeletal dysplasia.

    Evidence Knock-in mouse, in vivo/in vitro BMP-SMAD assays, SMOC2-COL9A1/HSPG/BMPR1B binding assays

    PMID:33059102

    Open questions at the time
    • Whether wild-type SMOC2 normally regulates BMPR1B unclear
    • Stoichiometry of competitive binding not quantified
  15. 2020 Medium

    Defined an integrin β3/FAK/paxillin pathway through which SMOC2 drives EMT and matrix production in renal cancer cells.

    Evidence Recombinant protein, enforced expression, siRNA, pathway western blots, xenograft

    PMID:35869056

    Open questions at the time
    • Direct SMOC2-ITGB3 binding not biochemically shown here
    • Single-lab pathway assignment
  16. 2020 Medium

    Established SMOC2 as a marker and functional regulator of dental/bone progenitors and bone homeostasis, with loss causing periodontal bone loss and excess osteoclast activity.

    Evidence Smoc2 knockout, GFP reporter, micro-CT, COX2 inhibitor rescue, MMP9 analysis

    PMID:32908163

    Open questions at the time
    • Molecular pathway linking SMOC2 to osteoclast/MMP9 control unclear
    • Cell-autonomous vs paracrine action undefined
  17. 2021 High

    Placed Smoc2 downstream of Runx2 as a transcriptional target required for osteoblastogenesis, with double Smoc1/Smoc2 loss producing severe skeletal defects.

    Evidence RNA-seq, siRNA, single and double KO mouse skeletal phenotyping

    PMID:34667264

    Open questions at the time
    • Functional redundancy of Smoc1/Smoc2 not molecularly dissected
    • Downstream effectors in osteoblasts unidentified
  18. 2021 Medium

    Identified AKT and ERK as effector pathways for SMOC2-driven lung fibroblast-to-myofibroblast transformation, broadening its pro-fibrotic signaling outputs.

    Evidence Overexpression with AKT/ERK inhibitor rescue and proliferation/migration assays

    PMID:34876240

    Open questions at the time
    • Upstream receptor not defined
    • Gain-of-function only
  19. 2022 High

    Demonstrated SMOC2 is secreted into the DRG basement membrane and directly binds and inhibits the P2X7 receptor on satellite glia to suppress mechanical nociception, revealing a neuro-immune signaling role.

    Evidence Smoc2 KO/KD, in vivo calcium imaging, HEK293 P2X7R co-expression, pharmacological epistasis, behavior

    PMID:35437277

    Open questions at the time
    • Structural basis of SMOC2-P2X7R inhibition not resolved
    • Generality beyond DRG untested
  20. 2022 Medium

    Revealed dual transcriptional (SOX4) and m6A (ALKBH5) control of MYO1C as the mechanism for SMOC2-driven synoviocyte invasion in rheumatoid arthritis.

    Evidence siRNA, transcriptomics, Co-IP, m6A analysis, migration/invasion assays, CIA model

    PMID:36513634

    Open questions at the time
    • How SMOC2 controls SOX4/ALKBH5 mechanistically unclear
    • Multiple layers attributed in a single study
  21. 2023 Medium

    Defined the ILK/p38 axis as the downstream effector of SMOC2-driven cardiac fibrosis, extending its pro-fibrotic role to heart.

    Evidence AAV9-shRNA in mice, ISO fibrosis model, TGFβ-treated fibroblasts, ILK overexpression rescue

    PMID:36935650

    Open questions at the time
    • Receptor linking SMOC2 to ILK in cardiac fibroblasts unknown
    • Single-lab assignment
  22. 2023 Medium

    Showed SMOC2 potentiates BMP9 osteogenesis through integrin β1-coupled FAK/PI3K/AKT signaling and is itself transcriptionally controlled by GTF2I, integrating integrin engagement with osteogenic differentiation.

    Evidence Overexpression/siRNA, Co-IP (integrin β1), ChIP (GTF2I), PI3K inhibitor, in vivo bone formation

    PMID:36698376

    Open questions at the time
    • Direct integrin β1-SMOC2 interface not mapped
    • Single-lab pathway
  23. 2025 Medium

    Identified METTL3-mediated m6A methylation as a stabilizer of SMOC2 mRNA driving post-MI cardiac fibrosis, adding a post-transcriptional layer to SMOC2 regulation.

    Evidence meRIP-Seq, actinomycin D stability assay, AAV9-shRNA in vivo, Masson staining

    PMID:40913254

    Open questions at the time
    • m6A reader mediating stabilization not identified
    • Single-lab finding
  24. 2026 High

    Showed SMOC2 binds integrin β3 to restrain the CCND1-CDK4/6 axis and arrest renal tubular cells in G1, protecting against acute kidney injury — a cytoprotective, anti-proliferative role contrasting its pro-proliferative ILK action.

    Evidence SMOC2 KO, recombinant protein rescue, transcriptomics, SMOC2-ITGB3 binding, palbociclib epistasis, two AKI models

    PMID:41663805

    Open questions at the time
    • Reconciliation with SMOC2's pro-proliferative ILK/cyclin D1 role across cell types unresolved
    • Determinants of pro- vs anti-proliferative output unknown
  25. 2026 Medium

    Identified SMOC2-integrin αvβ5 engagement as an inhibitor of LKB1/AMPKα/FOXO3 antioxidant signaling that enhances lipid peroxidation and post-MI cardiac fibrosis, linking SMOC2 to redox/metabolic control.

    Evidence Fibroblast-specific overexpression, SMOC2 KO, LAD ligation MI, RNA-seq, metabolomics, Co-IP (αvβ5)

    PMID:41825779

    Open questions at the time
    • Direct binding interface with αvβ5 not mapped
    • Single-lab multi-omics correlation

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unclear what molecular switch determines whether integrin-engaged SMOC2 drives pro-proliferative ILK/cyclin D1 signaling versus anti-proliferative CCND1-CDK4/6 restraint, and how its many integrin partners (αvβ6, αvβ1, β3, β1, αvβ5) are selected in a given cell type.
  • No unified structural model of SMOC2-integrin selectivity
  • Context-dependent opposite cell-cycle outcomes unexplained
  • No high-resolution structure of SMOC2 bound to any receptor

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0060089 molecular transducer activity 4 GO:0005198 structural molecule activity 2 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-1640170 Cell Cycle 2
Partners
BMPR1BCOL9A1FZD6ITGAVITGB1ITGB3LRP6P2RX7

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 SMOC2 is a secreted modular glycoprotein containing an EF-hand calcium-binding domain homologous to BM-40, two thyroglobulin-like domains, a follistatin-like domain, and a novel SMOC-specific domain. Recombinant protein analysis showed it has a calcium-dependent conformation. Recombinant protein expression, domain analysis, calcium-binding characterization The Biochemical journal High 12741954
2006 SMOC2 is localized to the extracellular periphery of endothelial cells and secreted into culture medium. Overexpression potentiates VEGF- and bFGF-induced DNA synthesis and angiogenic network formation; siRNA knockdown inhibits endothelial cell proliferation and network formation. In vivo, SMOC2 synergizes with bFGF to promote cell invasion into Matrigel plugs. Adenoviral overexpression, siRNA knockdown, DNA synthesis assay, in vitro Matrigel angiogenesis assay, subdermal Matrigel plug assay in mice The Journal of biological chemistry Medium 16774925
2007 SMOC2 promotes growth factor-induced cyclin D1 expression and DNA synthesis by maintaining integrin-linked kinase (ILK) activity during G1. SMOC2 ablation reduces ILK activity without affecting PDGFβR autophosphorylation or MAPK/Akt activation; ectopic hyperactive ILK rescues the mitogenic defect in SMOC2-deficient cells. Cyclin D1 overexpression also rescues G1 progression in SMOC2-deficient cells, placing cyclin D1 downstream of the SMOC2-ILK axis. siRNA knockdown, ILK activity assay, cyclin D1 expression analysis, epistasis rescue experiments with hyperactive ILK and cyclin D1 overexpression, DNA synthesis assay Molecular biology of the cell High 17989364
2008 SMOC2 stimulates attachment of primary epidermal keratinocytes and keratinocyte-derived cell lines via αvβ6 and αvβ1 integrins. Integrin blocking antibodies identify these as key receptors. The extracellular calcium-binding domain mediates both cell attachment, focal adhesion formation, and cell migration, but not proliferation. Cell attachment assay with recombinant protein, integrin-blocking antibody experiments, focal adhesion imaging, migration assay, domain deletion analysis Experimental cell research High 18582461
2008 SMOC2 expression is transcriptionally repressed by activated aryl-hydrocarbon receptor (AHR) signaling. The SMOC2 promoter contains consensus AHR-binding sites, and AHR ligands (benzo[a]pyrene, TCDD) repress SMOC2 promoter-driven reporter activity in an AHR-dependent manner. TCDD represses Smoc2 mRNA in Ahr+/+ but not Ahr-/- mouse testes in organ culture. Promoter-reporter assay, AHR ligand treatment, Ahr knockout organ culture, RT-PCR Gene Medium 19146932
2009 Smoc2 expression in the fetal gonad is dependent on Hedgehog signaling: organ culture experiments show that Smoc2 expression in testes, mesonephroi, and kidneys requires Hedgehog pathway activity. Smoc2 is expressed in Leydig cells and mesonephroi but not in wildtype ovaries, indicating sexually dimorphic regulation. Organ culture with Hedgehog pathway inhibition, in situ hybridization, transgenic mutant analysis Developmental dynamics Medium 19842175
2011 Loss-of-function of SMOC2 in zebrafish (smoc2 knockdown) causes pharyngeal tooth abnormalities resembling the human dentin dysplasia phenotype and reduces expression of key odontogenesis genes dlx2, bmp2, and pitx2, placing SMOC2 upstream of these odontogenic transcription factors. Morpholino knockdown in zebrafish, in situ hybridization for odontogenesis genes American journal of human genetics Medium 22152679
2014 Smoc2 morpholino knockdown in zebrafish impairs myelopoiesis: hemangioblast development and myeloid progenitor specification are disrupted, and BMP target genes are downregulated in smoc2 morphants, placing Smoc2 upstream of BMP target gene transcription during embryonic myeloid development. Morpholino knockdown in zebrafish, molecular marker analysis (in situ hybridization), BMP target gene expression analysis Developmental dynamics Medium 25044883
2015 SMOC2 expression is induced downstream of L1-ezrin-NF-κB signaling in colorectal cancer cells. SMOC2 is required for L1-mediated increases in cell motility, proliferation under stress, and liver metastasis. SMOC2 promotes a mesenchymal phenotype by decreasing E-cadherin and increasing Snail via integrin-linked kinase (ILK) signaling, and elevates Lgr5 expression. siRNA knockdown, overexpression, cell motility assay, liver metastasis mouse model, western blot for E-cadherin/Snail/ILK Oncogene Medium 25915847
2017 SMOC2 is upregulated in kidney tubular epithelial cells following fibrosis and critically mediates fibroblast-to-myofibroblast transition (FMT): SMOC2 activates stress fiber formation, proliferation, migration, and ECM production in fibroblasts. siRNA targeting SMOC2 attenuates TGFβ1-mediated FMT in vitro and kidney fibrosis in mice. Genetically manipulated mice (SMOC2 overexpression and knockdown), siRNA in vitro, TGFβ1 stimulation, fibrosis readouts (stress fiber, ECM production, migration) JCI insight High 28422762
2017 Canine brachycephaly is caused by an intronic retrotransposon insertion in SMOC2 that promotes cryptic splice site usage, drastically reducing SMOC2 gene expression. SMOC2 disruption affects facial skeletal length in a dose-dependent manner, accounting for 36% of facial length variation. Morphometrics, QTL mapping, splice site analysis, transcript quantification in brachycephalic dogs Current biology Medium 28552356
2018 SMOC2 directly interacts with WNT receptors Fzd6 and LRP6 (co-immunoprecipitation), enhances ligand-receptor interaction with canonical WNT ligands Wnt3a and Wnt10b, and thereby activates the WNT/β-catenin pathway to support endometrial cancer stem cell properties including stemness gene expression (SOX2, OCT4, NANOG) and chemoresistance. Co-immunoprecipitation assay, luciferase reporter assay, siRNA knockdown, sphere formation assay, western blotting EBioMedicine Medium 30594556
2018 SMOC2 knockout mice show reduced BLM-induced pulmonary fibrosis with decreased TGFβ1, α-SMA, p-SMAD2, and p-SMAD3 levels. In vitro, SMOC2 upregulation activates fibrosis in MRC-5 cells, and SMOC2 knockdown reduces TGFβ1-stimulated p-SMAD2 and p-SMAD3, placing SMOC2 upstream of the TGFβ1/SMAD2/3 signaling axis. SMOC2 knockout mice, BLM-induced pulmonary fibrosis model, siRNA knockdown in vitro, western blot for SMAD phosphorylation Biomedicine & pharmacotherapy Medium 30021376
2020 A SMOC2 missense mutation (c.1076T>G, Leu359Arg) prevents binding of SMOC2 to COL9A1 and HSPG, and causes the mutant protein to competitively bind BMPR1B, thereby inhibiting BMP-SMAD1/5/9 signaling and producing growth plate defects (disorganized proliferative zones, expanded hypertrophic zones) and short-limbed dwarfism in knock-in mice. Knock-in mouse model, in vivo and in vitro BMP-SMAD signaling assays, protein binding assays (SMOC2 vs COL9A1/HSPG/BMPR1B interactions) Bone High 33059102
2020 SMOC2 triggers EMT in kidney epithelial cells through the integrin β3, FAK, and paxillin pathway. Recombinant and enforced SMOC2 expression increases EMT markers, matrix production, proliferation, and migration in RCC cell lines, all inhibited by SMOC2 siRNA. Recombinant protein treatment, enforced expression, siRNA knockdown, western blot for integrin β3/FAK/paxillin/EMT markers, in vivo xenograft Cell death & disease Medium 35869056
2020 Smoc2 deficiency in mice results in age-induced periodontal bone loss, impaired bone healing after tooth avulsion, and increased osteoclast activity/bone resorption. Smoc2-GFP reporter marks dental and bone progenitors and is reactivated after tooth injury. COX2 inhibitor (ibuprofen) blocks injury-induced bone loss in Smoc2-/- mice by reducing MMP9. Smoc2 knockout mouse model, GFP reporter, micro-CT, histology, pharmacological COX2 inhibition, MMP9 analysis Scientific reports Medium 32908163
2021 Smoc1 and Smoc2 are downstream transcriptional targets of Runx2 in osteoblasts. Runx2 upregulates both genes; knockdown of Smoc1 or Smoc2 inhibits osteoblastogenesis. Smoc2 KO mice show mild craniofacial phenotypes, and Smoc1/Smoc2 double KO mice have severe defects including absent skull, shortened tibiae, and impaired endochondral bone formation. RNA-sequencing, siRNA knockdown, single and double KO mouse models, skeletal phenotyping Communications biology High 34667264
2021 SMOC2 promotes TGFβ1-induced fibroblast-to-myofibroblast transformation (FMT) in lung fibroblasts by activating AKT and ERK signaling. Inhibition of AKT or ERK reverses the promoting effects of SMOC2 overexpression on proliferation, migration, and FMT. Overexpression, western blot for p-AKT/p-ERK, AKT/ERK inhibitor rescue experiments, proliferation and migration assays Hereditas Medium 34876240
2022 SMOC2 is secreted by DRG fibroblasts to form a component of the basement membrane surrounding DRG neuron-satellite glial cell units. SMOC2 directly interacts with P2X7 receptor and suppresses ATP-induced P2X7R activation in HEK293 cells. Smoc2 KO increases coupled activation of adjacent DRG neurons in response to nociceptive mechanical stimuli, raising mechanical sensitivity. DRG injection of A740003 (P2X7R antagonist) does not further enhance SMOC2-inhibited coupling, placing SMOC2 upstream of P2X7R-mediated neuronal communication. Smoc2 KO mice, Smoc2 knockdown, in vivo calcium imaging of DRG neurons, HEK293 P2X7R expression with SMOC2 co-expression, DRG injection of recombinant SMOC2 and P2X7R antagonist, behavioral testing The Journal of neuroscience High 35437277
2022 SMOC2 promotes migration and invasion of RA fibroblast-like synoviocytes by controlling MYO1C expression through two mechanisms: SOX4-mediated transcriptional regulation and ALKBH5-mediated m6A post-transcriptional modification, leading to cytoskeletal remodeling. siRNA knockdown, transcriptomics, Co-IP, m6A modification analysis, in vitro migration/invasion assays, in vivo collagen-induced arthritis model with intra-articular shRNA Cell death & disease Medium 36513634
2023 SMOC2 promotes cardiac fibrosis through the ILK/p38 signaling pathway. SMOC2 knockdown inhibits TGFβ-induced cardiac fibroblast transdifferentiation and collagen deposition. ILK overexpression increases p38 phosphorylation and reverses the protective effect of SMOC2 silencing, establishing ILK→p38 as the downstream effector axis. AAV9-shRNA knockdown in mice, ISO-induced cardiac fibrosis model, TGFβ-treated neonatal fibroblasts, ILK overexpression rescue, western blot for ILK/p-p38 Frontiers in cardiovascular medicine Medium 36935650
2023 SMOC2 potentiates BMP9-induced osteogenic differentiation in mesenchymal stem cells by enhancing FAK/PI3K/AKT signaling. Integrin β1 interacts with SMOC2 in BMP9-treated cells. GTF2I is enriched at the SMOC2 promoter. SMOC2 knockdown or FAK silencing reduces BMP9-induced osteogenic markers, and LY294002 (PI3K inhibitor) partially abolishes SMOC2-enhanced osteogenesis. Overexpression, siRNA knockdown, Co-IP (integrin β1–SMOC2), ChIP (GTF2I at SMOC2 promoter), PI3K inhibitor, in vitro osteogenesis assay, ectopic bone formation in vivo Stem cells international Medium 36698376
2025 METTL3 increases SMOC2 mRNA stability by adding m6A methylation to SMOC2 transcripts, thereby promoting cardiac fibroblast proliferation and differentiation after hypoxia and cardiac fibrosis post-MI. METTL3 knockdown reduces m6A levels on SMOC2 mRNA and decreases SMOC2 expression, while actinomycin D chase experiments confirm reduced mRNA stability. meRIP-Seq, actinomycin D mRNA stability assay, AAV9-shRNA in vivo KD, western blot, Masson staining Journal of cellular and molecular medicine Medium 40913254
2026 SMOC2 protects renal tubular cells during acute kidney injury by interacting with integrin β3 (ITGB3), which restrains the CCND1-CDK4/6 axis, arresting tubular cells in G1 phase and facilitating DNA repair. SMOC2 KO exacerbates tubular injury, DNA damage, and apoptosis; recombinant SMOC2 treatment ameliorates injury. CDK4/6 inhibitor palbociclib phenocopies SMOC2 protection, confirming the downstream pathway. SMOC2 KO mice, recombinant SMOC2 treatment, transcriptomic profiling, biochemical binding assays (SMOC2–ITGB3), CDK4/6 inhibitor (palbociclib) rescue, AKI mouse models (AAI and cisplatin) Molecular biomedicine High 41663805
2026 SMOC2 interacts with integrin αvβ5 in cardiac fibroblasts to inhibit the LKB1/AMPKα/FOXO3 signaling pathway, reducing antioxidant defence and enhancing lipid peroxidation and oxidative stress, thereby promoting cardiac fibrosis after MI. Fibroblast-specific SMOC2 overexpression aggravates fibrosis; SMOC2 KO reduces fibrosis and improves cardiac function. Fibroblast-specific overexpression, SMOC2 KO mice, LAD ligation MI model, RNA sequencing, metabolomics, Co-IP (SMOC2–integrin αvβ5), western blot for LKB1/AMPKα/FOXO3 Journal of advanced research Medium 41825779

Source papers

Stage 0 corpus · 53 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Characterization of SMOC-2, a modular extracellular calcium-binding protein. The Biochemical journal 111 12741954
2006 The novel SPARC family member SMOC-2 potentiates angiogenic growth factor activity. The Journal of biological chemistry 106 16774925
2017 Canine Brachycephaly Is Associated with a Retrotransposon-Mediated Missplicing of SMOC2. Current biology : CB 88 28552356
2011 Homozygosity mapping and candidate prioritization identify mutations, missed by whole-exome sequencing, in SMOC2, causing major dental developmental defects. American journal of human genetics 81 22152679
2018 Targeting cancer stem cell signature gene SMOC-2 Overcomes chemoresistance and inhibits cell proliferation of endometrial carcinoma. EBioMedicine 74 30594556
2017 Silencing SMOC2 ameliorates kidney fibrosis by inhibiting fibroblast to myofibroblast transformation. JCI insight 69 28422762
2009 Genome-wide association study of generalized vitiligo in an isolated European founder population identifies SMOC2, in close proximity to IDDM8. The Journal of investigative dermatology 68 19890347
2015 Induction of the intestinal stem cell signature gene SMOC-2 is required for L1-mediated colon cancer progression. Oncogene 58 25915847
2007 The SPARC-related factor SMOC-2 promotes growth factor-induced cyclin D1 expression and DNA synthesis via integrin-linked kinase. Molecular biology of the cell 57 17989364
2008 The widely expressed extracellular matrix protein SMOC-2 promotes keratinocyte attachment and migration. Experimental cell research 56 18582461
2009 Developmental expression of Smoc1 and Smoc2 suggests potential roles in fetal gonad and reproductive tract differentiation. Developmental dynamics : an official publication of the American Association of Anatomists 51 19842175
2018 Suppression of SMOC2 reduces bleomycin (BLM)-induced pulmonary fibrosis by inhibition of TGF-β1/SMADs pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 42 30021376
2022 SMOC2 promotes aggressive behavior of fibroblast-like synoviocytes in rheumatoid arthritis through transcriptional and post-transcriptional regulating MYO1C. Cell death & disease 37 36513634
2013 Recessive oligodontia linked to a homozygous loss-of-function mutation in the SMOC2 gene. Archives of oral biology 36 23317772
2020 ARNTL2 knockdown suppressed the invasion and migration of colon carcinoma: decreased SMOC2-EMT expression through inactivation of PI3K/AKT pathway. American journal of translational research 30 32355542
2016 Smoc2 potentiates proliferation of hepatocellular carcinoma cells via promotion of cell cycle progression. World journal of gastroenterology 30 28018113
2021 Smoc1 and Smoc2 regulate bone formation as downstream molecules of Runx2. Communications biology 29 34667264
2013 Variants in PTPN22 and SMOC2 genes and the risk of thyroid disease in the Jordanian Arab population. Endocrine 22 23463390
2010 SMOC2 gene variant and the risk of vitiligo in Jordanian Arabs. European journal of dermatology : EJD 22 20965805
2022 SMOC2 promotes an epithelial-mesenchymal transition and a pro-metastatic phenotype in epithelial cells of renal cell carcinoma origin. Cell death & disease 21 35869056
2014 Smoc2 modulates embryonic myelopoiesis during zebrafish development. Developmental dynamics : an official publication of the American Association of Anatomists 21 25044883
2021 TGF-β1/SMOC2/AKT and ERK axis regulates proliferation, migration, and fibroblast to myofibroblast transformation in lung fibroblast, contributing with the asthma progression. Hereditas 19 34876240
2020 Deficiency of the SMOC2 matricellular protein impairs bone healing and produces age-dependent bone loss. Scientific reports 19 32908163
2020 A SMOC2 variant inhibits BMP signaling by competitively binding to BMPR1B and causes growth plate defects. Bone 19 33059102
2022 Fibroblastic SMOC2 Suppresses Mechanical Nociception by Inhibiting Coupled Activation of Primary Sensory Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 17 35437277
2017 The SPARC-related modular calcium binding protein 2 (SMOC2) gene polymorphism in primary glaucoma: a case-control study. Clinical ophthalmology (Auckland, N.Z.) 16 28356709
2008 The developmentally-regulated Smoc2 gene is repressed by Aryl-hydrocarbon receptor (Ahr) signaling. Gene 16 19146932
2023 Suppression of SMOC2 alleviates myocardial fibrosis via the ILK/p38 pathway. Frontiers in cardiovascular medicine 14 36935650
2022 microRNA-148a in Exosomes Derived from Bone Marrow Mesenchymal Stem Cells Alleviates Cardiomyocyte Apoptosis in Atrial Fibrillation by Inhibiting SMOC2. Molecular biotechnology 14 35397056
2023 SMOC2 promoted vascular smooth muscle cell proliferation, migration, and extracellular matrix degradation by activating BMP/TGF-β1 signaling pathway. Journal of clinical biochemistry and nutrition 9 37700850
2023 SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy. Open medicine (Warsaw, Poland) 8 37465345
2022 LncRNA LINC01857 drives pancreatic adenocarcinoma progression via modulating miR-19a-3p/SMOC2. Clinics (Sao Paulo, Brazil) 7 35662010
2024 FTO Positively Regulates Odontoblastic Differentiation via SMOC2 in Human Stem Cells from the Apical Papilla under Inflammatory Microenvironment. International journal of molecular sciences 6 38612855
2023 Matricellular Protein SMOC2 Potentiates BMP9-Induced Osteogenic Differentiation in Mesenchymal Stem Cells through the Enhancement of FAK/PI3K/AKT Signaling. Stem cells international 6 36698376
2017 Increased expression of ID2, PRELP and SMOC2 genes in patients with endometriosis. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 6 28678915
2025 SMOC2 promotes microglia activity and neuroinflammation in Alzheimer's disease. Journal of Alzheimer's disease : JAD 5 39791204
2022 SMOC2 gene interacts with APOL1 in the development of end-stage kidney disease: A genome-wide association study. Frontiers in medicine 5 36250097
2017 mmu-miR-1963 negatively regulates the ameloblast differentiation of LS8 cell line by directly targeting Smoc2 3'UTR. Experimental cell research 5 29233684
2025 METTL3 Silencing Suppresses Cardiac Fibrosis Post Myocardial Infarction via m6A Modification of SMOC2. Journal of cellular and molecular medicine 3 40913254
2024 Gene Misexpression in a Smoc2+ve/Sox2-Low Population in Juvenile Prop1-Mutant Pituitary Gland. Journal of the Endocrine Society 3 39253355
2024 SMOC2, OGN, FCN3, and SERPINA3 could be biomarkers for the evaluation of acute decompensated heart failure caused by venous congestion. Frontiers in cardiovascular medicine 2 39717447
2022 MicroRNA-19a-3p Acts as an Oncogene in Gastric Cancer and Exerts the Effect by Targeting SMOC2. Applied biochemistry and biotechnology 2 35543855
2025 Role of SMOC2 in adenomyosis: implications for ECM remodeling and EMT pathogenesis. BMC women's health 1 40181364
2024 Spatial and temporal expression analysis of BMP signal modifiers, Smoc1 and Smoc2, from postnatal to adult developmental stages in the mouse testis. Gene expression patterns : GEP 1 39510490
2024 Analysis of SMOC2 gene variants in familial and non-familial primary open angle glaucoma Pakistani patients. International journal of ophthalmology 1 39697889
2026 Matricellular protein SMOC2 safeguards tubular integrity in acute kidney injury via integrin β3-dependent inhibition of CCND1-CDK4/6 axis. Molecular biomedicine 0 41663805
2026 The Runx2-SMOC axis in skeletal development: Expanding roles of Smoc1 and Smoc2 in development and disease. Journal of oral biosciences 0 41714037
2026 Prussian blue nanozymes alleviate postoperative pain via upregulating endogenous SMOC2 secretion in dorsal root ganglion fibroblasts. Journal of advanced research 0 41720157
2026 SMOC2 accelerates myocardial fibrosis following myocardial infarction by promoting lipid peroxidation through inhibition of the LKB1/AMPKα/FOXO3 pathway. Journal of advanced research 0 41825779
2026 Bioinformatics and Immunohistochemistry Reveal the Diagnostic and Mechanistic Role of the Cuproptosis-Related Genes SMOC2/THY1 in Liver Fibrosis. Journal of cellular and molecular medicine 0 41998832
2025 SMOC2 promotes peritoneal metastasis of gastric cancer involving Wnt/β-catenin pathway modulation and inducing angiogenesis. Clinical and experimental medicine 0 41217531
2025 WNT10A-SMOC2-LRP4 network affects permanent tooth development via potential tooth-bone interaction. BMC oral health 0 41408627
2021 An iPS cell line SDUBMSi0011-A from a multiple epiphyseal dysplasia patient carrying c. 1076T > G mutation in the SMOC2 gene. Stem cell research 0 33892290

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