Affinage

ADAMTSL2

ADAMTS-like protein 2 · UniProt Q86TH1

Length
951 aa
Mass
104.6 kDa
Annotated
2026-04-28
26 papers in source corpus 13 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADAMTSL2 is a secreted extracellular matrix glycoprotein that orchestrates fibrillin microfibril assembly and TGF-β bioavailability in connective tissues. It directly binds LTBP1, LTBP4, FBN1, and FBN2, and loss of ADAMTSL2 leads to excessive fibrillin microfibril accumulation, increased TGF-β release, and enhanced phospho-SMAD2 signaling, disrupting chondrocyte differentiation, growth plate formation, and tendon integrity (PMID:18677313, PMID:25762570, PMID:30303737, PMID:30738849). O-Fucosylation of its thrombospondin type-1 repeats by POFUT2 is required for secretion, and geleophysic dysplasia mutations impair this modification and reduce ADAMTSL2 export, causally linking secretion defects to the skeletal and connective tissue pathology of geleophysic dysplasia (PMID:32913123, PMID:18677313). ADAMTSL2 also signals through LRP6/β-catenin in cardiomyocytes to limit apoptosis after ischemic injury and attenuates myofibroblast differentiation in cardiac fibroblasts by suppressing TGF-β production (PMID:40975504, PMID:34611183).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2007 Medium

    Establishing ADAMTSL2 as a heavily glycosylated secreted ECM protein with TSR repeats, and linking its expression to MyoD-driven myogenesis, provided the first molecular characterization of the gene product.

    Evidence Protein expression in HEK293F/COS-1 cells; northern blotting; in vitro myogenic differentiation assay

    PMID:17509843

    Open questions at the time
    • No binding partners or functional role in ECM assembly identified
    • Relevance beyond myogenesis unknown
  2. 2008 High

    Identifying LTBP1 as a direct ADAMTSL2 interactor and showing that ADAMTSL2 loss-of-function mutations cause elevated TGF-β and nuclear pSMAD2 established the gene as a regulator of TGF-β bioavailability and linked it to geleophysic dysplasia.

    Evidence Yeast two-hybrid screen; functional studies in HEK293 cells; pSMAD2 immunostaining in patient fibroblasts

    PMID:18677313

    Open questions at the time
    • Mechanism by which ADAMTSL2–LTBP1 interaction constrains TGF-β release not resolved
    • Relationship to fibrillin microfibrils not yet tested
  3. 2010 Medium

    Demonstrating that the MLS founder mutation p.R221C generates anomalous disulfide-bonded dimers with reduced secretion showed that pathogenic variants impair ADAMTSL2 export rather than simply altering ECM function.

    Evidence SDS-PAGE under reducing/non-reducing conditions in COS-1, HEK293F, CHO cells

    PMID:20862248

    Open questions at the time
    • Canine model; direct translation to human geleophysic dysplasia mechanism not confirmed
    • Downstream ECM and signaling consequences of reduced secretion not measured
  4. 2015 High

    Showing that ADAMTSL2 binds FBN2 directly and that Adamtsl2-null mice accumulate excess fibrillin microfibrils with enhanced bronchial TGF-β signaling revealed ADAMTSL2 as a negative regulator of microfibril assembly.

    Evidence Solid-phase binding assay; immunostaining and TGF-β-neutralizing antibody treatment in Adamtsl2−/− mouse tissues

    PMID:25762570

    Open questions at the time
    • Mechanism by which ADAMTSL2 limits microfibril assembly (inhibition vs. turnover) not distinguished
    • Relative contributions of FBN1 vs. FBN2 binding not dissected
  5. 2018 High

    Conditional deletion in chondrocytes demonstrated that ADAMTSL2 is required cell-autonomously for growth plate formation, chondrocyte differentiation, TGF-β signaling in limbs, and establishment of a fibrillin-1/LTBP1 microfibrillar network.

    Evidence Total and chondrocyte-specific Adamtsl2 knockout mice; growth plate histology; immunostaining; TGF-β assays

    PMID:30303737

    Open questions at the time
    • Whether ADAMTSL2 promotes microfibril assembly directly or stabilizes it indirectly unclear
    • Signaling consequences in hypertrophic vs. proliferative chondrocytes not separated
  6. 2019 High

    Two advances refined tissue-specific roles: (1) conditional limb deletion showed ADAMTSL2 limits fibrillin microfibril assembly in tendons, and (2) pathogenic missense variants caused intracellular retention with defective secretion and increased pSMAD2, linking secretion failure to TGF-β dysregulation.

    Evidence Conditional KO with Prx1-Cre/Scx-Cre; in vitro colocalization; electron microscopy of patient fibroblasts; SMAD2 phosphorylation in HEK293 cells

    PMID:30738849 PMID:31516831

    Open questions at the time
    • Whether ADAMTSL2 acts by sequestering latent TGF-β vs. promoting its degradation not resolved
    • The fate of intracellularly retained mutant ADAMTSL2 (ER stress vs. degradation) not fully characterized
  7. 2020 High

    Mapping O-fucosylation of ADAMTSL2 TSRs and showing that POFUT2-dependent modification is essential for secretion established glycosylation as a quality-control checkpoint and explained how the GD mutation S641L impairs secretion by eliminating TSR3 O-fucosylation.

    Evidence Mass spectrometry glycan mapping; POFUT2−/− and B3GLCT−/− cell secretion assays; site-directed mutagenesis

    PMID:32913123

    Open questions at the time
    • Whether O-fucosylation also affects ADAMTSL2 binding to fibrillin or LTBPs not tested
    • Contribution of each individual TSR to secretion not fully mapped
  8. 2021 Medium

    Two studies expanded ADAMTSL2 functions beyond skeletal tissues: recombinant ADAMTSL2 attenuated TGF-β signaling and myofibroblast differentiation in cardiac fibroblasts, and ADAMTSL2–LTBP4 interaction disruption by scoliosis-associated variants upregulated TGF-β signaling.

    Evidence Overexpression and recombinant protein in human cardiac fibroblasts; Co-IP of ADAMTSL2–LTBP4 variants; TGF-β assays in fibroblasts

    PMID:34611183 PMID:34958866

    Open questions at the time
    • LTBP4 interaction confirmed by single Co-IP approach; reciprocal domain-mapping not performed
    • Cardiac anti-fibrotic role demonstrated only in vitro
  9. 2023 Medium

    Adamtsl2 nonsense mutation in mice recapitulated endochondral ossification defects, stiff skin, and additionally revealed uterine hypoplasia and reduced IGF1, broadening the phenotypic spectrum to reproductive and endocrine systems.

    Evidence Mouse linkage analysis; growth plate and skin histology; plasma IGF1 and estradiol measurement

    PMID:37656189

    Open questions at the time
    • Whether IGF1 reduction is a direct consequence of ECM disruption or a secondary endocrine defect is unknown
    • Ovarian and pituitary mechanisms not dissected at the molecular level
  10. 2025 Medium

    ADAMTSL2 was shown to bind LRP6, activate β-catenin signaling in cardiomyocytes, and protect against post-MI apoptosis, revealing a TGF-β-independent signaling axis through Wnt/β-catenin.

    Evidence Co-immunoprecipitation; LRP6 phosphorylation; β-catenin nuclear translocation; adenoviral overexpression in mouse MI model

    PMID:40975504

    Open questions at the time
    • Single Co-IP without reciprocal pull-down or domain mapping for LRP6 interaction
    • Whether LRP6 binding and LTBP/fibrillin binding are independent or coordinated is unknown
    • In vivo cardiac benefit demonstrated only in acute MI; chronic effects not assessed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for ADAMTSL2 binding to fibrillins/LTBPs, the precise mechanism by which ADAMTSL2 limits microfibril assembly (competitive inhibition vs. promoting turnover), and whether the LRP6/Wnt signaling axis operates in skeletal tissues affected in geleophysic dysplasia.
  • No crystal or cryo-EM structure of ADAMTSL2 or its complexes
  • Mechanism of microfibril assembly limitation (sequestration vs. turnover) not distinguished
  • Crosstalk between TGF-β and Wnt/β-catenin axes downstream of ADAMTSL2 not explored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0060089 molecular transducer activity 1
Localization
GO:0031012 extracellular matrix 3 GO:0005576 extracellular region 2
Pathway
R-HSA-1474244 Extracellular matrix organization 3 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2
Partners
FBN1FBN2LRP6LTBP1LTBP4POFUT2

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 ADAMTSL2 interacts with latent TGF-β-binding protein 1 (LTBP1), as identified by yeast two-hybrid screen; loss-of-function mutations in ADAMTSL2 lead to increased total and active TGF-β in culture medium and nuclear localization of phosphorylated SMAD2 in patient fibroblasts, demonstrating ADAMTSL2 as a regulator of TGF-β bioavailability. Yeast two-hybrid screen; functional studies in HEK293 cells; phospho-SMAD2 nuclear localization in patient fibroblasts Nature genetics High 18677313
2007 ADAMTSL2 is a secreted glycoprotein that binds to the cell surface and extracellular matrix; it contains 7 thrombospondin type-1 repeats and an unusually long spacer module with six N-glycosylation sites, with N-linked carbohydrate constituting ~20% of its mass; expression is regulated during skeletal myogenesis downstream of MyoD. Protein expression in HEK293F and COS-1 cells; northern blotting; in situ hybridization; immunohistochemistry; in vitro myogenic differentiation assay Matrix biology Medium 17509843
2010 The Musladin-Lueke Syndrome (MLS) founder mutation p.R221C in ADAMTSL2 causes formation of anomalous disulfide-bonded dimers when expressed in COS-1, HEK293F and CHO cells, and results in reduced secretion of the mutant protein into the medium. Transient expression in COS-1, HEK293F, CHO cells; SDS-PAGE under reducing/non-reducing conditions; medium protein quantification PloS one Medium 20862248
2015 ADAMTSL2 binds directly to fibrillin-2 (FBN2) with an affinity comparable to fibrillin-1 (FBN1); loss of Adamtsl2 in mice leads to accumulation of fibrillin microfibrils, increased FBN2 and MAGP1 staining, increased LTBP1 in bronchial epithelium, and increased bronchial epithelial TGFβ signaling, revealing a role for ADAMTSL2 in modulating microfibril formation. Direct binding assay (solid-phase binding); immunostaining of Adamtsl2−/− mouse tissue; TGFβ-neutralizing antibody treatment; lacZ reporter expression analysis Disease models & mechanisms High 25762570
2018 Adamtsl2 deletion in chondrocytes impairs growth plate formation, disrupts chondrocyte differentiation and proliferation, impairs TGF-β signaling in limbs, and prevents establishment of a microfibrillar network composed of fibrillin-1 and LTBP1 fibrils in chondrocytes. Total and chondrocyte-specific Adamtsl2 knockout mice; histology of growth plates; immunostaining for fibrillin-1, LTBP1; TGF-β signaling assays FASEB journal High 30303737
2019 ADAMTSL2 is strongly expressed in limb tendons and regulates microfibril assembly therein; conditional deletion using Prx1-Cre causes tendon anomalies and distal limb shortening; recombinant ADAMTSL2 colocalizes with fibrillin microfibrils in vitro; enhanced fibrillin-1 microfibril staining is observed in Prx1-Cre Adamtsl2 tendons, suggesting ADAMTSL2 limits fibrillin microfibril assembly. Intragenic lacZ reporter expression analysis; conditional KO with Prx1-Cre and Scx-Cre; in vitro colocalization assay with recombinant ADAMTSL2; immunostaining Matrix biology High 30738849
2020 ADAMTSL2 thrombospondin type-1 repeats (TSRs) are modified by O-fucosylation via POFUT2 and subsequently elongated to a Glcβ1-3Fuc disaccharide by B3GLCT; O-fucosylation is required for ADAMTSL2 secretion (secretion is lost in POFUT2−/− but not B3GLCT−/− cells); the geleophysic dysplasia mutation S641L in TSR3 eliminates O-fucosylation of TSR3 and reduces secretion. Mass spectrometry glycan mapping; POFUT2−/− and B3GLCT−/− cell secretion assays; site-directed mutagenesis of GPHYSD1 mutations The Journal of biological chemistry High 32913123
2019 Pathogenic ADAMTSL2 missense variants result in defective intracellular localization of the mutant protein, failure to accumulate in lysosome-like inclusions, reduced secretion into medium, and increased SMAD2 phosphorylation in transfected HEK293 cells, linking impaired secretion to TGF-β signaling dysregulation. Electron microscopy of patient skin fibroblasts; transfection of HEK293 cells; SMAD2 phosphorylation assay Molecular genetics and metabolism reports Medium 31516831
2021 ADAMTSL2 overexpression or extracellular treatment in human cardiac fibroblasts reduces TGF-β production and signaling, attenuates myofibroblast differentiation (reduced α-smooth muscle actin and osteopontin), and inhibits pro-fibrotic phenotypes including proliferation, migration, and contractility. Overexpression and recombinant protein treatment in human cardiac fibroblasts; TGFβ signaling assays; myofibroblast differentiation markers; functional assays for proliferation, migration, contractility Scientific reports Medium 34611183
2021 Mutated ADAMTSL2 variants identified in adolescent idiopathic scoliosis patients affect the interaction between ADAMTSL2 and LTBP4, and these variant pairs upregulate TGF-β signaling in human fibroblasts. Co-immunoprecipitation/interaction assay with ADAMTSL2 and LTBP4 variants; TGF-β signaling assay in human fibroblasts Gene Medium 34958866
2025 Fibroblast-secreted ADAMTSL2 directly binds to LRP6 (as shown by Co-IP) and promotes LRP6 phosphorylation, leading to β-catenin stabilization and nuclear translocation in cardiomyocytes, protecting against apoptosis post-myocardial infarction; fibroblast-targeted overexpression in vivo reduces infarct size and adverse remodeling. Co-immunoprecipitation; LRP6 phosphorylation assay; β-catenin nuclear translocation; cardiomyocyte apoptosis assay; adenoviral overexpression in mouse MI model Cellular signalling Medium 40975504
2025 ADAMTSL2 activates Notch signaling to transcriptionally upregulate ACLY, driving lipid metabolic reprogramming in colorectal cancer cells; ADAMTSL2 knockdown suppresses proliferation and migration in HCT116 and SW620 cells and in patient-derived organoids. ADAMTSL2 knockdown in CRC cell lines and patient-derived organoids; xenograft models; Notch signaling pathway analysis; ACLY expression assay Cellular signalling Low 41407175
2025 Primary dermal fibroblasts from GD patients with ADAMTSL2 variants show impaired secretion of ECM proteins (ADAMTSL2, FBN1, fibronectin), increased cell migration associated with upregulation of MMP-1 and MMP-14; these findings were corroborated in Adamtsl2-knockout mouse fibroblasts and lung/heart tissues; pan-MMP inhibitor GM6001 inhibits GD fibroblast migration. Primary human and mouse fibroblast isolation; ECM secretion assays; cell migration assay; MMP-1/MMP-14 expression; GM6001 pharmacological inhibition; Adamtsl2 KO mouse tissue analysis bioRxivpreprint Medium
2023 Adamtsl2 nonsense mutation in mice causes disturbed endochondral ossification with a reduced hypertrophic chondrocyte layer, stiff skin with thickened dermis, uterine hypoplasia, and irregular estrous cycles; reduced IGF1 plasma levels in mutant females suggest Adamtsl2 acts in the ovary/pituitary to regulate reproductive development. Linkage analysis; histology of growth plate and skin; Adamtsl2 mRNA expression in reproductive organs; plasma IGF1 and estradiol measurement; Gh expression in pituitary Mammalian genome Medium 37656189

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-beta bioavailability regulation. Nature genetics 195 18677313
2021 ADAMTSL2 protein and a soluble biomarker signature identify at-risk non-alcoholic steatohepatitis and fibrosis in adults with NAFLD. Journal of hepatology 63 34600973
2015 Adamtsl2 deletion results in bronchial fibrillin microfibril accumulation and bronchial epithelial dysplasia--a novel mouse model providing insights into geleophysic dysplasia. Disease models & mechanisms 57 25762570
2007 ADAMTS-like 2 (ADAMTSL2) is a secreted glycoprotein that is widely expressed during mouse embryogenesis and is regulated during skeletal myogenesis. Matrix biology : journal of the International Society for Matrix Biology 50 17509843
2011 Molecular screening of ADAMTSL2 gene in 33 patients reveals the genetic heterogeneity of geleophysic dysplasia. Journal of medical genetics 46 21415077
2021 The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts. Scientific reports 35 34611183
2018 Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 30303737
2010 An ADAMTSL2 founder mutation causes Musladin-Lueke Syndrome, a heritable disorder of beagle dogs, featuring stiff skin and joint contractures. PloS one 29 20862248
2019 Limb- and tendon-specific Adamtsl2 deletion identifies a role for ADAMTSL2 in tendon growth in a mouse model for geleophysic dysplasia. Matrix biology : journal of the International Society for Matrix Biology 24 30738849
2020 O-Fucosylation of ADAMTSL2 is required for secretion and is impacted by geleophysic dysplasia-causing mutations. The Journal of biological chemistry 22 32913123
2019 Geleophysic dysplasia: novel missense variants and insights into ADAMTSL2 intracellular trafficking. Molecular genetics and metabolism reports 16 31516831
2020 ADAMTSL2 gene variant in patients with features of autosomal dominant connective tissue disorders. American journal of medical genetics. Part A 13 33369194
2021 Aberrant interaction between mutated ADAMTSL2 and LTBP4 is associated with adolescent idiopathic scoliosis. Gene 8 34958866
2013 Novel mutations in ADAMTSL2 gene underlying geleophysic dysplasia in families from United Arab Emirates. Birth defects research. Part A, Clinical and molecular teratology 8 24014090
2017 A chinese boy with geleophysic dysplasia caused by compound heterozygous mutations in ADAMTSL2. European journal of medical genetics 7 28917829
2024 Exploring the role of ADAMTSL2 across multiple cancer types: A pan-cancer analysis and validated in colorectal cancer. Discover oncology 4 39384622
2022 Case report: A homozygous ADAMTSL2 missense variant causes geleophysic dysplasia with high similarity to Weill-Marchesani syndrome. Frontiers in genetics 4 36246610
2021 The relationship of ADAMTSL2 and LRPAP1 gene methylation level with rheumatoid arthritis activity. Clinical and experimental rheumatology 4 34936547
2023 A nonsense mutation in mouse Adamtsl2 causes uterine hypoplasia and an irregular estrous cycle. Mammalian genome : official journal of the International Mammalian Genome Society 2 37656189
2024 Geleophysic dysplasia and Weill-Marchesani syndrome: ADAMTSL2 a possible common gene. Ophthalmic genetics 1 39044700
2020 Purification of Recombinant ADAMTSL2. Methods in molecular biology (Clifton, N.J.) 1 31463910
2026 Case Report: Novel ADAMTSL2 compound heterozygous mutations in geleophysic dysplasia with bilateral glaucoma and keratoconus-like corneal ectasia. Frontiers in genetics 0 41664703
2026 The Pathogenic ADAMTSL2 D167N Variant Causes Geleophysic Dysplasia-Like Connective Tissue Changes in Mice. The American journal of pathology 0 41864337
2025 Fibroblast-secreted ADAMTSL2 promotes cardiac repair after myocardial infarction by activating LRP6/β-catenin signaling. Cellular signalling 0 40975504
2025 ADAMTSL2 facilitates ACLY-mediated lipid metabolism in colorectal cancer by activating Notch signaling pathway. Cellular signalling 0 41407175
2020 Molecular Cloning, Lentiviral Transduction, and Expression of Recombinant ADAMTSL2 and ADAMTSL4. Methods in molecular biology (Clifton, N.J.) 0 31463909