Gene Ontology annotation through association of InterPro records with GO terms
Annotation inferences using phylogenetic trees
ADAMTSL-3/punctin-2, a novel glycoprotein in extracellular matrix related to the ADAMTS family of metalloproteases.
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ADAMTSL3/punctin-2 lacks both the metalloprotease and the disintegrin-like domain of the ADAMTS proteinases while preserving the rest of the ADAMTS domain order.
"These multi-domain proteins lack both a protease domain and a disintegrin-like domain but are remarkably similar in their domain organization to the ADAMTS proteases, hence the name ADAMTS-like."
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Punctin-2 is secreted as a 210-kDa glycoprotein that is deposited in the extracellular matrix of transfected cells - the direct experimental basis for UniProt's ECO:0000269 subcellular location.
"Using these and a monoclonal antibody to a C-terminal myc tag, we show that in transfected COS-7 cells, punctin-2 is expressed as a 210-kDa glycoprotein that is located in the extracellular matrix."
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The TSR arrays are interrupted by three immunoglobulin-like repeats, an architecture not seen in the ADAMTS proteinases.
"Punctin-2 contains 13 TSRs arranged in two arrays separated by a region containing three immunoglobulin-like repeats."
ADAMTSL3/punctin-2, a gene frequently mutated in colorectal tumors, is widely expressed in normal and malignant epithelial cells, vascular endothelial cells and other cell types, and its mRNA is reduced in colon cancer.
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ADAMTSL3 protein is broadly distributed across human epithelia, vasculature, fibroblasts, neurons and cardiac myocytes - the basis for treating the mouse cardiac and neuronal phenotypes as relevant to the human protein.
"ADAMTSL3 is expressed in epithelial cells of the colon, fallopian tube, skin, breast, prostate, epididymis, liver, pancreatic islets and bile ducts, as well as by vascular endothelial cells, smooth muscle cells, fibroblasts, cortical and ganglionic neurons and cardiac myocytes."
Microenvironmental regulation by fibrillin-1.
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The C-terminal region of ADAMTSL-3 binds the N-terminal half of fibrillin-1 by SPR; ADAMTSL-1 does not, so the interaction is selective within the family.
"Similar to ADAMTSL-6 [24], ADAMTSL-2, -3, and papilin polypeptides interacted with the N-terminal half of fibrillin-1, while ADAMTSL-1 did not."
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The Weill-Marchesani three-domain deletion in fibrillin-1 abolishes ADAMTSL binding, mapping the site.
"ADAMTSL-2, -3, and -6 and papilin polypeptides did not bind to recombinant fibrillin-1 polypeptides with the WMS three-domain deletion (Figure 5a and Table S1)."
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ADAMTSL-3 binds the non-catalytic C-terminal region of ADAMTS-10 with a KD of 2 nM, and this too is selective within the family.
"SPR also showed that the C-terminal end of ADAMTS-10 interacted with the C-terminal end of ADAMTSL-3 with high binding affinity (KD = 2 nM) (Figure 5c)."
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ADAMTSL-3 binds the C-terminal domains of LTBP-1 but not LTBP-4, connecting it to latent TGF-beta sequestration.
"Binding between ADAMTSL-3 and the C-terminal domains of LTBP-1 was also detected, but neither ADAMTSL-2 nor -3 interacted with LTBP-4."
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No colocalisation of ADAMTSL-3 with fibrillin-1 was tested, because ADAMTSL3-specific antibodies did not exist. This is the reason the elastic-fiber annotation cannot be treated as an established location.
"Since antibodies specific for ADAMTSL-2 and -3 are not yet available, we were unable to determine whether these proteins also colocalize with fibrillin-1 in skin and whether these are also reduced in WMΔ mutant mice."
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The Methods contradict the Results on the species of the ADAMTSL-3 reagent: the Results call it human, the Methods describe a RIKEN clone plus mouse lung cDNA.
"Constructs for ADAMTSL3 were made using a clone (RIKEN) and mouse lung cDNA."
Elastic fibres in health and disease.
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Elastic fibres consist of a cross-linked elastin core within a fibrillin microfibril template - the structure that makes ADAMTSL3's fibrillin-1 binding a plausible basis for the elastic-fiber annotation, without demonstrating it.
"They are laid down during development, and comprise a cross-linked elastin core within a template of fibrillin-based microfibrils."
A proteome-scale map of the human interactome network.
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HI-II-14 is a systematic proteome-scale binary interactome screen, not a targeted study of ADAMTSL3; five of ADAMTSL3's GO:0005515 rows come from it.
"While currently available information is highly biased and only covers a relatively small portion of the proteome, our systematic map appears strikingly more homogeneous"
A reference map of the human binary protein interactome.
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HuRI is a systematic Y2H map of the human proteome; ten of ADAMTSL3's GO:0005515 rows come from it, and it shares the CCSB ORFeome and search space with HI-II-14, so overlap between the two is not independent replication.
"Specifically, yeast two-hybrid (Y2H) represents the only binary PPI assay that can be operated at sufficient throughput to systematically screen the human proteome for binary PPIs."
ADAMTSL3 knock-out mice develop cardiac dysfunction and dilatation with increased TGFβ signalling after pressure overload.
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Overexpression of human ADAMTSL3 in human foetal cardiac fibroblasts lowers phospho-SMAD2 and active TGF-beta - the only human-cell functional experiment on this protein.
"Immunoblotting revealed reduced pSMAD (Fig. 4h) and reduced active TGFβ (Fig. 4i), indicating reduced TGFβ signalling."
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The gain-of-function experiment used adenoviral overexpression, so the appropriate evidence code is IMP rather than IDA.
"For further mechanistic insights, we overexpressed full-length ADAMTSL3 (L3) and a vehicle control adenovirus (veh) in cultures of human foetal CFBs (hfCFBs)"
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Loss and gain of function agree in sign, which is what makes the negative-regulation direction safe.
"Taken together, the loss-of-function and gain-of-function studies suggest ADAMTSL3 as an inhibitor of TGFβ signalling in the heart in vivo and in cardiac fibroblasts in vitro."
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Adamtsl3-null mouse hearts show raised active TGF-beta and cardiac fibroblast activation after aortic banding.
"We found that Adamtsl3 knock-out mice develop exacerbated cardiac dysfunction and dilatation with increased mortality, and hearts show increased TGFβ activity and CFB activation after pressure overload by aortic banding."
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The authors state the family-level premise independently: ADAMTSLs lack a catalytic domain.
"ADAMTSLs are structurally related to the ADAMTS ECM proteases12, but lack a catalytic domain, leaving their biological function largely unknown."
Adamtsl3 mediates DCC signaling to selectively promote GABAergic synapse function.
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Mouse conditional deletion of Adamtsl3 in neurons reduces DCC protein and the density of glutamatergic and GABAergic synapses.
"We demonstrate that early post-natal deletion of Adamtsl3 in neurons impairs DCC protein expression, causing reduced density of both glutamatergic and GABAergic synapses."
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Adamtsl3 acts as a hippocampal synapse organiser through the DCC receptor.
"Here, we identify that the secreted protein Adamtsl3 functions as critical hippocampal synapse organizer acting through the transmembrane receptor DCC (deleted in colorectal cancer)."
Schizophrenia-associated glycoprotein Adamtsl3 regulates perineuronal net formation, maintenance, and adult cortical plasticity.
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Adamtsl3 is required cell-autonomously by parvalbumin interneurons for perineuronal net integrity - independent evidence that this protein organises a specialised extracellular matrix.
"Here, we identify the schizophrenia-associated glycoprotein Adamtsl3 as a PV+ cell-autonomous regulator of PNN integrity."
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The proposed mechanism runs through MMP9: Adamtsl3 loss raises MMP9 and the perineuronal net defect is rescued by MMP9 inhibition.
"Mechanistically, Adamtsl3 modulates matrix metalloprotease-9 (MMP9) activity, and Adamtsl3 deletion results in elevated MMP9 levels, PNN reduction, decreased Otx2 uptake, and heightened oxidative stress in PV+ cells."
Affinage mechanistic annotation for ADAMTSL3 (human)
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Machine-generated record. Its one directly usable contribution is a corpus-level negative: no biochemical mechanism has been published for the effect of ADAMTSL3 on DCC. Independently confirmed here by searching the ADAMTSL3 literature.
"The biochemical mechanism by which this non-catalytic ECM protein controls DCC receptor levels has not been characterized in the available corpus."
C. elegans Punctin specifies cholinergic versus GABAergic identity of postsynaptic domains.
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The nematode orthologue is a secreted synaptic organiser that assigns neurotransmitter identity to postsynaptic domains, establishing that the synaptic role is ancestral.
"C. elegans Punctin specifies cholinergic versus GABAergic identity of postsynaptic domains."
MADD-4 is a secreted cue required for midline-oriented guidance in Caenorhabditis elegans.
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MADD-4 signals through UNC-40/DCC, the same receptor that mediates Adamtsl3's effect in the mouse hippocampus - so the receptor pairing, not just the protein, is conserved.
"MADD-4's activity is dependent on UNC-40/DCC, a netrin receptor, which functions cell-autonomously to direct membrane extension."
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MADD-4 is the co-orthologue of both ADAMTSL1 and ADAMTSL3, so worm phenotypes cannot be assigned to either human paralogue alone.
"The biological role of MADD-4 orthologs, including ADAMTSL1 and 3 in mammals, is unknown."
Genome-wide association analysis identifies 20 loci that influence adult height.
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ADAMTSL3 is one of the reproducible genome-wide association loci for adult height, and was interpreted by the authors as an extracellular matrix gene. This motivates the growth-plate experiment but supports no GO term on its own.
"The genes implicate a number of biological pathways and processes in the normal determination of human height, including Hedgehog signaling (IHH, HHIP, PTCH1), basic cell cycle regulation (CDK6, one of the cyclin-dependent kinases implicated in cell cycle progression13), extracellular matrix (ADAMTSL3 and EFEMP1) and chromatin rearrangement and polycomb proteins (HMGA2 and SCMH1)."
ADAMTSL3 as a candidate gene for schizophrenia: gene sequencing and ultra-high density association analysis by imputation.
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The schizophrenia association at ADAMTSL3 is refined but not resolved; the paper's own conclusion is that the gene remains a candidate.
"Our study confirms ADAMTSL3 as a candidate for further investigation in schizophrenia, using the variants identified here."
Genome-wide CRISPR knockout screens identify ADAMTSL3 and PTEN genes as suppressors of HCC proliferation and metastasis, respectively.
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ADAMTSL3 emerged from a genome-wide CRISPR screen in one hepatocellular carcinoma line as a suppressor of proliferation. Single screen, single line, no mechanism.
"Moreover, knocking out either the ADAMTSL3 or PTEN genes promoted either the proliferation or metastasis of HCC cells, respectively."
Antiangiogenic characteristics of astrocytes from optic nerve heads with primary open-angle glaucoma.
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ADAMTSL-3 transcript is raised in optic-nerve-head astrocytes from glaucoma donors. The reduced tube formation reported in the same paper is a property of the astrocyte populations, not of ADAMTSL3, which was never perturbed.
"The ONH astrocytes from donors with POAG decreased expression of proangiogenic factors (vascular endothelial growth factor C and platelet-derived growth factor A) and increased expression of antiangiogenic factors (collagen XVIII and ADAMTSL-3) when compared with normal ONH astrocytes."