{"gene":"THBS1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2021,"finding":"THBS1 binds and activates the endoplasmic reticulum stress effector PERK, inducing downstream transcription factor ATF4 and causing lethal autophagy-mediated cardiac atrophy. Deletion of PERK in Thbs1 transgenic mice blunted ATF4 induction and autophagy and largely corrected the lethal cardiac atrophy. Deletion of other THBS1 effectors/receptors (ATF6α, CD36, CD47) did not diminish this effect.","method":"Transgenic overexpression, genetic knockout (Thbs1-/-, PERK-/-, ATF6α-/-, CD36-/-, CD47-/-), AAV9 gene transfer, in vivo cardiac phenotyping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models with orthogonal methods, receptor deletion epistasis, AAV rescue experiments in a single rigorous study","pmids":["34168130"],"is_preprint":false},{"year":2024,"finding":"THBS1 activates TGFβ-Smad2/3 signaling in skeletal muscle, which induces ATF4 expression that together modulates the autophagy-lysosomal pathway (ALP) and ubiquitin-proteasome system (UPS) to drive muscle atrophy. Myofiber-specific inhibition of TGFβ-receptor signaling, deletion of Smad2/3, or deletion of Atf4 each antagonized Thbs1-induced muscle atrophy. Thbs1-/- mice showed reduced denervation- and caloric restriction-induced atrophy.","method":"Skeletal muscle-specific Thbs1 transgenic mice, myofiber-specific TGFβR inhibition, conditional Smad2/3 knockout, Atf4 knockout, loss-of-function (Thbs1-/-) with denervation/caloric restriction models","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent genetic models with epistasis, replicated across atrophy paradigms in a single rigorous study","pmids":["38678560"],"is_preprint":false},{"year":2017,"finding":"TSP1 promotes endothelial cell senescence through its receptor CD47 by activating NADPH oxidase 1 (Nox1), but not other Nox isoforms, leading to increased ROS, p53 nuclear accumulation, and p21cip upregulation via a DNA damage response. Nox1 inhibition blocked TSP1-induced p53 nuclear localization and senescence. Mice lacking TSP1 showed decreased ROS, p21cip, and aging-induced senescence.","method":"TSP1-/- mice, pharmacological Nox1 inhibition, siRNA knockdown, co-immunoprecipitation (CD47-Nox1 axis), human endothelial cell culture, aged human lung tissue analysis","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mice, pharmacological inhibition, siRNA), replicated in human tissue and mouse model","pmids":["29042481"],"is_preprint":false},{"year":2017,"finding":"TSP1 (encoded by Thbs1) is suppressed downstream of KRIT1/KLF2/KLF4 signaling in brain microvascular endothelial cells. Loss of TSP1 enables heightened VEGF signaling and loss of tight junctions. In vitro reconstitution of TSP1 (full-length or the 3TSR anti-angiogenic fragment) suppressed VEGF signaling and preserved tight junctions. Administration of 3TSR prevented cerebral cavernous malformation (CCM) lesion development in Krit1 knockout mice, while inactivation of one or two copies of Thbs1 exacerbated CCM formation.","method":"Krit1 mouse knockout, Thbs1 conditional knockout/heterozygous models, in vitro TSP1 reconstitution, 3TSR peptide administration, histology and micro-CT quantification","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro reconstitution plus multiple in vivo genetic models with functional rescue, orthogonal readouts","pmids":["28970240"],"is_preprint":false},{"year":2015,"finding":"TSP1 expressed on monocytic cells (not endothelial or other cells) contributes to their adhesion and migration capacity. Adoptive transfer of wild-type monocytic cells or bone marrow reconstitution rescued aneurysm development in Thbs1-/- mice, demonstrating that monocyte-intrinsic TSP1 drives inflammatory cell infiltration into the aortic wall during AAA development.","method":"Thbs1-/- mice, three AAA induction models (CaPO4, elastase, angiotensin II), adoptive transfer of monocytic cells, bone marrow reconstitution, in vitro adhesion/migration assays","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — adoptive transfer and bone marrow reconstitution establish cell-autonomous mechanism; three independent AAA models","pmids":["25940549"],"is_preprint":false},{"year":2020,"finding":"Myeloid/macrophage-derived TSP1 contributes to abdominal aortic aneurysm by suppressing TIMP1 expression, which enables macrophage matrix invasion. Myeloid-specific Thbs1 deletion (Thbs1flox/flox × Lyz2-cre) protected mice from CaCl2-induced AAA. TSP1-deficient macrophages had elevated TIMP1 and reduced gelatinase activity; Timp1 knockdown restored the ability of Thbs1-null macrophages to invade matrix.","method":"Myeloid-specific conditional Thbs1 knockout (Lyz2-cre), RNA FISH, gelatinase activity assays, Timp1 siRNA knockdown, in vivo AAA model","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with epistasis (Timp1 rescue), multiple orthogonal methods","pmids":["33028100"],"is_preprint":false},{"year":2005,"finding":"TSP-1 is strongly induced in ischemic kidney proximal tubules and causes apoptosis (caspase-3 activation, cytochrome c release) in normal and ATP-depleted proximal tubule cells. TSP-1-null mice were significantly protected from ischemia/reperfusion-induced renal failure and tubular damage, identifying TSP-1 as a mediator of ischemic kidney injury.","method":"DNA microarray followed by Northern hybridization, immunocytochemistry (caspase-3, cytochrome c), purified TSP-1 addition to kidney cells in vitro, TSP-1 null mouse IR injury model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro mechanistic assays (caspase-3, cytochrome c) combined with in vivo genetic KO model with renal function readout","pmids":["16294224"],"is_preprint":false},{"year":2007,"finding":"CD36 is an endothelial cell receptor required for TSP-1 and TSP-2 anti-angiogenic activity. CD36-mediated anti-angiogenic signaling redirects pro-angiogenic responses toward apoptosis. The TSP type I repeat (TSR) domain of TSP-1 mediates this activity.","method":"Receptor identification studies, endothelial cell functional assays, CD36 signaling cascade characterization (literature synthesis with experimental basis cited)","journal":"Current pharmaceutical design","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor identification supported by cell-based functional assays; abstract summarizes prior experimental work without full method detail","pmids":["18220792"],"is_preprint":false},{"year":2017,"finding":"TSP-1 is a BMP-2 and BMP-4 antagonist. Recombinant human TSP-1 binds BMP-2 and BMP-4 as demonstrated by surface plasmon resonance and co-immunoprecipitation, and antagonizes their effects on C3H10T1/2 cells. The von Willebrand type C domain of TSP-1 is implicated in this BMP-2/4-binding activity based on sequence similarity with Crossveinless 2.","method":"Surface plasmon resonance, co-immunoprecipitation, BMP-responsive element bioactivity assay in C3H10T1/2 cells, high-resolution mass spectrometry, domain analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding confirmed by SPR and co-IP with functional antagonism assay; multiple orthogonal biochemical methods in one study","pmids":["28747434"],"is_preprint":false},{"year":2016,"finding":"TSP1-CD47 signaling promotes pulmonary arterial vasculopathy. In hypoxic wild-type mice, TSP1 and CD47 are upregulated concordantly with ET-1/ETA and downregulation of cMyc. In CD47-/- mice, PH was attenuated, cMyc was overexpressed, and ET-1 was reduced. In CD47+/+ cells, forced cMyc induction suppressed ET-1 transcript; suppression of cMyc increased ET-1 signaling. TSP1 treatment of control pulmonary arteries inhibited vasodilation and potentiated ET-1-mediated vasoconstriction; CD47 blocking antibody improved vasodilator sensitivity in diseased PAs.","method":"CD47-/- mice with hypoxia-induced PH, exogenous TSP1 treatment of ex vivo pulmonary arteries, cMyc overexpression/knockdown in CD47+/+ cells, CD47 blocking antibody in rat monocrotaline model, myography","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic and pharmacological models across species with mechanistic pathway dissection (cMyc/ET-1 axis)","pmids":["27742621"],"is_preprint":false},{"year":2019,"finding":"TSP1 interacts with CD47 to promote pulmonary hypertension in sickle cell disease by increasing reactive oxygen species (ROS) generation in pulmonary endothelial cells. Genetic absence of CD47 in chimeric sickle mice reduced right ventricular pressure, mean pulmonary artery pressure, and pulmonary vascular resistance. TSP1 treatment of human pulmonary artery endothelial cells stimulated ROS generation that was abrogated by CD47 blockade.","method":"Bone marrow chimeric mice (BERK sickle marrow into CD47KO hosts), right heart catheterization, ex vivo myography, ROS measurements in human pulmonary endothelial cells with TSP1 treatment and CD47 blockade","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — chimeric animal model plus in vitro mechanistic assays with receptor blockade, multiple orthogonal readouts","pmids":["30892078"],"is_preprint":false},{"year":2018,"finding":"In prostate cancer, androgen deprivation therapy (ADT) activates CREB, which enhances EZH2 activity. EZH2 directly epigenetically represses THBS1 (TSP1), reducing this anti-angiogenic factor and enabling angiogenesis and neuroendocrine differentiation. Repressing CREB inhibited the CREB/EZH2 axis, tumor growth, neuroendocrine differentiation, and angiogenesis in vivo.","method":"In vivo castration/ADT models in xenografts, CREB inhibition, EZH2 ChIP assays, TSP1 promoter methylation analysis, in vivo tumor experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP establishing direct EZH2 binding at THBS1 locus, in vivo rescue/inhibition experiments, multiple orthogonal approaches","pmids":["30287808"],"is_preprint":false},{"year":2018,"finding":"YAP transcriptionally activates THBS1 in a TEAD-dependent manner in breast cancer cells. THBS1 then activates FAK phosphorylation to promote focal adhesion and tumor invasiveness. Silencing THBS1 reversed YAP-induced FAK activation and focal adhesion.","method":"Chromatin immunoprecipitation (ChIP), dual luciferase assay, gene expression profiling, Western blot for pFAK, siRNA-mediated THBS1 silencing, transwell invasion assays","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP and dual luciferase establish direct transcriptional regulation; siRNA epistasis links THBS1 to FAK activation; multiple orthogonal methods","pmids":["30055645"],"is_preprint":false},{"year":2013,"finding":"Lactate induces THBS1 protein expression in glioma cells, and THBS1 in turn activates TGF-β2 (a latent form requiring proteolytic activation). Inhibition of THBS1 by siRNA reduces TGF-β2 protein and glioma cell migration. Addition of synthetic THBS1 rescues reduced TGF-β2 protein levels and glioma cell migration in LDH-A knockdown (low-lactate) cells.","method":"siRNA knockdown of LDH-A and THBS1, lactate addition/rescue experiments, Western blot, ELISA, spheroid/scratch/Boyden chamber migration assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA epistasis with synthetic THBS1 rescue and multiple migration assays; single lab but orthogonal approaches","pmids":["24223867"],"is_preprint":false},{"year":2020,"finding":"Intermittent hypoxia (IH) induces TSP1 expression in cardiac fibroblasts through STAT3 phosphorylation at Tyr705. TSP1 upregulation mediates IH-induced cardiac fibroblast activation and cardiac fibrosis. STAT3 inhibition (pharmacological S3I-201 or AAV9-shStat3 in cardiac fibroblasts) significantly attenuated synergistic cardiac fibrosis from IH and angiotensin II.","method":"IH mouse model, in vitro cardiac fibroblast culture, STAT3 pharmacological inhibition and AAV9-driven shRNA knockdown, plasma TSP1 ELISA in OSA patients","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro corroboration, genetic/pharmacological STAT3 inhibition, but single lab","pmids":["31934850"],"is_preprint":false},{"year":2007,"finding":"Androgen receptor (AR) expression increases TSP1 secretion by prostate cancer cells, decreasing their angiogenic potential. AR activation also decreases RelA (NFκB subunit) nuclear localization and transcriptional activity, reducing Bcl-2 and IL-6 expression. Combined NFκB suppression and increased TSP1 underlie AR anti-tumor activity in vivo.","method":"Stable AR-expressing prostate cancer cell lines, tumor xenografts in male mice, ELISA for TSP1 secretion, immunostaining for vascularity/apoptosis, NFκB reporter assays","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo xenograft with molecular pathway analysis; single lab with multiple functional readouts","pmids":["17487836"],"is_preprint":false},{"year":2015,"finding":"B cell-derived TSP1 converts latent TGF-β to active TGF-β in dendritic cells, generating TGF-β-producing tolerogenic dendritic cells (TolDCs). IL-13 inhibits TSP1 expression in B cells by enhancing TSP1 gene DNA methylation, thereby impairing TolDC generation.","method":"B cell-deficient mouse model (anti-CD20 antibody), flow cytometry, ELISA, qRT-PCR, Western blot, methylation-specific PCR","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods linking B cell TSP1 to TGF-β activation and TolDC generation; single lab","pmids":["25839231"],"is_preprint":false},{"year":2019,"finding":"TSP1 activates SHP-2 through its receptor CD47, reducing STAT3 phosphorylation and thereby blocking the STAT3-iNOS pathway and reducing nitric oxide concentration in retinal endothelial cells. This mechanism protects against choroidal neovascularization (CNV) in age-related macular degeneration. Co-immunoprecipitation showed CD47-SHP-2 binding in response to TSP1.","method":"Co-immunoprecipitation (CD47-SHP-2), TSP1 overexpression in RF/6A cells, CCK-8 viability, flow cytometry (apoptosis), transwell migration, Western blot for STAT3/iNOS, CNV mouse model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying CD47-SHP-2 interaction and downstream STAT3-iNOS pathway; in vivo CNV model; single lab","pmids":["31899207"],"is_preprint":false},{"year":2019,"finding":"Senescent cells produce TSP1, which prevents senescence escape in breast cancer cells. Senescence escape is mediated by CD47low cells that arise when p21waf1 is downregulated, enabling Myc upregulation, which binds the CD47 promoter to repress CD47 expression, allowing cells to escape TSP1-mediated suppression.","method":"SWATH quantitative proteomic analysis, in vitro and in vivo senescence models, ChIP (Myc binding to CD47 promoter), p21 siRNA-mediated downregulation, serum TSP1 measurement in breast cancer patients","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for Myc-CD47 promoter binding, quantitative proteomics, functional siRNA epistasis; single lab","pmids":["30814491"],"is_preprint":false},{"year":2019,"finding":"TSP1 promotes follicular angiogenesis, luteinization, and ovulation in primates. THBS1 treatment of monkey ovarian microvascular endothelial cells stimulated migration, proliferation, and capillary sprout formation in vitro. Intra-follicular injection of anti-THBS1 antibody reduced follicle rupture, oocyte release, granulosa cell layer expansion, endothelial cell invasion, and capillary formation.","method":"In vitro endothelial cell migration/proliferation/tube formation assays, intra-follicular anti-THBS1 antibody injection in cynomolgus macaques, follicle histology","journal":"Frontiers in endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo primate antibody neutralization with functional follicle readout; in vitro corroboration; single lab","pmids":["31787928"],"is_preprint":false},{"year":2025,"finding":"THBS1 in macrophage-derived exosomes binds directly to OTUD5 and promotes GPX4 ubiquitination, leading to ferroptosis in endothelial cells during cerebral ischemia-reperfusion injury. Modulation of THBS1 in macrophage-derived exosomes affected endothelial ferroptosis. Salvianolic acid B inhibited the THBS1-OTUD5 interaction, reducing GPX4 ubiquitination and protecting against CIRI.","method":"RNA interference, AAV transfection, endothelial-specific Gpx4 knockout mice, proteomic sequencing, THBS1-OTUD5 binding assay, cellular thermal shift assay, molecular docking/MD simulation, tMCAO mouse model","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay (THBS1-OTUD5), genetic KO epistasis, in vivo tMCAO model; single lab with multiple orthogonal approaches","pmids":["39994679"],"is_preprint":false},{"year":2023,"finding":"THBS1 from bone marrow-derived monocyte-like cells (recruited by CXCL12) contributes to colorectal cancer metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. THBS1 loss in the tumor microenvironment rendered tumors partially sensitive to immune checkpoint inhibitors.","method":"Orthotopic CRC mouse models, THBS1 knockout in TME, immune cell profiling, tumor growth and metastasis assays, immune checkpoint inhibitor combination experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo orthotopic models with genetic THBS1 deletion in TME; functional immune readouts; single lab","pmids":["37749092"],"is_preprint":false},{"year":2019,"finding":"P2Y4 receptor activation regulates TSP-1 expression, which activates TGF-β1/pSmad2/3 signaling to promote angiogenesis and blood-brain barrier damage during acute seizures. Inhibition of TSP-1 by siRNA or LSKL peptide (TGF-β1 activation inhibitor) prevented KA-induced Smad2/3 phosphorylation, angiogenesis, BBB damage, and acute seizures.","method":"siRNA-mediated TSP-1 knockdown, LSKL peptide inhibition, P2 receptor antagonists, kainic acid seizure model in rats, immunostaining and Western blot","journal":"Brain research bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA epistasis with LSKL peptide for pathway ordering; in vivo rodent model with functional readouts; single lab","pmids":["31005663"],"is_preprint":false},{"year":2022,"finding":"Sestrin2 overexpression modulates the activity of the TSP-1/TGF-β1/Smad3 pathway in podocytes under high glucose conditions. TSP-1 inhibition by LSKL peptide or TGF-β1 blockade arrested high-glucose-induced podocyte injury, placing TSP-1 upstream of TGF-β1 activation in diabetic kidney disease.","method":"Sestrin2 transgenic mice, STZ-induced diabetes model, podocyte cell culture, LSKL peptide inhibition, Pirfenidone (TGF-β blocker), pathway protein analysis by Western blot","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro corroboration with pharmacological inhibitors establishing pathway order; single lab","pmids":["35908070"],"is_preprint":false},{"year":2023,"finding":"LRRK2 G2019S mutation promotes ER stress in neurons by directly interacting with THBS1, which in turn interacts with TGF-β1. Knocking down THBS1 rescued ER stress and behavioral burden caused by the LRRK2 mutation. Suppression of TGF-β1 had a similar effect, placing THBS1 between LRRK2 G2019S and TGF-β1 in ER stress signaling.","method":"iPSC-derived dopamine neurons, LRRK2 G2019S mouse model, co-immunoprecipitation (LRRK2-THBS1 interaction), THBS1 and TGF-β1 knockdown, LRRK2 kinase inhibition","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishing direct LRRK2-THBS1 interaction; genetic epistasis via knockdown; iPSC and mouse models; single lab","pmids":["37672887"],"is_preprint":false},{"year":2021,"finding":"USF2 transcriptionally activates THBS1 to activate the TGF-β/Smad3/NLRP3/Caspase-1 signaling pathway, promoting pyroptosis in sepsis-induced acute kidney injury. USF2 knockdown downregulated THBS1 and inhibited the TGF-β/Smad3 pathway and pyroptosis.","method":"USF2 and THBS1 siRNA knockdown, sepsis AKI mouse model, in vitro cell model, qRT-PCR, ELISA, Western blot for NLRP3/Caspase-1/GSDMD pathway components","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pathway placement via knockdown with multiple molecular readouts; in vitro and in vivo corroboration; single lab","pmids":["34756923"],"is_preprint":false},{"year":2013,"finding":"PRMT6 overexpression strongly upregulates TSP-1 expression in MCF7 and PC3 cancer cells. Specific knockdown of TSP-1 significantly rescued the suppression of migration and invasion caused by PRMT6 overexpression, placing TSP-1 downstream of PRMT6 in the regulation of cancer cell motility.","method":"Stable PRMT6-overexpressing cell lines, siRNA knockdown of TSP-1, cell migration/invasion assays, Western blot","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single approach (overexpression + siRNA rescue); no direct binding or enzymatic assay","pmids":["23380452"],"is_preprint":false},{"year":2019,"finding":"In endothelial cells, MT1-MMP cleaves TSP1, and the C-terminal fragment of TSP1 binds CD47/αvβ3 integrin to promote nitric oxide production required for vasodilation and intussusceptive angiogenesis. MT1-MMP deletion in endothelial cells limited IA and reduced NO production; lentiviral rescue experiments confirmed requirement for MT1-MMP activity.","method":"MT1-MMP endothelial conditional knockout mice, intravital microscopy, lentiviral rescue, in vitro cell culture, anti-MT1-MMP antibody and αvβ3-binding TSP1 peptide administration in colitis model","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and lentiviral rescue experiments establishing MT1-MMP/TSP1 C-terminal fragment/CD47-αvβ3/NO axis; single lab with multiple orthogonal methods","pmids":["31793743"],"is_preprint":false},{"year":2021,"finding":"TSP1 promotes keloid fibroblast proliferation and collagen I deposition through the IL6/JAK2/STAT3 signaling pathway. Knockdown of TSP1 decreased proliferation and collagen I; exogenous TSP1 treatment increased both in normal fibroblasts. TSP1 expression positively correlated with IL6/STAT3 signaling activity in keloid tissues.","method":"siRNA knockdown of TSP1 in keloid fibroblasts, exogenous TSP1 treatment of normal fibroblasts, Western blot and immunohistochemistry, IL6/JAK2/STAT3 pathway analysis","journal":"Experimental dermatology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown and exogenous treatment without definitive receptor identification or in vivo validation","pmids":["35661430"],"is_preprint":false},{"year":2022,"finding":"Inhibiting THBS1 expression in ECFC-derived exosomes activates PI3K, AKT, and ERK phosphorylation in endothelial cells, promoting VEGF and bFGF expression and enhancing angiogenesis and bone formation in distraction osteogenesis.","method":"Lentiviral THBS1 knockdown in ECFCs, exosome isolation and application to HUVECs, Western blot for PI3K/AKT/ERK, tube formation/migration/proliferation assays, in vivo canine mandibular DO model with peripheral blood exosome injection","journal":"Journal of orthopaedic translation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway activation via knockdown; in vivo model is non-standard; single lab","pmids":["36196150"],"is_preprint":false},{"year":2025,"finding":"Under normoxic conditions, TGFβ1 inhibits angiogenesis by upregulating TSP1 in endothelial cells via TGFβR1-SMAD2/3 signaling. In hypoxia, HIF1α induces miR-145, which represses SMAD2/3 and subsequently reduces TSP1 levels in endothelial cells, thereby abrogating the anti-angiogenic effect of TGFβ1.","method":"Chick chorioallantoic membrane assays, zebrafish angiogenesis models, mouse hepatoma xenografts, HIF1α inhibitor/stabilizer treatments, miR-145 overexpression, SMAD2/3 knockdown, TSP1 measurement in endothelial cells and human HCC specimens","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vivo models (chick, zebrafish, mouse) with molecular pathway dissection; single lab with orthogonal approaches","pmids":["39356626"],"is_preprint":false},{"year":2022,"finding":"m6A reader IGF2BP1 binds and stabilizes THBS1 mRNA in an m6A-dependent manner in macrophages, promoting macrophage M2 polarization and glycolytic reprogramming. THBS1 physically interacts with TLR4 to mediate these downstream effects. TLR4 overexpression reversed the inhibitory effect of THBS1 knockdown on M2 polarization and glycolysis.","method":"IGF2BP1 knockdown in BLM-induced PF mice, RIP (RNA immunoprecipitation) for THBS1 mRNA, co-immunoprecipitation (THBS1-TLR4), THBS1 overexpression rescue, glycolysis assays, M2 polarization flow cytometry","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP establishing m6A-dependent mRNA stabilization, Co-IP for THBS1-TLR4 interaction, in vivo mouse model; single lab","pmids":["40220148"],"is_preprint":false},{"year":2022,"finding":"Cell surface GRP78 (csGRP78) regulates high-glucose-induced TSP1 transcriptional upregulation via PI3K/Akt signaling in glomerular mesangial cells, enabling TSP1-dependent TGF-β1 activation and downstream Smad3 signaling. Inhibition of csGRP78 prevented HG-induced TSP1 upregulation and TGF-β1 activation.","method":"csGRP78 inhibitors (vaspin, C38 antibody, MTJ-1 siRNA, α2M* neutralization), TSP1 promoter assays, Smad3 activation assays, PI3K/Akt inhibitors, primary mouse mesangial cells","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple csGRP78 inhibition strategies converging on TSP1 promoter regulation; pathway ordering via PI3K/Akt; single lab","pmids":["36909183"],"is_preprint":false},{"year":2021,"finding":"Platelet TSP-1 controls prostate cancer-induced osteoclast differentiation and bone marrow-derived cell (BMDC) mobilization through TGF-β1. TSP-1 deletion in tumor-bearing mice reduced BMDC mobilization and increased osteoclast formation. Platelet-specific TGF-β1 deletion (PF4-cre) phenocopied TSP-1 deletion effects on osteoclastogenesis and bone formation, placing TSP-1 upstream of TGF-β1 release from platelets.","method":"TSP-1 null mice with RM1 tumor implantation, platelet-specific TGF-β1 deletion (PF4-cre), microcomputed tomography, immunohistochemistry, bone marrow cell mobilization assay","journal":"American journal of clinical and experimental urology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (TSP-1 KO and platelet TGF-β1 KO) with in vivo readouts; single lab","pmids":["33816691"],"is_preprint":false},{"year":2015,"finding":"TSP1 and its receptors CD36 and CD47 are upregulated in sporadic inclusion body myositis muscle. TNF-α upregulates TSP1 and CD47 production by myoblasts in vitro, suggesting TNF-α drives TSP1-CD36/CD47 complex formation in chronic muscle inflammation.","method":"mRNA and protein expression analysis in IBM muscle biopsies, immunolocalization, cytokine stimulation (TNF-α) of human myoblasts in vitro","journal":"Journal of neuroimmunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, expression-level findings with limited mechanistic functional experiments","pmids":["17572512"],"is_preprint":false},{"year":2015,"finding":"TSP1 loss in mice lacking TSP1 is associated with decreased expression of voltage-dependent calcium channel subunit CACNA2D2 mRNA and α2δ-1/2 protein in the cortex, correlating with increased seizure susceptibility in PTZ kindling. TSP2 knockout did not affect kindling, placing TSP1 specifically in the regulation of CACNA2D2 levels and seizure threshold.","method":"TSP1-/-, TSP2-/-, and double TSP1/2-/- mice, PTZ kindling model, qRT-PCR for CACNA2D2 and CACNA2D1, Western blot for α2δ-1/2 protein","journal":"Neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, genetic KO with mRNA/protein correlations but no direct mechanistic link established between TSP1 and CACNA2D2 regulation","pmids":["26241338"],"is_preprint":false}],"current_model":"THBS1 (thrombospondin-1) is a secreted matricellular glycoprotein that signals through multiple cell-surface receptors (primarily CD36, CD47, and integrins) to regulate angiogenesis, cellular senescence, apoptosis, inflammation, and tissue remodeling. Key established mechanisms include: (1) direct binding and activation of the ER stress kinase PERK, inducing ATF4-dependent autophagy and cardiac/skeletal muscle atrophy via a TGFβ-Smad2/3-ATF4 axis; (2) engagement of CD47 to activate Nox1-ROS-p53-p21 signaling driving endothelial cell senescence; (3) interaction with CD47 to suppress vasodilation and promote pulmonary hypertension through a cMyc/ET-1 axis; (4) anti-angiogenic activity mediated by CD36 on endothelial cells, redirecting pro-angiogenic signals toward apoptosis; (5) activation of latent TGF-β, linking THBS1 to fibrosis and immune regulation across multiple tissues; (6) antagonism of BMP-2/4 through its von Willebrand type C domain; (7) transcriptional regulation by tumor suppressors (p53, AR, EZH2 repression) and oncogenic pathways (YAP-TEAD); and (8) cell-autonomous promotion of monocyte/macrophage migration contributing to vascular inflammation and aneurysm development."},"narrative":{"mechanistic_narrative":"THBS1 (thrombospondin-1) is a secreted matricellular glycoprotein that signals through multiple cell-surface receptors and an intracellular ER stress effector to control angiogenesis, cellular senescence, apoptosis, tissue atrophy, inflammation, and fibrotic remodeling [PMID:34168130, PMID:29042481, PMID:18220792]. A recurring theme is THBS1-driven activation of latent TGF-β followed by Smad2/3 signaling, a module exploited across diverse pathologies: skeletal muscle atrophy via a TGFβ-Smad2/3-ATF4 axis coupling autophagy-lysosomal and ubiquitin-proteasome degradation [PMID:38678560], diabetic and septic kidney injury [PMID:35908070, PMID:34756923], blood-brain barrier damage in seizures [PMID:31005663], and tolerogenic dendritic cell generation [PMID:25839231]. THBS1 also activates the ER stress kinase PERK to induce ATF4-dependent autophagy and lethal cardiac atrophy, an effect independent of its canonical receptors CD36, CD47, and ATF6α [PMID:34168130]. Through CD47, THBS1 drives Nox1-ROS-p53-p21 endothelial senescence [PMID:29042481] and promotes pulmonary vasculopathy via cMyc/ET-1 and ROS pathways [PMID:27742621, PMID:30892078]. Its anti-angiogenic activity is mediated by CD36 and resides in the thrombospondin type I repeat (TSR) domain, redirecting pro-angiogenic signaling toward apoptosis [PMID:18220792]; a separate von Willebrand type C domain antagonizes BMP-2 and BMP-4 by direct binding [PMID:28747434]. THBS1 expression is set by tumor suppressor and oncogenic transcriptional inputs—repression by an ADT-CREB-EZH2 axis [PMID:30287808] and activation by YAP-TEAD to drive FAK-dependent invasion [PMID:30055645]. In myeloid cells, THBS1 acts cell-autonomously to promote monocyte adhesion, migration, and matrix invasion (via TIMP1 suppression) during aortic aneurysm formation [PMID:25940549, PMID:33028100].","teleology":[{"year":2005,"claim":"Established THBS1 as an active mediator rather than a passive matrix marker of tissue injury by showing it directly triggers apoptosis in stressed epithelium.","evidence":"Microarray induction analysis plus purified TSP-1 apoptosis assays (caspase-3, cytochrome c) and TSP-1-null renal ischemia/reperfusion model","pmids":["16294224"],"confidence":"High","gaps":["Receptor mediating the pro-apoptotic signal not defined","Downstream apoptotic effector pathway not mapped"]},{"year":2007,"claim":"Identified CD36 as the endothelial receptor and the TSR domain as the active element for THBS1 anti-angiogenic signaling, defining a structural basis for vascular suppression.","evidence":"Endothelial functional assays and CD36 signaling cascade characterization","pmids":["18220792"],"confidence":"Medium","gaps":["Abstract-level synthesis without full method detail","Molecular link from CD36 to apoptotic conversion incompletely resolved"]},{"year":2007,"claim":"Linked androgen receptor signaling to THBS1 secretion, showing a hormonal input that tunes tumor angiogenic potential.","evidence":"AR-expressing prostate cancer lines, xenografts, TSP1 ELISA, NFκB reporter assays","pmids":["17487836"],"confidence":"Medium","gaps":["Whether AR acts directly on THBS1 transcription not established","Relative contributions of TSP1 versus NFκB suppression not separated"]},{"year":2015,"claim":"Demonstrated cell-autonomous, myeloid-intrinsic THBS1 function driving inflammatory cell infiltration in aneurysm, shifting the model from secreted matrix factor to monocyte-intrinsic effector.","evidence":"Thbs1-/- mice across three AAA models with adoptive transfer and bone marrow reconstitution rescue","pmids":["25940549"],"confidence":"High","gaps":["Receptor mediating monocyte adhesion/migration not identified","Downstream signaling in monocytes undefined"]},{"year":2015,"claim":"Extended the TGF-β-activating role of THBS1 to immune tolerance, showing B cell-derived TSP1 converts latent TGF-β to generate tolerogenic dendritic cells.","evidence":"B cell-deficient mice, methylation-specific PCR, ELISA/flow cytometry","pmids":["25839231"],"confidence":"Medium","gaps":["Direct demonstration of TSP1-latent TGF-β binding in this context not shown","IL-13 methylation mechanism correlative"]},{"year":2016,"claim":"Defined a TSP1-CD47-cMyc/ET-1 axis controlling pulmonary vascular tone, mechanistically connecting THBS1 to pulmonary hypertension.","evidence":"CD47-/- mice with hypoxic PH, ex vivo myography, cMyc gain/loss, CD47 blocking antibody in rat monocrotaline model","pmids":["27742621"],"confidence":"High","gaps":["How CD47 engagement regulates cMyc transcriptionally not resolved","Endothelial versus smooth muscle contributions not fully separated"]},{"year":2017,"claim":"Established a CD47-Nox1-ROS-p53-p21 pathway through which THBS1 drives endothelial senescence and vascular aging.","evidence":"TSP1-/- mice, Nox1 pharmacological inhibition, siRNA, CD47-Nox1 co-IP, aged human lung tissue","pmids":["29042481"],"confidence":"High","gaps":["Direct biochemical coupling of CD47 to Nox1 activation not fully defined","Nox1 isoform selectivity mechanism unexplained"]},{"year":2017,"claim":"Positioned THBS1 as a downstream effector of KRIT1/KLF2/KLF4 that restrains VEGF signaling and preserves endothelial barrier integrity, linking its loss to cerebral cavernous malformation.","evidence":"Krit1 and Thbs1 mouse genetic models, in vitro TSP1/3TSR reconstitution, 3TSR therapeutic administration","pmids":["28970240"],"confidence":"High","gaps":["Receptor mediating VEGF/tight-junction effects not pinned down","Mechanism of KLF-driven THBS1 repression not detailed"]},{"year":2017,"claim":"Identified a TGF-β-independent ligand activity of THBS1 as a direct BMP-2/4 antagonist, broadening its growth factor regulatory repertoire and mapping it to the von Willebrand type C domain.","evidence":"Surface plasmon resonance, co-IP, BMP-responsive bioactivity assay in C3H10T1/2 cells","pmids":["28747434"],"confidence":"High","gaps":["Direct domain-deletion proof of the vWC domain requirement not shown","Physiological context of BMP antagonism not addressed"]},{"year":2018,"claim":"Defined opposing transcriptional control of THBS1 in cancer: EZH2-mediated epigenetic repression enabling angiogenesis versus YAP-TEAD activation driving FAK-dependent invasion.","evidence":"EZH2 ChIP and promoter methylation in ADT prostate models; YAP/TEAD ChIP, luciferase, and siRNA epistasis to pFAK in breast cancer","pmids":["30287808","30055645"],"confidence":"High","gaps":["How a single gene is anti-angiogenic yet pro-invasive across contexts not reconciled","Receptor for FAK activation not identified"]},{"year":2019,"claim":"Resolved the receptor-proximal events of THBS1-CD47 signaling in distinct vascular beds, showing SHP-2 activation suppressing STAT3-iNOS and ROS-dependent endothelial injury.","evidence":"CD47-SHP-2 co-IP and STAT3/iNOS readouts in retinal cells with CNV model; sickle bone marrow chimeras into CD47KO hosts with ROS assays","pmids":["31899207","30892078"],"confidence":"Medium","gaps":["Reciprocal validation of CD47-SHP-2 binding limited","How CD47 toggles between ROS-inducing and SHP-2/STAT3-suppressing outputs unclear"]},{"year":2019,"claim":"Revealed a proteolytic switch in which MT1-MMP cleavage releases a C-terminal THBS1 fragment that engages CD47/αvβ3 to promote NO production and intussusceptive angiogenesis, indicating fragment-specific, context-opposite activities.","evidence":"Endothelial MT1-MMP conditional knockout, intravital microscopy, lentiviral rescue, peptide administration in colitis","pmids":["31793743"],"confidence":"Medium","gaps":["Cleavage site and fragment identity not biochemically pinned","How fragment activity reconciles with full-length anti-angiogenic role unresolved"]},{"year":2020,"claim":"Refined the myeloid-intrinsic aneurysm mechanism by showing macrophage THBS1 suppresses TIMP1 to license matrix invasion.","evidence":"Myeloid-specific Thbs1 knockout (Lyz2-cre), RNA FISH, gelatinase assays, Timp1 siRNA rescue","pmids":["33028100"],"confidence":"High","gaps":["Mechanism by which THBS1 represses TIMP1 not defined","Whether intracellular or secreted THBS1 mediates the effect unclear"]},{"year":2021,"claim":"Identified a receptor-independent intracellular mechanism in which THBS1 binds and activates PERK to drive ATF4-dependent autophagy and lethal cardiac atrophy, distinguishing this from canonical CD36/CD47 signaling.","evidence":"Thbs1 transgenic mice with PERK, ATF6α, CD36, and CD47 knockouts and AAV9 rescue","pmids":["34168130"],"confidence":"High","gaps":["Structural basis of THBS1-PERK binding not solved","How a secreted protein accesses the ER lumen to engage PERK not explained"]},{"year":2024,"claim":"Generalized the THBS1 atrophy program to skeletal muscle through a TGFβ-Smad2/3-ATF4 axis controlling both autophagy-lysosomal and ubiquitin-proteasome degradation.","evidence":"Muscle-specific Thbs1 transgenics, myofiber TGFβR inhibition, conditional Smad2/3 and Atf4 knockouts, Thbs1-/- denervation/caloric restriction models","pmids":["38678560"],"confidence":"High","gaps":["Relationship between the PERK-ATF4 and TGFβ-Smad2/3-ATF4 routes to ATF4 not reconciled","Receptor initiating muscle TGFβ activation not identified"]},{"year":2025,"claim":"Uncovered a non-matricellular intracellular function whereby exosomal THBS1 binds the deubiquitinase OTUD5 to promote GPX4 ubiquitination and endothelial ferroptosis in cerebral ischemia.","evidence":"THBS1-OTUD5 binding assay, cellular thermal shift, endothelial Gpx4 knockout mice, tMCAO model","pmids":["39994679"],"confidence":"Medium","gaps":["Mechanism by which THBS1 promotes GPX4 ubiquitination unclear","Single lab; reciprocal validation of THBS1-OTUD5 interaction limited"]},{"year":null,"claim":"How THBS1 partitions among its mutually exclusive activities—extracellular receptor signaling, latent TGF-β activation, intracellular PERK/OTUD5 engagement, and fragment-specific functions—within a single cell or tissue remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model for how localization and proteolysis dictate which pathway dominates","Structural determinants of receptor versus intracellular partner selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[7,8,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,8,13,16]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,9,10,27]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[4,6,16,19]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[5,7]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,7,9,27]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[5,27]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[16,21,31]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,20,25]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["CD47","CD36","PERK","BMP2","BMP4","OTUD5","TLR4","LRRK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P07996","full_name":"Thrombospondin-1","aliases":["Glycoprotein G"],"length_aa":1170,"mass_kda":129.4,"function":"Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions (PubMed:15014436, PubMed:18285447, PubMed:2430973, PubMed:6489349). Multifunctional, involved in inflammation, angiogenesis, wound healing, reactive oxygen species (ROS) signaling, nitrous oxide (NO) signaling, apoptosis, senescence, aging, cellular self-renewal, stemness, and cardiovascular and metabolic homeostasis (PubMed:10613822, PubMed:11134179, PubMed:1371676, PubMed:14568985, PubMed:24511121, PubMed:29042481, PubMed:32679764). Negatively modulates dendritic cell activation and cytokine release, as part of an autocrine feedback loop, contributing to the resolution of inflammation and immune homeostasis (PubMed:14568985). Ligand for receptor CD47 (PubMed:19004835, PubMed:8550562). Modulates nitrous oxide (NO) signaling via CD47, hence playing a role as a pressor agent, supporting blood pressure (By similarity). Plays a role in endothelial cell senescence, acting via CD47, by increasing the abundance and activation of NADPH oxidase NOX1, and so generating excess ROS (PubMed:29042481). Inhibits stem cell self-renewal, acting via CD47 signaling, probably by regulation of the stem cell transcription factors POU5F1/OCT4, SOX2, MYC/c-Myc and KLF4 (By similarity). Negatively modulates wound healing, acting via CD47 (By similarity). Ligand for receptor CD36 (PubMed:10613822, PubMed:11134179, PubMed:1371676). Involved in inducing apoptosis in podocytes in response to elevated free fatty acids, acting via CD36 (By similarity). Plays a role in suppressing angiogenesis, acting, depending on context, via CD36 or CD47 (PubMed:10613822, PubMed:11134179, PubMed:1371676, PubMed:32679764). Promotes cellular senescence in a TP53-CDKN1A-RB1 signaling-dependent manner (PubMed:29042481). Ligand for immunoglobulin-like cell surface receptor SIRPA (PubMed:24511121). Involved in ROS signaling in non-phagocytic cells, stimulating NADPH oxidase-derived ROS production, acting via interaction with SIRPA (PubMed:24511121). Plays a role in metabolic dysfunction in diet-induced obesity, perhaps acting by exacerbating adipose inflammatory activity; its effects may be mediated, at least in part, through enhanced adipocyte proliferation (By similarity). Plays a role in ER stress response, via its interaction with the activating transcription factor 6 alpha (ATF6) which produces adaptive ER stress response factors (By similarity). May be involved in age-related conditions, including metabolic dysregulation, during normal aging (PubMed:29042481, PubMed:32679764)","subcellular_location":"Secreted; Cell surface; Secreted, extracellular space, extracellular matrix; Endoplasmic reticulum; Sarcoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/P07996/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/THBS1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/THBS1","total_profiled":1310},"omim":[{"mim_id":"621470","title":"ADAMTS-LIKE PROTEIN 5; ADAMTSL5","url":"https://www.omim.org/entry/621470"},{"mim_id":"611681","title":"A DISINTEGRIN-LIKE AND METALLOPROTEINASE WITH THROMBOSPONDIN TYPE 1 MOTIF, 20; ADAMTS20","url":"https://www.omim.org/entry/611681"},{"mim_id":"611533","title":"NUCLEOLAR PROTEIN 7; NOL7","url":"https://www.omim.org/entry/611533"},{"mim_id":"611162","title":"MALARIA, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/611162"},{"mim_id":"610575","title":"R-SPONDIN 2; RSPO2","url":"https://www.omim.org/entry/610575"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/THBS1"},"hgnc":{"alias_symbol":["TSP1","THBS","TSP","THBS-1","TSP-1"],"prev_symbol":[]},"alphafold":{"accession":"P07996","domains":[{"cath_id":"2.60.120.200","chopping":"31-231","consensus_level":"high","plddt":87.8617,"start":31,"end":231},{"cath_id":"2.10.25.10","chopping":"559-648","consensus_level":"medium","plddt":87.684,"start":559,"end":648},{"cath_id":"2.10.25.10","chopping":"655-740","consensus_level":"medium","plddt":92.5734,"start":655,"end":740},{"cath_id":"2.60.120.200","chopping":"961-1168","consensus_level":"high","plddt":94.6484,"start":961,"end":1168}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P07996","model_url":"https://alphafold.ebi.ac.uk/files/AF-P07996-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P07996-F1-predicted_aligned_error_v6.png","plddt_mean":84.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=THBS1","jax_strain_url":"https://www.jax.org/strain/search?query=THBS1"},"sequence":{"accession":"P07996","fasta_url":"https://rest.uniprot.org/uniprotkb/P07996.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P07996/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P07996"}},"corpus_meta":[{"pmid":"12213711","id":"PMC_12213711","title":"The 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Deletion of PERK in Thbs1 transgenic mice blunted ATF4 induction and autophagy and largely corrected the lethal cardiac atrophy. Deletion of other THBS1 effectors/receptors (ATF6α, CD36, CD47) did not diminish this effect.\",\n      \"method\": \"Transgenic overexpression, genetic knockout (Thbs1-/-, PERK-/-, ATF6α-/-, CD36-/-, CD47-/-), AAV9 gene transfer, in vivo cardiac phenotyping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models with orthogonal methods, receptor deletion epistasis, AAV rescue experiments in a single rigorous study\",\n      \"pmids\": [\"34168130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"THBS1 activates TGFβ-Smad2/3 signaling in skeletal muscle, which induces ATF4 expression that together modulates the autophagy-lysosomal pathway (ALP) and ubiquitin-proteasome system (UPS) to drive muscle atrophy. Myofiber-specific inhibition of TGFβ-receptor signaling, deletion of Smad2/3, or deletion of Atf4 each antagonized Thbs1-induced muscle atrophy. Thbs1-/- mice showed reduced denervation- and caloric restriction-induced atrophy.\",\n      \"method\": \"Skeletal muscle-specific Thbs1 transgenic mice, myofiber-specific TGFβR inhibition, conditional Smad2/3 knockout, Atf4 knockout, loss-of-function (Thbs1-/-) with denervation/caloric restriction models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent genetic models with epistasis, replicated across atrophy paradigms in a single rigorous study\",\n      \"pmids\": [\"38678560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TSP1 promotes endothelial cell senescence through its receptor CD47 by activating NADPH oxidase 1 (Nox1), but not other Nox isoforms, leading to increased ROS, p53 nuclear accumulation, and p21cip upregulation via a DNA damage response. Nox1 inhibition blocked TSP1-induced p53 nuclear localization and senescence. Mice lacking TSP1 showed decreased ROS, p21cip, and aging-induced senescence.\",\n      \"method\": \"TSP1-/- mice, pharmacological Nox1 inhibition, siRNA knockdown, co-immunoprecipitation (CD47-Nox1 axis), human endothelial cell culture, aged human lung tissue analysis\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO mice, pharmacological inhibition, siRNA), replicated in human tissue and mouse model\",\n      \"pmids\": [\"29042481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TSP1 (encoded by Thbs1) is suppressed downstream of KRIT1/KLF2/KLF4 signaling in brain microvascular endothelial cells. Loss of TSP1 enables heightened VEGF signaling and loss of tight junctions. In vitro reconstitution of TSP1 (full-length or the 3TSR anti-angiogenic fragment) suppressed VEGF signaling and preserved tight junctions. Administration of 3TSR prevented cerebral cavernous malformation (CCM) lesion development in Krit1 knockout mice, while inactivation of one or two copies of Thbs1 exacerbated CCM formation.\",\n      \"method\": \"Krit1 mouse knockout, Thbs1 conditional knockout/heterozygous models, in vitro TSP1 reconstitution, 3TSR peptide administration, histology and micro-CT quantification\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro reconstitution plus multiple in vivo genetic models with functional rescue, orthogonal readouts\",\n      \"pmids\": [\"28970240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TSP1 expressed on monocytic cells (not endothelial or other cells) contributes to their adhesion and migration capacity. Adoptive transfer of wild-type monocytic cells or bone marrow reconstitution rescued aneurysm development in Thbs1-/- mice, demonstrating that monocyte-intrinsic TSP1 drives inflammatory cell infiltration into the aortic wall during AAA development.\",\n      \"method\": \"Thbs1-/- mice, three AAA induction models (CaPO4, elastase, angiotensin II), adoptive transfer of monocytic cells, bone marrow reconstitution, in vitro adhesion/migration assays\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — adoptive transfer and bone marrow reconstitution establish cell-autonomous mechanism; three independent AAA models\",\n      \"pmids\": [\"25940549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Myeloid/macrophage-derived TSP1 contributes to abdominal aortic aneurysm by suppressing TIMP1 expression, which enables macrophage matrix invasion. Myeloid-specific Thbs1 deletion (Thbs1flox/flox × Lyz2-cre) protected mice from CaCl2-induced AAA. TSP1-deficient macrophages had elevated TIMP1 and reduced gelatinase activity; Timp1 knockdown restored the ability of Thbs1-null macrophages to invade matrix.\",\n      \"method\": \"Myeloid-specific conditional Thbs1 knockout (Lyz2-cre), RNA FISH, gelatinase activity assays, Timp1 siRNA knockdown, in vivo AAA model\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with epistasis (Timp1 rescue), multiple orthogonal methods\",\n      \"pmids\": [\"33028100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TSP-1 is strongly induced in ischemic kidney proximal tubules and causes apoptosis (caspase-3 activation, cytochrome c release) in normal and ATP-depleted proximal tubule cells. TSP-1-null mice were significantly protected from ischemia/reperfusion-induced renal failure and tubular damage, identifying TSP-1 as a mediator of ischemic kidney injury.\",\n      \"method\": \"DNA microarray followed by Northern hybridization, immunocytochemistry (caspase-3, cytochrome c), purified TSP-1 addition to kidney cells in vitro, TSP-1 null mouse IR injury model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro mechanistic assays (caspase-3, cytochrome c) combined with in vivo genetic KO model with renal function readout\",\n      \"pmids\": [\"16294224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD36 is an endothelial cell receptor required for TSP-1 and TSP-2 anti-angiogenic activity. CD36-mediated anti-angiogenic signaling redirects pro-angiogenic responses toward apoptosis. The TSP type I repeat (TSR) domain of TSP-1 mediates this activity.\",\n      \"method\": \"Receptor identification studies, endothelial cell functional assays, CD36 signaling cascade characterization (literature synthesis with experimental basis cited)\",\n      \"journal\": \"Current pharmaceutical design\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor identification supported by cell-based functional assays; abstract summarizes prior experimental work without full method detail\",\n      \"pmids\": [\"18220792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TSP-1 is a BMP-2 and BMP-4 antagonist. Recombinant human TSP-1 binds BMP-2 and BMP-4 as demonstrated by surface plasmon resonance and co-immunoprecipitation, and antagonizes their effects on C3H10T1/2 cells. The von Willebrand type C domain of TSP-1 is implicated in this BMP-2/4-binding activity based on sequence similarity with Crossveinless 2.\",\n      \"method\": \"Surface plasmon resonance, co-immunoprecipitation, BMP-responsive element bioactivity assay in C3H10T1/2 cells, high-resolution mass spectrometry, domain analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding confirmed by SPR and co-IP with functional antagonism assay; multiple orthogonal biochemical methods in one study\",\n      \"pmids\": [\"28747434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TSP1-CD47 signaling promotes pulmonary arterial vasculopathy. In hypoxic wild-type mice, TSP1 and CD47 are upregulated concordantly with ET-1/ETA and downregulation of cMyc. In CD47-/- mice, PH was attenuated, cMyc was overexpressed, and ET-1 was reduced. In CD47+/+ cells, forced cMyc induction suppressed ET-1 transcript; suppression of cMyc increased ET-1 signaling. TSP1 treatment of control pulmonary arteries inhibited vasodilation and potentiated ET-1-mediated vasoconstriction; CD47 blocking antibody improved vasodilator sensitivity in diseased PAs.\",\n      \"method\": \"CD47-/- mice with hypoxia-induced PH, exogenous TSP1 treatment of ex vivo pulmonary arteries, cMyc overexpression/knockdown in CD47+/+ cells, CD47 blocking antibody in rat monocrotaline model, myography\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic and pharmacological models across species with mechanistic pathway dissection (cMyc/ET-1 axis)\",\n      \"pmids\": [\"27742621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TSP1 interacts with CD47 to promote pulmonary hypertension in sickle cell disease by increasing reactive oxygen species (ROS) generation in pulmonary endothelial cells. Genetic absence of CD47 in chimeric sickle mice reduced right ventricular pressure, mean pulmonary artery pressure, and pulmonary vascular resistance. TSP1 treatment of human pulmonary artery endothelial cells stimulated ROS generation that was abrogated by CD47 blockade.\",\n      \"method\": \"Bone marrow chimeric mice (BERK sickle marrow into CD47KO hosts), right heart catheterization, ex vivo myography, ROS measurements in human pulmonary endothelial cells with TSP1 treatment and CD47 blockade\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — chimeric animal model plus in vitro mechanistic assays with receptor blockade, multiple orthogonal readouts\",\n      \"pmids\": [\"30892078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In prostate cancer, androgen deprivation therapy (ADT) activates CREB, which enhances EZH2 activity. EZH2 directly epigenetically represses THBS1 (TSP1), reducing this anti-angiogenic factor and enabling angiogenesis and neuroendocrine differentiation. Repressing CREB inhibited the CREB/EZH2 axis, tumor growth, neuroendocrine differentiation, and angiogenesis in vivo.\",\n      \"method\": \"In vivo castration/ADT models in xenografts, CREB inhibition, EZH2 ChIP assays, TSP1 promoter methylation analysis, in vivo tumor experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP establishing direct EZH2 binding at THBS1 locus, in vivo rescue/inhibition experiments, multiple orthogonal approaches\",\n      \"pmids\": [\"30287808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"YAP transcriptionally activates THBS1 in a TEAD-dependent manner in breast cancer cells. THBS1 then activates FAK phosphorylation to promote focal adhesion and tumor invasiveness. Silencing THBS1 reversed YAP-induced FAK activation and focal adhesion.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), dual luciferase assay, gene expression profiling, Western blot for pFAK, siRNA-mediated THBS1 silencing, transwell invasion assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and dual luciferase establish direct transcriptional regulation; siRNA epistasis links THBS1 to FAK activation; multiple orthogonal methods\",\n      \"pmids\": [\"30055645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Lactate induces THBS1 protein expression in glioma cells, and THBS1 in turn activates TGF-β2 (a latent form requiring proteolytic activation). Inhibition of THBS1 by siRNA reduces TGF-β2 protein and glioma cell migration. Addition of synthetic THBS1 rescues reduced TGF-β2 protein levels and glioma cell migration in LDH-A knockdown (low-lactate) cells.\",\n      \"method\": \"siRNA knockdown of LDH-A and THBS1, lactate addition/rescue experiments, Western blot, ELISA, spheroid/scratch/Boyden chamber migration assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA epistasis with synthetic THBS1 rescue and multiple migration assays; single lab but orthogonal approaches\",\n      \"pmids\": [\"24223867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Intermittent hypoxia (IH) induces TSP1 expression in cardiac fibroblasts through STAT3 phosphorylation at Tyr705. TSP1 upregulation mediates IH-induced cardiac fibroblast activation and cardiac fibrosis. STAT3 inhibition (pharmacological S3I-201 or AAV9-shStat3 in cardiac fibroblasts) significantly attenuated synergistic cardiac fibrosis from IH and angiotensin II.\",\n      \"method\": \"IH mouse model, in vitro cardiac fibroblast culture, STAT3 pharmacological inhibition and AAV9-driven shRNA knockdown, plasma TSP1 ELISA in OSA patients\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro corroboration, genetic/pharmacological STAT3 inhibition, but single lab\",\n      \"pmids\": [\"31934850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Androgen receptor (AR) expression increases TSP1 secretion by prostate cancer cells, decreasing their angiogenic potential. AR activation also decreases RelA (NFκB subunit) nuclear localization and transcriptional activity, reducing Bcl-2 and IL-6 expression. Combined NFκB suppression and increased TSP1 underlie AR anti-tumor activity in vivo.\",\n      \"method\": \"Stable AR-expressing prostate cancer cell lines, tumor xenografts in male mice, ELISA for TSP1 secretion, immunostaining for vascularity/apoptosis, NFκB reporter assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo xenograft with molecular pathway analysis; single lab with multiple functional readouts\",\n      \"pmids\": [\"17487836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"B cell-derived TSP1 converts latent TGF-β to active TGF-β in dendritic cells, generating TGF-β-producing tolerogenic dendritic cells (TolDCs). IL-13 inhibits TSP1 expression in B cells by enhancing TSP1 gene DNA methylation, thereby impairing TolDC generation.\",\n      \"method\": \"B cell-deficient mouse model (anti-CD20 antibody), flow cytometry, ELISA, qRT-PCR, Western blot, methylation-specific PCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods linking B cell TSP1 to TGF-β activation and TolDC generation; single lab\",\n      \"pmids\": [\"25839231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TSP1 activates SHP-2 through its receptor CD47, reducing STAT3 phosphorylation and thereby blocking the STAT3-iNOS pathway and reducing nitric oxide concentration in retinal endothelial cells. This mechanism protects against choroidal neovascularization (CNV) in age-related macular degeneration. Co-immunoprecipitation showed CD47-SHP-2 binding in response to TSP1.\",\n      \"method\": \"Co-immunoprecipitation (CD47-SHP-2), TSP1 overexpression in RF/6A cells, CCK-8 viability, flow cytometry (apoptosis), transwell migration, Western blot for STAT3/iNOS, CNV mouse model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying CD47-SHP-2 interaction and downstream STAT3-iNOS pathway; in vivo CNV model; single lab\",\n      \"pmids\": [\"31899207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Senescent cells produce TSP1, which prevents senescence escape in breast cancer cells. Senescence escape is mediated by CD47low cells that arise when p21waf1 is downregulated, enabling Myc upregulation, which binds the CD47 promoter to repress CD47 expression, allowing cells to escape TSP1-mediated suppression.\",\n      \"method\": \"SWATH quantitative proteomic analysis, in vitro and in vivo senescence models, ChIP (Myc binding to CD47 promoter), p21 siRNA-mediated downregulation, serum TSP1 measurement in breast cancer patients\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for Myc-CD47 promoter binding, quantitative proteomics, functional siRNA epistasis; single lab\",\n      \"pmids\": [\"30814491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TSP1 promotes follicular angiogenesis, luteinization, and ovulation in primates. THBS1 treatment of monkey ovarian microvascular endothelial cells stimulated migration, proliferation, and capillary sprout formation in vitro. Intra-follicular injection of anti-THBS1 antibody reduced follicle rupture, oocyte release, granulosa cell layer expansion, endothelial cell invasion, and capillary formation.\",\n      \"method\": \"In vitro endothelial cell migration/proliferation/tube formation assays, intra-follicular anti-THBS1 antibody injection in cynomolgus macaques, follicle histology\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo primate antibody neutralization with functional follicle readout; in vitro corroboration; single lab\",\n      \"pmids\": [\"31787928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"THBS1 in macrophage-derived exosomes binds directly to OTUD5 and promotes GPX4 ubiquitination, leading to ferroptosis in endothelial cells during cerebral ischemia-reperfusion injury. Modulation of THBS1 in macrophage-derived exosomes affected endothelial ferroptosis. Salvianolic acid B inhibited the THBS1-OTUD5 interaction, reducing GPX4 ubiquitination and protecting against CIRI.\",\n      \"method\": \"RNA interference, AAV transfection, endothelial-specific Gpx4 knockout mice, proteomic sequencing, THBS1-OTUD5 binding assay, cellular thermal shift assay, molecular docking/MD simulation, tMCAO mouse model\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay (THBS1-OTUD5), genetic KO epistasis, in vivo tMCAO model; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"39994679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"THBS1 from bone marrow-derived monocyte-like cells (recruited by CXCL12) contributes to colorectal cancer metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. THBS1 loss in the tumor microenvironment rendered tumors partially sensitive to immune checkpoint inhibitors.\",\n      \"method\": \"Orthotopic CRC mouse models, THBS1 knockout in TME, immune cell profiling, tumor growth and metastasis assays, immune checkpoint inhibitor combination experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo orthotopic models with genetic THBS1 deletion in TME; functional immune readouts; single lab\",\n      \"pmids\": [\"37749092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"P2Y4 receptor activation regulates TSP-1 expression, which activates TGF-β1/pSmad2/3 signaling to promote angiogenesis and blood-brain barrier damage during acute seizures. Inhibition of TSP-1 by siRNA or LSKL peptide (TGF-β1 activation inhibitor) prevented KA-induced Smad2/3 phosphorylation, angiogenesis, BBB damage, and acute seizures.\",\n      \"method\": \"siRNA-mediated TSP-1 knockdown, LSKL peptide inhibition, P2 receptor antagonists, kainic acid seizure model in rats, immunostaining and Western blot\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA epistasis with LSKL peptide for pathway ordering; in vivo rodent model with functional readouts; single lab\",\n      \"pmids\": [\"31005663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Sestrin2 overexpression modulates the activity of the TSP-1/TGF-β1/Smad3 pathway in podocytes under high glucose conditions. TSP-1 inhibition by LSKL peptide or TGF-β1 blockade arrested high-glucose-induced podocyte injury, placing TSP-1 upstream of TGF-β1 activation in diabetic kidney disease.\",\n      \"method\": \"Sestrin2 transgenic mice, STZ-induced diabetes model, podocyte cell culture, LSKL peptide inhibition, Pirfenidone (TGF-β blocker), pathway protein analysis by Western blot\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro corroboration with pharmacological inhibitors establishing pathway order; single lab\",\n      \"pmids\": [\"35908070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LRRK2 G2019S mutation promotes ER stress in neurons by directly interacting with THBS1, which in turn interacts with TGF-β1. Knocking down THBS1 rescued ER stress and behavioral burden caused by the LRRK2 mutation. Suppression of TGF-β1 had a similar effect, placing THBS1 between LRRK2 G2019S and TGF-β1 in ER stress signaling.\",\n      \"method\": \"iPSC-derived dopamine neurons, LRRK2 G2019S mouse model, co-immunoprecipitation (LRRK2-THBS1 interaction), THBS1 and TGF-β1 knockdown, LRRK2 kinase inhibition\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishing direct LRRK2-THBS1 interaction; genetic epistasis via knockdown; iPSC and mouse models; single lab\",\n      \"pmids\": [\"37672887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USF2 transcriptionally activates THBS1 to activate the TGF-β/Smad3/NLRP3/Caspase-1 signaling pathway, promoting pyroptosis in sepsis-induced acute kidney injury. USF2 knockdown downregulated THBS1 and inhibited the TGF-β/Smad3 pathway and pyroptosis.\",\n      \"method\": \"USF2 and THBS1 siRNA knockdown, sepsis AKI mouse model, in vitro cell model, qRT-PCR, ELISA, Western blot for NLRP3/Caspase-1/GSDMD pathway components\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pathway placement via knockdown with multiple molecular readouts; in vitro and in vivo corroboration; single lab\",\n      \"pmids\": [\"34756923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PRMT6 overexpression strongly upregulates TSP-1 expression in MCF7 and PC3 cancer cells. Specific knockdown of TSP-1 significantly rescued the suppression of migration and invasion caused by PRMT6 overexpression, placing TSP-1 downstream of PRMT6 in the regulation of cancer cell motility.\",\n      \"method\": \"Stable PRMT6-overexpressing cell lines, siRNA knockdown of TSP-1, cell migration/invasion assays, Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single approach (overexpression + siRNA rescue); no direct binding or enzymatic assay\",\n      \"pmids\": [\"23380452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In endothelial cells, MT1-MMP cleaves TSP1, and the C-terminal fragment of TSP1 binds CD47/αvβ3 integrin to promote nitric oxide production required for vasodilation and intussusceptive angiogenesis. MT1-MMP deletion in endothelial cells limited IA and reduced NO production; lentiviral rescue experiments confirmed requirement for MT1-MMP activity.\",\n      \"method\": \"MT1-MMP endothelial conditional knockout mice, intravital microscopy, lentiviral rescue, in vitro cell culture, anti-MT1-MMP antibody and αvβ3-binding TSP1 peptide administration in colitis model\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and lentiviral rescue experiments establishing MT1-MMP/TSP1 C-terminal fragment/CD47-αvβ3/NO axis; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31793743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TSP1 promotes keloid fibroblast proliferation and collagen I deposition through the IL6/JAK2/STAT3 signaling pathway. Knockdown of TSP1 decreased proliferation and collagen I; exogenous TSP1 treatment increased both in normal fibroblasts. TSP1 expression positively correlated with IL6/STAT3 signaling activity in keloid tissues.\",\n      \"method\": \"siRNA knockdown of TSP1 in keloid fibroblasts, exogenous TSP1 treatment of normal fibroblasts, Western blot and immunohistochemistry, IL6/JAK2/STAT3 pathway analysis\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown and exogenous treatment without definitive receptor identification or in vivo validation\",\n      \"pmids\": [\"35661430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Inhibiting THBS1 expression in ECFC-derived exosomes activates PI3K, AKT, and ERK phosphorylation in endothelial cells, promoting VEGF and bFGF expression and enhancing angiogenesis and bone formation in distraction osteogenesis.\",\n      \"method\": \"Lentiviral THBS1 knockdown in ECFCs, exosome isolation and application to HUVECs, Western blot for PI3K/AKT/ERK, tube formation/migration/proliferation assays, in vivo canine mandibular DO model with peripheral blood exosome injection\",\n      \"journal\": \"Journal of orthopaedic translation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway activation via knockdown; in vivo model is non-standard; single lab\",\n      \"pmids\": [\"36196150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Under normoxic conditions, TGFβ1 inhibits angiogenesis by upregulating TSP1 in endothelial cells via TGFβR1-SMAD2/3 signaling. In hypoxia, HIF1α induces miR-145, which represses SMAD2/3 and subsequently reduces TSP1 levels in endothelial cells, thereby abrogating the anti-angiogenic effect of TGFβ1.\",\n      \"method\": \"Chick chorioallantoic membrane assays, zebrafish angiogenesis models, mouse hepatoma xenografts, HIF1α inhibitor/stabilizer treatments, miR-145 overexpression, SMAD2/3 knockdown, TSP1 measurement in endothelial cells and human HCC specimens\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vivo models (chick, zebrafish, mouse) with molecular pathway dissection; single lab with orthogonal approaches\",\n      \"pmids\": [\"39356626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"m6A reader IGF2BP1 binds and stabilizes THBS1 mRNA in an m6A-dependent manner in macrophages, promoting macrophage M2 polarization and glycolytic reprogramming. THBS1 physically interacts with TLR4 to mediate these downstream effects. TLR4 overexpression reversed the inhibitory effect of THBS1 knockdown on M2 polarization and glycolysis.\",\n      \"method\": \"IGF2BP1 knockdown in BLM-induced PF mice, RIP (RNA immunoprecipitation) for THBS1 mRNA, co-immunoprecipitation (THBS1-TLR4), THBS1 overexpression rescue, glycolysis assays, M2 polarization flow cytometry\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP establishing m6A-dependent mRNA stabilization, Co-IP for THBS1-TLR4 interaction, in vivo mouse model; single lab\",\n      \"pmids\": [\"40220148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cell surface GRP78 (csGRP78) regulates high-glucose-induced TSP1 transcriptional upregulation via PI3K/Akt signaling in glomerular mesangial cells, enabling TSP1-dependent TGF-β1 activation and downstream Smad3 signaling. Inhibition of csGRP78 prevented HG-induced TSP1 upregulation and TGF-β1 activation.\",\n      \"method\": \"csGRP78 inhibitors (vaspin, C38 antibody, MTJ-1 siRNA, α2M* neutralization), TSP1 promoter assays, Smad3 activation assays, PI3K/Akt inhibitors, primary mouse mesangial cells\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple csGRP78 inhibition strategies converging on TSP1 promoter regulation; pathway ordering via PI3K/Akt; single lab\",\n      \"pmids\": [\"36909183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Platelet TSP-1 controls prostate cancer-induced osteoclast differentiation and bone marrow-derived cell (BMDC) mobilization through TGF-β1. TSP-1 deletion in tumor-bearing mice reduced BMDC mobilization and increased osteoclast formation. Platelet-specific TGF-β1 deletion (PF4-cre) phenocopied TSP-1 deletion effects on osteoclastogenesis and bone formation, placing TSP-1 upstream of TGF-β1 release from platelets.\",\n      \"method\": \"TSP-1 null mice with RM1 tumor implantation, platelet-specific TGF-β1 deletion (PF4-cre), microcomputed tomography, immunohistochemistry, bone marrow cell mobilization assay\",\n      \"journal\": \"American journal of clinical and experimental urology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (TSP-1 KO and platelet TGF-β1 KO) with in vivo readouts; single lab\",\n      \"pmids\": [\"33816691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TSP1 and its receptors CD36 and CD47 are upregulated in sporadic inclusion body myositis muscle. TNF-α upregulates TSP1 and CD47 production by myoblasts in vitro, suggesting TNF-α drives TSP1-CD36/CD47 complex formation in chronic muscle inflammation.\",\n      \"method\": \"mRNA and protein expression analysis in IBM muscle biopsies, immunolocalization, cytokine stimulation (TNF-α) of human myoblasts in vitro\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, expression-level findings with limited mechanistic functional experiments\",\n      \"pmids\": [\"17572512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TSP1 loss in mice lacking TSP1 is associated with decreased expression of voltage-dependent calcium channel subunit CACNA2D2 mRNA and α2δ-1/2 protein in the cortex, correlating with increased seizure susceptibility in PTZ kindling. TSP2 knockout did not affect kindling, placing TSP1 specifically in the regulation of CACNA2D2 levels and seizure threshold.\",\n      \"method\": \"TSP1-/-, TSP2-/-, and double TSP1/2-/- mice, PTZ kindling model, qRT-PCR for CACNA2D2 and CACNA2D1, Western blot for α2δ-1/2 protein\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, genetic KO with mRNA/protein correlations but no direct mechanistic link established between TSP1 and CACNA2D2 regulation\",\n      \"pmids\": [\"26241338\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"THBS1 (thrombospondin-1) is a secreted matricellular glycoprotein that signals through multiple cell-surface receptors (primarily CD36, CD47, and integrins) to regulate angiogenesis, cellular senescence, apoptosis, inflammation, and tissue remodeling. Key established mechanisms include: (1) direct binding and activation of the ER stress kinase PERK, inducing ATF4-dependent autophagy and cardiac/skeletal muscle atrophy via a TGFβ-Smad2/3-ATF4 axis; (2) engagement of CD47 to activate Nox1-ROS-p53-p21 signaling driving endothelial cell senescence; (3) interaction with CD47 to suppress vasodilation and promote pulmonary hypertension through a cMyc/ET-1 axis; (4) anti-angiogenic activity mediated by CD36 on endothelial cells, redirecting pro-angiogenic signals toward apoptosis; (5) activation of latent TGF-β, linking THBS1 to fibrosis and immune regulation across multiple tissues; (6) antagonism of BMP-2/4 through its von Willebrand type C domain; (7) transcriptional regulation by tumor suppressors (p53, AR, EZH2 repression) and oncogenic pathways (YAP-TEAD); and (8) cell-autonomous promotion of monocyte/macrophage migration contributing to vascular inflammation and aneurysm development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"THBS1 (thrombospondin-1) is a secreted matricellular glycoprotein that signals through multiple cell-surface receptors and an intracellular ER stress effector to control angiogenesis, cellular senescence, apoptosis, tissue atrophy, inflammation, and fibrotic remodeling [#0, #2, #7]. A recurring theme is THBS1-driven activation of latent TGF-\\u03b2 followed by Smad2/3 signaling, a module exploited across diverse pathologies: skeletal muscle atrophy via a TGF\\u03b2-Smad2/3-ATF4 axis coupling autophagy-lysosomal and ubiquitin-proteasome degradation [#1], diabetic and septic kidney injury [#23, #25], blood-brain barrier damage in seizures [#22], and tolerogenic dendritic cell generation [#16]. THBS1 also activates the ER stress kinase PERK to induce ATF4-dependent autophagy and lethal cardiac atrophy, an effect independent of its canonical receptors CD36, CD47, and ATF6\\u03b1 [#0]. Through CD47, THBS1 drives Nox1-ROS-p53-p21 endothelial senescence [#2] and promotes pulmonary vasculopathy via cMyc/ET-1 and ROS pathways [#9, #10]. Its anti-angiogenic activity is mediated by CD36 and resides in the thrombospondin type I repeat (TSR) domain, redirecting pro-angiogenic signaling toward apoptosis [#7]; a separate von Willebrand type C domain antagonizes BMP-2 and BMP-4 by direct binding [#8]. THBS1 expression is set by tumor suppressor and oncogenic transcriptional inputs\\u2014repression by an ADT-CREB-EZH2 axis [#11] and activation by YAP-TEAD to drive FAK-dependent invasion [#12]. In myeloid cells, THBS1 acts cell-autonomously to promote monocyte adhesion, migration, and matrix invasion (via TIMP1 suppression) during aortic aneurysm formation [#4, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established THBS1 as an active mediator rather than a passive matrix marker of tissue injury by showing it directly triggers apoptosis in stressed epithelium.\",\n      \"evidence\": \"Microarray induction analysis plus purified TSP-1 apoptosis assays (caspase-3, cytochrome c) and TSP-1-null renal ischemia/reperfusion model\",\n      \"pmids\": [\"16294224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating the pro-apoptotic signal not defined\", \"Downstream apoptotic effector pathway not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified CD36 as the endothelial receptor and the TSR domain as the active element for THBS1 anti-angiogenic signaling, defining a structural basis for vascular suppression.\",\n      \"evidence\": \"Endothelial functional assays and CD36 signaling cascade characterization\",\n      \"pmids\": [\"18220792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Abstract-level synthesis without full method detail\", \"Molecular link from CD36 to apoptotic conversion incompletely resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked androgen receptor signaling to THBS1 secretion, showing a hormonal input that tunes tumor angiogenic potential.\",\n      \"evidence\": \"AR-expressing prostate cancer lines, xenografts, TSP1 ELISA, NF\\u03baB reporter assays\",\n      \"pmids\": [\"17487836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AR acts directly on THBS1 transcription not established\", \"Relative contributions of TSP1 versus NF\\u03baB suppression not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated cell-autonomous, myeloid-intrinsic THBS1 function driving inflammatory cell infiltration in aneurysm, shifting the model from secreted matrix factor to monocyte-intrinsic effector.\",\n      \"evidence\": \"Thbs1-/- mice across three AAA models with adoptive transfer and bone marrow reconstitution rescue\",\n      \"pmids\": [\"25940549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating monocyte adhesion/migration not identified\", \"Downstream signaling in monocytes undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended the TGF-\\u03b2-activating role of THBS1 to immune tolerance, showing B cell-derived TSP1 converts latent TGF-\\u03b2 to generate tolerogenic dendritic cells.\",\n      \"evidence\": \"B cell-deficient mice, methylation-specific PCR, ELISA/flow cytometry\",\n      \"pmids\": [\"25839231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of TSP1-latent TGF-\\u03b2 binding in this context not shown\", \"IL-13 methylation mechanism correlative\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a TSP1-CD47-cMyc/ET-1 axis controlling pulmonary vascular tone, mechanistically connecting THBS1 to pulmonary hypertension.\",\n      \"evidence\": \"CD47-/- mice with hypoxic PH, ex vivo myography, cMyc gain/loss, CD47 blocking antibody in rat monocrotaline model\",\n      \"pmids\": [\"27742621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD47 engagement regulates cMyc transcriptionally not resolved\", \"Endothelial versus smooth muscle contributions not fully separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established a CD47-Nox1-ROS-p53-p21 pathway through which THBS1 drives endothelial senescence and vascular aging.\",\n      \"evidence\": \"TSP1-/- mice, Nox1 pharmacological inhibition, siRNA, CD47-Nox1 co-IP, aged human lung tissue\",\n      \"pmids\": [\"29042481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical coupling of CD47 to Nox1 activation not fully defined\", \"Nox1 isoform selectivity mechanism unexplained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Positioned THBS1 as a downstream effector of KRIT1/KLF2/KLF4 that restrains VEGF signaling and preserves endothelial barrier integrity, linking its loss to cerebral cavernous malformation.\",\n      \"evidence\": \"Krit1 and Thbs1 mouse genetic models, in vitro TSP1/3TSR reconstitution, 3TSR therapeutic administration\",\n      \"pmids\": [\"28970240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating VEGF/tight-junction effects not pinned down\", \"Mechanism of KLF-driven THBS1 repression not detailed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a TGF-\\u03b2-independent ligand activity of THBS1 as a direct BMP-2/4 antagonist, broadening its growth factor regulatory repertoire and mapping it to the von Willebrand type C domain.\",\n      \"evidence\": \"Surface plasmon resonance, co-IP, BMP-responsive bioactivity assay in C3H10T1/2 cells\",\n      \"pmids\": [\"28747434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct domain-deletion proof of the vWC domain requirement not shown\", \"Physiological context of BMP antagonism not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined opposing transcriptional control of THBS1 in cancer: EZH2-mediated epigenetic repression enabling angiogenesis versus YAP-TEAD activation driving FAK-dependent invasion.\",\n      \"evidence\": \"EZH2 ChIP and promoter methylation in ADT prostate models; YAP/TEAD ChIP, luciferase, and siRNA epistasis to pFAK in breast cancer\",\n      \"pmids\": [\"30287808\", \"30055645\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single gene is anti-angiogenic yet pro-invasive across contexts not reconciled\", \"Receptor for FAK activation not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the receptor-proximal events of THBS1-CD47 signaling in distinct vascular beds, showing SHP-2 activation suppressing STAT3-iNOS and ROS-dependent endothelial injury.\",\n      \"evidence\": \"CD47-SHP-2 co-IP and STAT3/iNOS readouts in retinal cells with CNV model; sickle bone marrow chimeras into CD47KO hosts with ROS assays\",\n      \"pmids\": [\"31899207\", \"30892078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal validation of CD47-SHP-2 binding limited\", \"How CD47 toggles between ROS-inducing and SHP-2/STAT3-suppressing outputs unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a proteolytic switch in which MT1-MMP cleavage releases a C-terminal THBS1 fragment that engages CD47/\\u03b1v\\u03b23 to promote NO production and intussusceptive angiogenesis, indicating fragment-specific, context-opposite activities.\",\n      \"evidence\": \"Endothelial MT1-MMP conditional knockout, intravital microscopy, lentiviral rescue, peptide administration in colitis\",\n      \"pmids\": [\"31793743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage site and fragment identity not biochemically pinned\", \"How fragment activity reconciles with full-length anti-angiogenic role unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Refined the myeloid-intrinsic aneurysm mechanism by showing macrophage THBS1 suppresses TIMP1 to license matrix invasion.\",\n      \"evidence\": \"Myeloid-specific Thbs1 knockout (Lyz2-cre), RNA FISH, gelatinase assays, Timp1 siRNA rescue\",\n      \"pmids\": [\"33028100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which THBS1 represses TIMP1 not defined\", \"Whether intracellular or secreted THBS1 mediates the effect unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a receptor-independent intracellular mechanism in which THBS1 binds and activates PERK to drive ATF4-dependent autophagy and lethal cardiac atrophy, distinguishing this from canonical CD36/CD47 signaling.\",\n      \"evidence\": \"Thbs1 transgenic mice with PERK, ATF6\\u03b1, CD36, and CD47 knockouts and AAV9 rescue\",\n      \"pmids\": [\"34168130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of THBS1-PERK binding not solved\", \"How a secreted protein accesses the ER lumen to engage PERK not explained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Generalized the THBS1 atrophy program to skeletal muscle through a TGF\\u03b2-Smad2/3-ATF4 axis controlling both autophagy-lysosomal and ubiquitin-proteasome degradation.\",\n      \"evidence\": \"Muscle-specific Thbs1 transgenics, myofiber TGF\\u03b2R inhibition, conditional Smad2/3 and Atf4 knockouts, Thbs1-/- denervation/caloric restriction models\",\n      \"pmids\": [\"38678560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between the PERK-ATF4 and TGF\\u03b2-Smad2/3-ATF4 routes to ATF4 not reconciled\", \"Receptor initiating muscle TGF\\u03b2 activation not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a non-matricellular intracellular function whereby exosomal THBS1 binds the deubiquitinase OTUD5 to promote GPX4 ubiquitination and endothelial ferroptosis in cerebral ischemia.\",\n      \"evidence\": \"THBS1-OTUD5 binding assay, cellular thermal shift, endothelial Gpx4 knockout mice, tMCAO model\",\n      \"pmids\": [\"39994679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which THBS1 promotes GPX4 ubiquitination unclear\", \"Single lab; reciprocal validation of THBS1-OTUD5 interaction limited\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How THBS1 partitions among its mutually exclusive activities\\u2014extracellular receptor signaling, latent TGF-\\u03b2 activation, intracellular PERK/OTUD5 engagement, and fragment-specific functions\\u2014within a single cell or tissue remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model for how localization and proteolysis dictate which pathway dominates\", \"Structural determinants of receptor versus intracellular partner selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [7, 8, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 8, 13, 16]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 9, 10, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [4, 6, 16, 19]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 7, 9, 27]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [5, 27]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16, 21, 31]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 20, 25]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD47\", \"CD36\", \"PERK\", \"BMP2\", \"BMP4\", \"OTUD5\", \"TLR4\", \"LRRK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}