{"gene":"CD47","run_date":"2026-06-13T19:06:35","timeline":{"discoveries":[{"year":2000,"finding":"CD47 functions as a 'marker of self' on red blood cells by binding to the inhibitory receptor SIRPα on splenic macrophages, thereby preventing phagocytic clearance; CD47-null mouse RBCs were rapidly cleared from the bloodstream by splenic red pulp macrophages, and this was rescued by CD47-SIRPα engagement.","method":"In vivo adoptive transfer of CD47-null vs. wild-type mouse RBCs; macrophage phagocytosis assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO model with defined cellular phenotype, replicated across labs and highly cited foundational study","pmids":["10856220"],"is_preprint":false},{"year":2001,"finding":"CD47 (IAP) acts as a receptor for thrombospondin family members (via their C-terminal VVM motif), a ligand for SIRPα, and a component of a supramolecular complex with specific integrins, heterotrimeric G proteins, and cholesterol; CD47 agonist peptides initiate heterotrimeric Gi protein signaling that augments β1, β2, and β3 integrin functions.","method":"Biochemical reconstitution, peptide agonist assays, co-immunoprecipitation of complex components","journal":"Trends in cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — multiple interaction partners identified but abstract-level summary of prior biochemical work; highly replicated concept","pmids":["11306274"],"is_preprint":false},{"year":2005,"finding":"CD47 associates with Fas (CD95) upon Fas activation and augments Fas-mediated apoptosis; Jurkat T cells lacking CD47 are relatively resistant to Fas-mediated death, and re-expression of CD47 rescues killing; CD47 deficiency impairs caspase activation, cytochrome c release, loss of mitochondrial membrane potential, and DNA cleavage downstream of Fas.","method":"CD47-knockout Jurkat cells, CD47 re-expression, co-immunoprecipitation of Fas and CD47, primary T cells from CD47-null mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, KO + rescue, primary cell validation, multiple downstream readouts in single study","pmids":["15917238"],"is_preprint":false},{"year":2005,"finding":"Human SIRPα1 binds CD47 on human and pig RBCs but not mouse, rat, or cow RBCs, demonstrating species- and cell-type specificity; deglycosylation of SIRPα1 strengthens binding; low SIRPα copy numbers on phagocytes explain absence of RBC adhesion under physiological conditions; bone marrow-derived mesenchymal stem cells display CD47 but do not significantly bind soluble SIRPα1.","method":"SIRPα1 binding assay, atomic force microscopy, centrifugation-based adhesion assay, antibody inhibition","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biophysical methods (AFM, centrifugation, antibody inhibition), single lab","pmids":["16291597"],"is_preprint":false},{"year":2009,"finding":"SIRPα binds to protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region; CD47 binding to SIRPα constitutes a bidirectional cell-cell communication system important for regulating migration and phagocytosis; activating SIRPβ shows negligible CD47 binding despite extensive extracellular sequence similarity to SIRPα.","method":"Biochemical binding assays, structural analysis, functional phagocytosis assays","journal":"Trends in cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — review summarizing multiple prior biochemical experiments; SHP-1/2 recruitment and SIRPβ non-binding well established across labs","pmids":["19144521"],"is_preprint":false},{"year":2014,"finding":"Cell rigidity and shape of a phagocytic target can override CD47's 'self' signaling by hyperactivating myosin-II at the phagocytic synapse; controlled stiffening of normal human RBCs does not compromise CD47-SIRPα interaction, but rigid RBC discocytes show maximal myosin-II activation that overcomes CD47 inhibitory signaling; shape (stomatocyte vs. discocyte) modulates how effectively CD47 inhibits phagocytosis.","method":"RBC stiffening manipulation, phagocytosis assays with macrophages, myosin-II activity measurements, CD47-SIRPα binding confirmed by antibody inhibition","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (mechanical manipulation, activity assays, antibody controls), single lab","pmids":["25411427"],"is_preprint":false},{"year":2015,"finding":"MYC oncogene directly binds the promoters of Cd47 and Pd-l1 genes to transcriptionally regulate their expression; MYC inactivation reduces CD47 and PD-L1 mRNA and protein; enforced expression of CD47 in MYC-inactivated tumors suppresses the antitumor immune response and allows continued tumor growth.","method":"ChIP of MYC at Cd47/Pd-l1 promoters, MYC inducible mouse tumor models, CD47 enforced expression rescue experiments, qRT-PCR, Western blot","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP establishing direct promoter binding, genetic rescue experiment, multiple orthogonal methods in one study","pmids":["26966191"],"is_preprint":false},{"year":2015,"finding":"CD47 blockade requires dendritic cell cross-priming of T cell responses (not macrophage phagocytosis) in syngeneic immunocompetent mouse tumor models; therapeutic effects are abrogated in T cell-deficient mice; antitumor effects require STING (but not MyD88 or TRIF) in CD11c+ cells, linking cytosolic DNA sensing to CD47 blockade activity.","method":"Syngeneic mouse tumor models, T cell-deficient mice, STING/MyD88/TRIF genetic knockouts, macrophage/DC depletion","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis via multiple genetic KOs, complementary cell depletion experiments, single rigorous study with multiple orthogonal approaches","pmids":["26322579"],"is_preprint":false},{"year":2012,"finding":"CD47 deficiency or blockade activates autophagic flux in irradiated T cells and endothelial cells; this enhanced autophagy (evidenced by increased BECN1, ATG5, ATG7, LC3+ puncta, autophagosomes by EM, reduced p62) is necessary for the radioprotective effect of CD47 blockade; pharmacological or siRNA inhibition of autophagy selectively sensitizes CD47-deficient cells to radiation, and re-expression of CD47 reverses autophagy and restores radiosensitivity.","method":"CD47-null T cells, CD47 re-expression, siRNA/pharmacological autophagy inhibition, electron microscopy, flow cytometry, Western blot","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO + rescue, multiple orthogonal autophagy readouts (EM, LC3, Western blots), epistasis via autophagy inhibition in one study","pmids":["22874555"],"is_preprint":false},{"year":2016,"finding":"TNF-α drives upregulation of CD47 on diseased vascular cells in atherosclerosis, impairing efferocytosis; CD47-blocking antibodies restore macrophage-mediated phagocytic clearance of apoptotic vascular cells and ameliorate atherosclerosis in multiple mouse models.","method":"Multiple atherosclerosis mouse models, anti-CD47 antibody treatment, TNF-α mechanistic studies, efferocytosis assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mouse models, identified upstream regulator (TNF-α), functional efferocytosis readout, replicated across models","pmids":["27437576"],"is_preprint":false},{"year":2018,"finding":"CD47 on synapses protects them from excessive microglia-mediated pruning during development via CD47-SIRPα signaling; CD47-deficient mice show increased microglial engulfment of retinogeniculate inputs, reduced synapse numbers in dLGN, and increased functional pruning; CD47 is required for neuronal activity-dependent preferential protection of active inputs from microglial engulfment.","method":"CD47 knockout mice, microglial engulfment assays, electrophysiology, confocal imaging of retinogeniculate system","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO model with multiple readouts (engulfment, synapse number, electrophysiology, activity-dependent regulation), single rigorous study","pmids":["30308165"],"is_preprint":false},{"year":2021,"finding":"NK cell SIRPα is upregulated by IL-2 stimulation and interacts with target cell CD47 in a threshold-dependent manner, counteracting stimulatory signals (IL-2, CD16, NKG2D); elevated CD47 on target cells protects against SIRPα+ primary NK cells but not SIRPα- NK cell lines; SIRPα deficiency or antibody blockade increases NK cell killing capacity.","method":"NK cell SIRPα characterization, CD47-overexpressing target cells, SIRPα KO, antibody blockade, cytotoxicity assays","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO and antibody blockade with functional cytotoxicity readouts, single lab with multiple cell-type validations","pmids":["33416832"],"is_preprint":false},{"year":2022,"finding":"Senescent cells upregulate CD47 coinciding with increased expression of CD47-modifying enzymes QPCT/L; this enhanced CD47 suppresses macrophage-mediated efferocytosis of both senescent cells and bystander apoptotic corpses (SCES) via the SIRPα-CD47-SHP-1 axis; SCES requires direct macrophage-senescent cell contact and is reversible by interfering with SIRPα-CD47-SHP-1 signaling or QPCT/L activity.","method":"Senescent fibroblast and epithelial cell models, efferocytosis assays, CD47/QPCT/L knockout and inhibition, contact-dependent assays, in vitro and in vivo senescence models","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple genetic and pharmacological interventions, identified writer enzymes (QPCT/L) and signaling axis (SHP-1), in vitro and in vivo validation","pmids":["36459066"],"is_preprint":false},{"year":2023,"finding":"EGFR activation induces c-Src binding to CD47, leading to c-Src-mediated CD47 Y288 phosphorylation; this phosphorylation inhibits TRIM21 (ubiquitin E3 ligase) binding to CD47, preventing TRIM21-mediated K99/102 polyubiquitylation and proteasomal degradation of CD47; CD47 Y288F knock-in reduces CD47 expression and increases macrophage phagocytosis, while CD47 K99/102R knock-in has opposite effects.","method":"Co-IP of c-Src and CD47, mutagenesis (Y288F and K99/102R knock-in), ubiquitylation assays, in vitro EGFR/c-Src kinase assays, phagocytosis assays, in vivo brain tumor models","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase/ubiquitylation assays, site-directed mutagenesis with knock-in validation, Co-IP, functional rescue, in vivo confirmation in single study","pmids":["37541303"],"is_preprint":false},{"year":2023,"finding":"The CD47/SIRPα axis requires deneddylation of SHP2 for its downstream signaling: SHP2 is constitutively neddylated on K358 and K364 (maintaining autoinhibited conformation); upon CD47-liganded SIRPα activation, SENP8 deneddylates SHP2, enabling dephosphorylation of substrates at the phagocytic cup and inhibition of macrophage phagocytosis.","method":"Mass spectrometry identification of neddylation sites, mutagenesis of K358/K364, SENP8 siRNA/KO, phagocytosis assays, substrate dephosphorylation assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — identification of PTM writer (SENP8-mediated deneddylation), site-specific mutagenesis, mechanistic substrate assays, functional phagocytosis readout in single study","pmids":["36626230"],"is_preprint":false},{"year":2021,"finding":"IFN-γ upregulates CD47 expression on cancer cells via the JAK1/STAT1/IRF1 signaling pathway; IFN-γ-induced CD47 surface expression strengthens CD47-SIRPα binding and decreases macrophage phagocytosis of cancer cells; JAK1/2 inhibition or siRNA silencing of JAK1, STAT1, or IRF1 reverses this effect.","method":"siRNA knockdown, JAK1/2 inhibitor (ruxolitinib), flow cytometry for surface CD47, phagocytosis assays, TCGA correlation analysis","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway epistasis via multiple siRNA targets, pharmacological inhibition, functional phagocytosis readout, single lab","pmids":["34171557"],"is_preprint":false},{"year":2022,"finding":"Statins suppress CD47 expression by inhibiting nuclear translocation of NFκB1 p50, thereby reducing CD47-mediated anti-phagocytic signaling and amplifying the anti-atherosclerotic effects of CD47-SIRPα blockade in an additive manner.","method":"RNA sequencing, in vivo and in vitro statin treatment, NFκB1 p50 nuclear translocation assays, CD47 expression assays, phagocytosis assays, atherosclerosis mouse models","journal":"Nature cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway identified (NFκB1 p50), in vivo and in vitro validation, single lab with multiple orthogonal methods","pmids":["35990913"],"is_preprint":false},{"year":2024,"finding":"CD47 expression is critical for CAR T-cell survival in vivo; CD47-knockout CAR T cells are sensitized to macrophage-mediated phagocytosis and fail to expand and persist in vivo despite potent in vitro activity; a CD47 variant (CD47 Q31P/47E) engages SIRPα and resists blockade by anti-CD47 antibodies, protecting adoptively transferred T cells from macrophage clearance while enabling macrophage recruitment to tumors.","method":"CD47 knockout in T cells, xenograft models, in vitro phagocytosis assays, CD47 Q31P engineered variant, adoptive transfer experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with mechanistic rescue via engineered variant, in vivo and in vitro orthogonal validation, identifies macrophage phagocytosis as mechanism of T cell clearance","pmids":["38750365"],"is_preprint":false},{"year":2022,"finding":"Extracellular vesicles (exosomes) released from CD47-overexpressing cells can transfer CD47 to the surface of recipient cells ('cross-dressing'), enabling the cross-dressed CD47 to interact with SIRPα and inhibit phagocytosis; however, unlike autogenous CD47, ligation of cross-dressed CD47 does not induce cell death.","method":"Exosome isolation, flow cytometry for surface CD47, SIRPα binding assays, phagocytosis assays, cell death assays comparing autogenous vs. cross-dressed CD47","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional distinction between autogenous and cross-dressed CD47 established with multiple assays, single lab","pmids":["36454036"],"is_preprint":false},{"year":2022,"finding":"Macrophage-specific SIRPα loss (but not global CD47 deletion) attenuates atherosclerosis by stimulating efferocytosis, reducing cholesterol accumulation, promoting lipid efflux, and inducing M2 polarization; conversely, myeloid cell-specific CD47 deletion inhibits efferocytosis, impairs cholesterol efflux, augments inflammation, and increases atherosclerosis, demonstrating cell-specific and opposite roles for CD47 vs. SIRPα in myeloid cells.","method":"Myeloid cell-specific and global conditional knockout mice, efferocytosis assays, cholesterol efflux assays, macrophage polarization, atherosclerosis mouse models","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-specific genetic KO models revealing opposite functional roles, multiple mechanistic readouts, replicated with different genetic strategies","pmids":["34940829"],"is_preprint":false},{"year":2023,"finding":"TSP1 inhibits lymphangiogenesis through CD47 activation in lymphatic endothelial cells (LECs): TSP1 inhibits VEGF-C-induced AKT and eNOS activation and attenuates NO production; CD47 silencing in LECs prevents TSP1's effects on lymphangiogenic AKT-eNOS signaling; LEC-specific Cd47 knockout mice show reduced atherosclerosis and increased lymphatic vessel density.","method":"LEC-specific Cd47 KO mice (Cd47ΔLEC), AAV8-PCSK9 atherosclerosis model, in vitro LEC assays, siRNA, Western blot for AKT/eNOS, Matrigel plug assay, immunostaining","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-specific KO with in vivo phenotype, mechanistic pathway (AKT-eNOS) identified by siRNA and in vitro assays, multiple orthogonal methods","pmids":["37259865"],"is_preprint":false},{"year":2024,"finding":"CD47 associates with TLR2 in macrophages; CD47 blocking leads to decreased intracellular P. gingivalis survival dependent on bacterial major fimbriae; P. gingivalis infection induces increased TSP-1 expression and secretion, which broadly suppresses neutrophil bactericidal activity; CD47-TLR2 co-signaling induces TSP-1 to suppress neutrophil activity.","method":"Co-immunoprecipitation of CD47 and TLR2, anti-CD47 antibody blockade, CD47 knockout mice, intracellular survival assays, TSP-1 expression/secretion measurements","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing CD47-TLR2 association, KO mice for in vivo validation, functional bactericidal assays, single lab","pmids":["39536084"],"is_preprint":false},{"year":2019,"finding":"Thrombospondin-1 (TSP-1) signaling through CD47 inhibits Th17 differentiation and promotes Treg differentiation from CD4+ T cells; TSP-1 functions as a negative regulator of T cell activation, with CD47 as the receptor; siRNA knockdown of TSP-1 in T cells and moDCs confirms this negative regulatory role.","method":"Th17/Treg differentiation assays, exogenous TSP-1 treatment, siRNA knockdown of TSP-1, immunofluorescence, RT-PCR in patient samples","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional differentiation assays, siRNA confirmation, patient and in vitro data, single lab","pmids":["31214201"],"is_preprint":false}],"current_model":"CD47 is a ubiquitously expressed transmembrane receptor that functions as a 'don't eat me' signal by binding SIRPα on myeloid and NK cells, activating SHP-1/SHP-2 (via SENP8-mediated SHP2 deneddylation) to inhibit phagocytosis; it also serves as a high-affinity signaling receptor for thrombospondin-1 that modulates integrin function, Gi protein signaling, autophagy, nitric oxide/eNOS pathways, and T cell differentiation; its expression is transcriptionally regulated by MYC, NFκB, IFN-γ/JAK/STAT1/IRF1, and ZEB1, and post-translationally regulated by EGFR-c-Src-mediated Y288 phosphorylation that blocks TRIM21-dependent polyubiquitylation and degradation, while it also associates with Fas to augment apoptosis and with TLR2 to modulate innate immune responses."},"narrative":{"mechanistic_narrative":"CD47 is a ubiquitously expressed transmembrane receptor that functions as a self-recognition signal restraining phagocytic and immune clearance of cells [PMID:10856220, PMID:11306274]. Its canonical activity is to bind the inhibitory receptor SIRPα on splenic and myeloid phagocytes, marking red blood cells and other targets as 'self' and preventing their engulfment [PMID:10856220]; this engagement is species- and cell-type specific and operates in a threshold-dependent manner that can be overridden by target rigidity-driven myosin-II activation at the phagocytic synapse [PMID:16291597, PMID:25411427]. Downstream of CD47-liganded SIRPα, the protein tyrosine phosphatases SHP-1 and SHP-2 are recruited [PMID:19144521], and productive inhibitory signaling requires SENP8-mediated deneddylation of SHP2 at K358/K364 to relieve its autoinhibited conformation and permit substrate dephosphorylation at the phagocytic cup [PMID:36626230]. This 'don't eat me' axis governs efferocytosis in diverse settings: it limits clearance of apoptotic and senescent cells in atherosclerosis [PMID:27437576, PMID:36459066, PMID:34940829], restrains developmental microglial synaptic pruning [PMID:30308165], and counteracts NK-cell cytotoxicity through SIRPα on activated NK cells [PMID:33416832]. CD47 is also a high-affinity receptor for thrombospondin-1, through which it organizes a supramolecular complex with integrins, heterotrimeric Gi proteins, and cholesterol to modulate integrin function [PMID:11306274], suppresses AKT-eNOS-dependent lymphangiogenesis [PMID:37259865], inhibits Th17 and promotes Treg differentiation [PMID:31214201], and regulates autophagic flux to control radiosensitivity [PMID:22874555]; it further associates with Fas to augment apoptotic signaling [PMID:15917238] and with TLR2 to drive TSP-1-dependent suppression of innate antibacterial activity [PMID:39536084]. CD47 abundance is transcriptionally driven by MYC, IFN-γ via JAK1/STAT1/IRF1, and NFκB1 p50 [PMID:26966191, PMID:34171557, PMID:35990913], and stabilized post-translationally by EGFR-c-Src-mediated Y288 phosphorylation that blocks TRIM21-dependent K99/102 polyubiquitylation and proteasomal degradation [PMID:37541303]. Therapeutically, CD47 blockade requires dendritic-cell cross-priming and STING-dependent cytosolic DNA sensing rather than macrophage phagocytosis alone for antitumor T-cell responses [PMID:26322579], and CD47 expression is essential for the persistence of adoptively transferred CAR T cells in vivo [PMID:38750365].","teleology":[{"year":2000,"claim":"Established CD47's foundational role as a self-marker: it was unknown how cells avoid phagocytic clearance, and CD47-null RBCs demonstrated that CD47-SIRPα engagement is required to prevent splenic macrophage destruction.","evidence":"In vivo adoptive transfer of CD47-null vs. wild-type mouse RBCs with macrophage phagocytosis assays","pmids":["10856220"],"confidence":"High","gaps":["Did not resolve the intracellular signaling steps downstream of SIRPα","Limited to RBC clearance in spleen"]},{"year":2001,"claim":"Defined CD47 as a multifunctional receptor beyond self-recognition by identifying thrombospondin as a ligand and placing CD47 in a complex with integrins, Gi proteins, and cholesterol that modulates integrin function.","evidence":"Biochemical reconstitution, peptide agonist assays, and co-immunoprecipitation of complex components","pmids":["11306274"],"confidence":"Medium","gaps":["Abstract-level summary of prior biochemistry, not a single primary dataset","Stoichiometry and architecture of the supramolecular complex undefined"]},{"year":2005,"claim":"Connected CD47 to apoptotic signaling, showing it physically associates with Fas and is required for efficient Fas-mediated death, expanding CD47 function from anti-phagocytic to pro-apoptotic.","evidence":"CD47-knockout Jurkat cells with re-expression rescue, reciprocal Fas/CD47 Co-IP, and primary T cells from CD47-null mice","pmids":["15917238"],"confidence":"High","gaps":["Molecular mechanism by which CD47 couples to caspase activation unresolved","Relationship to SIRPα signaling not addressed"]},{"year":2005,"claim":"Quantified the CD47-SIRPα interaction's species and cell-type specificity, explaining why phagocytes do not adhere to RBCs under physiological conditions despite CD47 display.","evidence":"SIRPα1 binding assays, atomic force microscopy, centrifugation-based adhesion, and antibody inhibition","pmids":["16291597"],"confidence":"Medium","gaps":["Single lab biophysical characterization","Functional consequence of weak MSC binding not pursued"]},{"year":2009,"claim":"Identified the inhibitory effectors of the axis, establishing that SIRPα recruits SHP-1 and SHP-2 and that CD47-SIRPα is a bidirectional system regulating migration and phagocytosis.","evidence":"Biochemical binding assays, structural analysis, and functional phagocytosis assays (review synthesis)","pmids":["19144521"],"confidence":"Medium","gaps":["Did not define the regulatory steps controlling SHP-2 activation","SIRPβ non-binding mechanism unexplained"]},{"year":2012,"claim":"Revealed a thrombospondin/CD47-linked cytoprotection pathway, showing CD47 loss or blockade activates autophagic flux that mediates radioprotection of T and endothelial cells.","evidence":"CD47-null cells with re-expression, siRNA/pharmacological autophagy inhibition, EM, flow cytometry, and Western blot","pmids":["22874555"],"confidence":"High","gaps":["Signaling link between CD47 and autophagy machinery not defined","Whether SIRPα or TSP1 mediates the effect unclear"]},{"year":2015,"claim":"Placed CD47 under direct oncogenic transcriptional control, showing MYC binds the Cd47 promoter and that CD47 contributes to MYC-driven immune evasion.","evidence":"ChIP of MYC at Cd47/Pd-l1 promoters, inducible MYC mouse tumors, and CD47 enforced-expression rescue","pmids":["26966191"],"confidence":"High","gaps":["Did not address other transcriptional inputs","Relative contribution of CD47 vs. PD-L1 to evasion not dissected"]},{"year":2015,"claim":"Redefined the cellular basis of CD47-blockade therapy, demonstrating it requires dendritic-cell cross-priming and STING-dependent DNA sensing rather than macrophage phagocytosis alone.","evidence":"Syngeneic tumor models with T cell-deficient mice, STING/MyD88/TRIF knockouts, and macrophage/DC depletion","pmids":["26322579"],"confidence":"High","gaps":["Source of cytosolic DNA activating STING not identified","How CD47 blockade triggers DC priming mechanistically unresolved"]},{"year":2016,"claim":"Extended the anti-efferocytosis role to cardiovascular disease, identifying TNF-α-driven CD47 upregulation as a barrier to apoptotic cell clearance in atherosclerosis reversible by CD47 blockade.","evidence":"Multiple atherosclerosis mouse models, anti-CD47 antibody treatment, and efferocytosis assays","pmids":["27437576"],"confidence":"High","gaps":["Transcription factor downstream of TNF-α not defined here","Cell-type-specific contributions not separated"]},{"year":2018,"claim":"Demonstrated a neurodevelopmental function, showing CD47-SIRPα protects active synapses from excessive microglial pruning in an activity-dependent manner.","evidence":"CD47 knockout mice, microglial engulfment assays, electrophysiology, and confocal imaging of the retinogeniculate system","pmids":["30308165"],"confidence":"High","gaps":["How neuronal activity regulates synaptic CD47 levels unknown","Microglial SHP signaling in pruning not directly tested"]},{"year":2021,"claim":"Established transcriptional and innate-immune extensions of CD47 regulation: IFN-γ induces CD47 via JAK1/STAT1/IRF1 to strengthen SIRPα binding, and NK cells use IL-2-induced SIRPα to read target CD47.","evidence":"siRNA and JAK inhibitor studies with phagocytosis assays (IFN-γ); NK SIRPα characterization with CD47-overexpressing targets and cytotoxicity assays","pmids":["34171557","33416832"],"confidence":"Medium","gaps":["Single-lab pathway epistasis for the IFN-γ axis","NK SIRPα threshold-setting mechanism not defined"]},{"year":2022,"claim":"Resolved cell-specific and context-specific roles in atherosclerosis and senescence: myeloid CD47 and SIRPα have opposite effects, statins suppress CD47 via NFκB1 p50, and senescent cells exploit QPCT/L-modified CD47 to block efferocytosis.","evidence":"Cell-specific and global conditional knockout mice, statin treatment with NFκB1 p50 translocation assays, senescent cell models with QPCT/L inhibition, and efferocytosis assays","pmids":["34940829","35990913","36459066"],"confidence":"High","gaps":["Mechanism distinguishing CD47 vs. SIRPα myeloid outcomes incomplete","QPCT/L modification site on CD47 not fully mapped in these studies"]},{"year":2022,"claim":"Showed CD47 can act in trans via exosomal transfer, with cross-dressed CD47 inhibiting phagocytosis through SIRPα but failing to transmit the pro-death signal of autogenous CD47.","evidence":"Exosome isolation, surface CD47 flow cytometry, SIRPα binding, and comparative phagocytosis and cell-death assays","pmids":["36454036"],"confidence":"Medium","gaps":["Structural basis for the death-signaling difference unknown","Physiological prevalence of cross-dressing untested"]},{"year":2023,"claim":"Defined post-translational stabilization of CD47, showing EGFR-c-Src Y288 phosphorylation blocks TRIM21-mediated K99/102 polyubiquitylation and degradation, controlling surface CD47 and phagocytosis.","evidence":"Co-IP, Y288F and K99/102R knock-in mutagenesis, in vitro kinase and ubiquitylation assays, phagocytosis assays, and in vivo brain tumor models","pmids":["37541303"],"confidence":"High","gaps":["Upstream signals coupling EGFR activity to CD47 in vivo not fully mapped","Whether TRIM21 acts on other CD47 pools unknown"]},{"year":2023,"claim":"Uncovered a NEDD8 regulatory layer in inhibitory signaling, showing SHP2 is constitutively neddylated and that CD47-SIRPα-triggered SENP8 deneddylation is required to activate SHP2 at the phagocytic cup.","evidence":"Mass spectrometry mapping of neddylation sites, K358/K364 mutagenesis, SENP8 siRNA/KO, and substrate dephosphorylation and phagocytosis assays","pmids":["36626230"],"confidence":"High","gaps":["How SIRPα engagement activates SENP8 not defined","Role of SHP-1 neddylation not addressed"]},{"year":2023,"claim":"Linked TSP1-CD47 signaling to lymphatic biology, showing CD47 mediates TSP1 inhibition of VEGF-C-driven AKT-eNOS signaling and lymphangiogenesis with consequences for atherosclerosis.","evidence":"LEC-specific Cd47 knockout mice, AAV8-PCSK9 atherosclerosis model, siRNA, AKT/eNOS Western blots, and Matrigel plug assays","pmids":["37259865"],"confidence":"High","gaps":["Direct biochemical link between CD47 and AKT/eNOS not fully defined","Contribution relative to SIRPα-mediated efferocytosis unclear"]},{"year":2024,"claim":"Demonstrated that CD47 expression is essential for adoptive T-cell persistence and that an engineered CD47 variant can protect cells from clearance while permitting macrophage recruitment, with TLR2 co-signaling identified as an additional CD47 partnership.","evidence":"CD47 KO in T cells, xenograft and adoptive transfer models, the CD47 Q31P/47E variant (CAR T study); CD47-TLR2 Co-IP, KO mice, and bactericidal assays (TLR2 study)","pmids":["38750365","39536084"],"confidence":"High","gaps":["Long-term safety of engineered CD47 variants untested","Mechanism of CD47-TLR2 co-signaling to TSP-1 induction incompletely defined"]},{"year":null,"claim":"How CD47's many context-specific functions—SIRPα inhibition, Fas-coupled apoptosis, TSP1-Gi/integrin signaling, autophagy, and TLR2 co-signaling—are mechanistically partitioned within a single receptor remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model coupling the distinct ligand-engaged states","Lack of data on how cell type dictates which CD47 output dominates"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,13]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,7,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,20]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[13,14]}],"complexes":["CD47-SIRPα signaling complex","CD47-integrin-Gi protein supramolecular complex"],"partners":["SIRPA","THBS1","FAS","TLR2","SRC","TRIM21","SHP-2 (PTPN11)","SHP-1 (PTPN6)"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q08722","full_name":"Leukocyte surface antigen CD47","aliases":["Antigenic surface determinant protein OA3","Integrin-associated protein","IAP","Protein MER6"],"length_aa":323,"mass_kda":35.2,"function":"Adhesive protein that mediates cell-to-cell interactions (PubMed:11509594, PubMed:15383453). Acts as a receptor for thrombospondin THBS1 and as modulator of integrin signaling through the activation of heterotrimeric G proteins (PubMed:19004835, PubMed:7691831, PubMed:8550562). Involved in signal transduction, cardiovascular homeostasis, inflammation, apoptosis, angiogenesis, cellular self-renewal, and immunoregulation (PubMed:11509594, PubMed:15383453, PubMed:19004835, PubMed:27742621, PubMed:32679764, PubMed:7691831, PubMed:8550562). Plays a role in modulating pulmonary endothelin EDN1 signaling (PubMed:27742621). Modulates nitrous oxide (NO) signaling, in response to THBS1, hence playing a role as a pressor agent, supporting blood pressure (By similarity). Plays an important role in memory formation and synaptic plasticity in the hippocampus (By similarity). Receptor for SIRPA, binding to which prevents maturation of immature dendritic cells and inhibits cytokine production by mature dendritic cells (PubMed:11509594). Interaction with SIRPG mediates cell-cell adhesion, enhances superantigen-dependent T-cell-mediated proliferation and costimulates T-cell activation (PubMed:15383453). Positively modulates FAS-dependent apoptosis in T-cells, perhaps by enhancing FAS clustering (By similarity). Plays a role in suppressing angiogenesis and may be involved in metabolic dysregulation during normal aging (PubMed:32679764). In response to THBS1, negatively modulates wound healing (By similarity). Inhibits stem cell self-renewal, in response to THBS1, probably by regulation of the stem cell transcription factors POU5F1/OCT4, SOX2, MYC/c-Myc and KLF4 (By similarity). May play a role in membrane transport and/or integrin dependent signal transduction (PubMed:7691831). May prevent premature elimination of red blood cells (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q08722/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD47","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD47","total_profiled":1310},"omim":[{"mim_id":"610459","title":"PROLINE-RICH PROTEIN 13; PRR13","url":"https://www.omim.org/entry/610459"},{"mim_id":"606625","title":"SLAM FAMILY, MEMBER 7; SLAMF7","url":"https://www.omim.org/entry/606625"},{"mim_id":"605466","title":"SIGNAL REGULATORY PROTEIN, GAMMA; SIRPG","url":"https://www.omim.org/entry/605466"},{"mim_id":"605402","title":"CD274 MOLECULE; CD274","url":"https://www.omim.org/entry/605402"},{"mim_id":"603850","title":"DYNAMIN 1-LIKE; DNM1L","url":"https://www.omim.org/entry/603850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CD47"},"hgnc":{"alias_symbol":["IAP","OA3"],"prev_symbol":["MER6"]},"alphafold":{"accession":"Q08722","domains":[{"cath_id":"2.60.40.10","chopping":"19-132","consensus_level":"high","plddt":94.1877,"start":19,"end":132},{"cath_id":"-","chopping":"140-298","consensus_level":"high","plddt":89.7713,"start":140,"end":298}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08722","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q08722-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q08722-F1-predicted_aligned_error_v6.png","plddt_mean":86.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD47","jax_strain_url":"https://www.jax.org/strain/search?query=CD47"},"sequence":{"accession":"Q08722","fasta_url":"https://rest.uniprot.org/uniprotkb/Q08722.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q08722/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08722"}},"corpus_meta":[{"pmid":"10856220","id":"PMC_10856220","title":"Role 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inhibits phagocytosis without transmitting cell death signals.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36454036","citation_count":29,"is_preprint":false},{"pmid":"26914699","id":"PMC_26914699","title":"Enhanced biocompatibility of CD47-functionalized vascular stents.","date":"2016","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/26914699","citation_count":28,"is_preprint":false},{"pmid":"38464520","id":"PMC_38464520","title":"Opportunities and challenges for anti-CD47 antibodies in hematological malignancies.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38464520","citation_count":27,"is_preprint":false},{"pmid":"28693236","id":"PMC_28693236","title":"Significance of CD47 expression in gastric cancer.","date":"2017","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/28693236","citation_count":27,"is_preprint":false},{"pmid":"32576628","id":"PMC_32576628","title":"Clinicopathological significance of CD47 expression in hepatocellular carcinoma.","date":"2020","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32576628","citation_count":27,"is_preprint":false},{"pmid":"34203368","id":"PMC_34203368","title":"CD47 in the Brain and Neurodegeneration: An Update on the Role in Neuroinflammatory Pathways.","date":"2021","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34203368","citation_count":26,"is_preprint":false},{"pmid":"32882841","id":"PMC_32882841","title":"CD47 as a Potential Target to Therapy for Infectious Diseases.","date":"2020","source":"Antibodies (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32882841","citation_count":26,"is_preprint":false},{"pmid":"27163531","id":"PMC_27163531","title":"Divergent modulation of normal and neoplastic stem cells by thrombospondin-1 and CD47 signaling.","date":"2016","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27163531","citation_count":25,"is_preprint":false},{"pmid":"33061420","id":"PMC_33061420","title":"Potential New Cancer Immunotherapy: Anti-CD47-SIRPα Antibodies.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33061420","citation_count":24,"is_preprint":false},{"pmid":"33864853","id":"PMC_33864853","title":"Comparative sensitivity study of primary cells, vero, OA3.Ts and ESH-L cell lines to lumpy skin disease, sheeppox, and goatpox viruses detection and growth.","date":"2021","source":"Journal of virological methods","url":"https://pubmed.ncbi.nlm.nih.gov/33864853","citation_count":24,"is_preprint":false},{"pmid":"38477522","id":"PMC_38477522","title":"Biomimetic Nano-Degrader Based CD47-SIRPα Immune Checkpoint Inhibition Promotes Macrophage Efferocytosis for Cardiac Repair.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38477522","citation_count":23,"is_preprint":false},{"pmid":"33629544","id":"PMC_33629544","title":"An antitumor peptide RS17-targeted CD47, design, synthesis, and antitumor activity.","date":"2021","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33629544","citation_count":22,"is_preprint":false},{"pmid":"27190273","id":"PMC_27190273","title":"The use of CD47-modified biomaterials to mitigate the immune response.","date":"2016","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/27190273","citation_count":22,"is_preprint":false},{"pmid":"35301709","id":"PMC_35301709","title":"Checkpoint CD47 expression in classical Hodgkin lymphoma.","date":"2022","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/35301709","citation_count":21,"is_preprint":false},{"pmid":"25914268","id":"PMC_25914268","title":"The effects of obesity on CD47 expression in erythrocytes.","date":"2015","source":"Cytometry. Part B, Clinical cytometry","url":"https://pubmed.ncbi.nlm.nih.gov/25914268","citation_count":21,"is_preprint":false},{"pmid":"38362603","id":"PMC_38362603","title":"Tolerating CD47.","date":"2024","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38362603","citation_count":20,"is_preprint":false},{"pmid":"39536084","id":"PMC_39536084","title":"CD47 and thrombospondin-1 contribute to immune evasion by Porphyromonas gingivalis.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39536084","citation_count":20,"is_preprint":false},{"pmid":"38183060","id":"PMC_38183060","title":"Hypoxia-induced ZEB1 promotes cervical cancer immune evasion by strengthening the CD47-SIRPα axis.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/38183060","citation_count":20,"is_preprint":false},{"pmid":"35404426","id":"PMC_35404426","title":"Macrophage-associated immune checkpoint CD47 blocking ameliorates endometriosis.","date":"2022","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/35404426","citation_count":20,"is_preprint":false},{"pmid":"38383737","id":"PMC_38383737","title":"m6A-methylated KCTD21-AS1 regulates macrophage phagocytosis through CD47 and cell autophagy through TIPR.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/38383737","citation_count":20,"is_preprint":false},{"pmid":"31214201","id":"PMC_31214201","title":"Thrombospondin-1/CD47 Interaction Regulates Th17 and Treg Differentiation in Psoriasis.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31214201","citation_count":20,"is_preprint":false},{"pmid":"38414061","id":"PMC_38414061","title":"Targeting HDAC6 improves anti-CD47 immunotherapy.","date":"2024","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/38414061","citation_count":19,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":89344,"output_tokens":6233,"usd":0.294516,"retried_sync":true},"stage2":{"model":"claude-opus-4-8","input_tokens":15115,"output_tokens":5789,"usd":0.11015,"stage2_stop_reason":"end_turn"},"total_usd":0.404666,"stage1_batch_id":"msgbatch_0147LFpL5iCPFZF66xp23BqC","stage2_batch_id":"msgbatch_01Crtwc6eCsZh1CrnfJhY7J7","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"CD47 functions as a 'marker of self' on red blood cells by binding to the inhibitory receptor SIRPα on splenic macrophages, thereby preventing phagocytic clearance; CD47-null mouse RBCs were rapidly cleared from the bloodstream by splenic red pulp macrophages, and this was rescued by CD47-SIRPα engagement.\",\n      \"method\": \"In vivo adoptive transfer of CD47-null vs. wild-type mouse RBCs; macrophage phagocytosis assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO model with defined cellular phenotype, replicated across labs and highly cited foundational study\",\n      \"pmids\": [\"10856220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD47 (IAP) acts as a receptor for thrombospondin family members (via their C-terminal VVM motif), a ligand for SIRPα, and a component of a supramolecular complex with specific integrins, heterotrimeric G proteins, and cholesterol; CD47 agonist peptides initiate heterotrimeric Gi protein signaling that augments β1, β2, and β3 integrin functions.\",\n      \"method\": \"Biochemical reconstitution, peptide agonist assays, co-immunoprecipitation of complex components\",\n      \"journal\": \"Trends in cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — multiple interaction partners identified but abstract-level summary of prior biochemical work; highly replicated concept\",\n      \"pmids\": [\"11306274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD47 associates with Fas (CD95) upon Fas activation and augments Fas-mediated apoptosis; Jurkat T cells lacking CD47 are relatively resistant to Fas-mediated death, and re-expression of CD47 rescues killing; CD47 deficiency impairs caspase activation, cytochrome c release, loss of mitochondrial membrane potential, and DNA cleavage downstream of Fas.\",\n      \"method\": \"CD47-knockout Jurkat cells, CD47 re-expression, co-immunoprecipitation of Fas and CD47, primary T cells from CD47-null mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, KO + rescue, primary cell validation, multiple downstream readouts in single study\",\n      \"pmids\": [\"15917238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human SIRPα1 binds CD47 on human and pig RBCs but not mouse, rat, or cow RBCs, demonstrating species- and cell-type specificity; deglycosylation of SIRPα1 strengthens binding; low SIRPα copy numbers on phagocytes explain absence of RBC adhesion under physiological conditions; bone marrow-derived mesenchymal stem cells display CD47 but do not significantly bind soluble SIRPα1.\",\n      \"method\": \"SIRPα1 binding assay, atomic force microscopy, centrifugation-based adhesion assay, antibody inhibition\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biophysical methods (AFM, centrifugation, antibody inhibition), single lab\",\n      \"pmids\": [\"16291597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SIRPα binds to protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region; CD47 binding to SIRPα constitutes a bidirectional cell-cell communication system important for regulating migration and phagocytosis; activating SIRPβ shows negligible CD47 binding despite extensive extracellular sequence similarity to SIRPα.\",\n      \"method\": \"Biochemical binding assays, structural analysis, functional phagocytosis assays\",\n      \"journal\": \"Trends in cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — review summarizing multiple prior biochemical experiments; SHP-1/2 recruitment and SIRPβ non-binding well established across labs\",\n      \"pmids\": [\"19144521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cell rigidity and shape of a phagocytic target can override CD47's 'self' signaling by hyperactivating myosin-II at the phagocytic synapse; controlled stiffening of normal human RBCs does not compromise CD47-SIRPα interaction, but rigid RBC discocytes show maximal myosin-II activation that overcomes CD47 inhibitory signaling; shape (stomatocyte vs. discocyte) modulates how effectively CD47 inhibits phagocytosis.\",\n      \"method\": \"RBC stiffening manipulation, phagocytosis assays with macrophages, myosin-II activity measurements, CD47-SIRPα binding confirmed by antibody inhibition\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (mechanical manipulation, activity assays, antibody controls), single lab\",\n      \"pmids\": [\"25411427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MYC oncogene directly binds the promoters of Cd47 and Pd-l1 genes to transcriptionally regulate their expression; MYC inactivation reduces CD47 and PD-L1 mRNA and protein; enforced expression of CD47 in MYC-inactivated tumors suppresses the antitumor immune response and allows continued tumor growth.\",\n      \"method\": \"ChIP of MYC at Cd47/Pd-l1 promoters, MYC inducible mouse tumor models, CD47 enforced expression rescue experiments, qRT-PCR, Western blot\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP establishing direct promoter binding, genetic rescue experiment, multiple orthogonal methods in one study\",\n      \"pmids\": [\"26966191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD47 blockade requires dendritic cell cross-priming of T cell responses (not macrophage phagocytosis) in syngeneic immunocompetent mouse tumor models; therapeutic effects are abrogated in T cell-deficient mice; antitumor effects require STING (but not MyD88 or TRIF) in CD11c+ cells, linking cytosolic DNA sensing to CD47 blockade activity.\",\n      \"method\": \"Syngeneic mouse tumor models, T cell-deficient mice, STING/MyD88/TRIF genetic knockouts, macrophage/DC depletion\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis via multiple genetic KOs, complementary cell depletion experiments, single rigorous study with multiple orthogonal approaches\",\n      \"pmids\": [\"26322579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD47 deficiency or blockade activates autophagic flux in irradiated T cells and endothelial cells; this enhanced autophagy (evidenced by increased BECN1, ATG5, ATG7, LC3+ puncta, autophagosomes by EM, reduced p62) is necessary for the radioprotective effect of CD47 blockade; pharmacological or siRNA inhibition of autophagy selectively sensitizes CD47-deficient cells to radiation, and re-expression of CD47 reverses autophagy and restores radiosensitivity.\",\n      \"method\": \"CD47-null T cells, CD47 re-expression, siRNA/pharmacological autophagy inhibition, electron microscopy, flow cytometry, Western blot\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO + rescue, multiple orthogonal autophagy readouts (EM, LC3, Western blots), epistasis via autophagy inhibition in one study\",\n      \"pmids\": [\"22874555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TNF-α drives upregulation of CD47 on diseased vascular cells in atherosclerosis, impairing efferocytosis; CD47-blocking antibodies restore macrophage-mediated phagocytic clearance of apoptotic vascular cells and ameliorate atherosclerosis in multiple mouse models.\",\n      \"method\": \"Multiple atherosclerosis mouse models, anti-CD47 antibody treatment, TNF-α mechanistic studies, efferocytosis assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mouse models, identified upstream regulator (TNF-α), functional efferocytosis readout, replicated across models\",\n      \"pmids\": [\"27437576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD47 on synapses protects them from excessive microglia-mediated pruning during development via CD47-SIRPα signaling; CD47-deficient mice show increased microglial engulfment of retinogeniculate inputs, reduced synapse numbers in dLGN, and increased functional pruning; CD47 is required for neuronal activity-dependent preferential protection of active inputs from microglial engulfment.\",\n      \"method\": \"CD47 knockout mice, microglial engulfment assays, electrophysiology, confocal imaging of retinogeniculate system\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO model with multiple readouts (engulfment, synapse number, electrophysiology, activity-dependent regulation), single rigorous study\",\n      \"pmids\": [\"30308165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NK cell SIRPα is upregulated by IL-2 stimulation and interacts with target cell CD47 in a threshold-dependent manner, counteracting stimulatory signals (IL-2, CD16, NKG2D); elevated CD47 on target cells protects against SIRPα+ primary NK cells but not SIRPα- NK cell lines; SIRPα deficiency or antibody blockade increases NK cell killing capacity.\",\n      \"method\": \"NK cell SIRPα characterization, CD47-overexpressing target cells, SIRPα KO, antibody blockade, cytotoxicity assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO and antibody blockade with functional cytotoxicity readouts, single lab with multiple cell-type validations\",\n      \"pmids\": [\"33416832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Senescent cells upregulate CD47 coinciding with increased expression of CD47-modifying enzymes QPCT/L; this enhanced CD47 suppresses macrophage-mediated efferocytosis of both senescent cells and bystander apoptotic corpses (SCES) via the SIRPα-CD47-SHP-1 axis; SCES requires direct macrophage-senescent cell contact and is reversible by interfering with SIRPα-CD47-SHP-1 signaling or QPCT/L activity.\",\n      \"method\": \"Senescent fibroblast and epithelial cell models, efferocytosis assays, CD47/QPCT/L knockout and inhibition, contact-dependent assays, in vitro and in vivo senescence models\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and pharmacological interventions, identified writer enzymes (QPCT/L) and signaling axis (SHP-1), in vitro and in vivo validation\",\n      \"pmids\": [\"36459066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EGFR activation induces c-Src binding to CD47, leading to c-Src-mediated CD47 Y288 phosphorylation; this phosphorylation inhibits TRIM21 (ubiquitin E3 ligase) binding to CD47, preventing TRIM21-mediated K99/102 polyubiquitylation and proteasomal degradation of CD47; CD47 Y288F knock-in reduces CD47 expression and increases macrophage phagocytosis, while CD47 K99/102R knock-in has opposite effects.\",\n      \"method\": \"Co-IP of c-Src and CD47, mutagenesis (Y288F and K99/102R knock-in), ubiquitylation assays, in vitro EGFR/c-Src kinase assays, phagocytosis assays, in vivo brain tumor models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase/ubiquitylation assays, site-directed mutagenesis with knock-in validation, Co-IP, functional rescue, in vivo confirmation in single study\",\n      \"pmids\": [\"37541303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The CD47/SIRPα axis requires deneddylation of SHP2 for its downstream signaling: SHP2 is constitutively neddylated on K358 and K364 (maintaining autoinhibited conformation); upon CD47-liganded SIRPα activation, SENP8 deneddylates SHP2, enabling dephosphorylation of substrates at the phagocytic cup and inhibition of macrophage phagocytosis.\",\n      \"method\": \"Mass spectrometry identification of neddylation sites, mutagenesis of K358/K364, SENP8 siRNA/KO, phagocytosis assays, substrate dephosphorylation assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — identification of PTM writer (SENP8-mediated deneddylation), site-specific mutagenesis, mechanistic substrate assays, functional phagocytosis readout in single study\",\n      \"pmids\": [\"36626230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IFN-γ upregulates CD47 expression on cancer cells via the JAK1/STAT1/IRF1 signaling pathway; IFN-γ-induced CD47 surface expression strengthens CD47-SIRPα binding and decreases macrophage phagocytosis of cancer cells; JAK1/2 inhibition or siRNA silencing of JAK1, STAT1, or IRF1 reverses this effect.\",\n      \"method\": \"siRNA knockdown, JAK1/2 inhibitor (ruxolitinib), flow cytometry for surface CD47, phagocytosis assays, TCGA correlation analysis\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway epistasis via multiple siRNA targets, pharmacological inhibition, functional phagocytosis readout, single lab\",\n      \"pmids\": [\"34171557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Statins suppress CD47 expression by inhibiting nuclear translocation of NFκB1 p50, thereby reducing CD47-mediated anti-phagocytic signaling and amplifying the anti-atherosclerotic effects of CD47-SIRPα blockade in an additive manner.\",\n      \"method\": \"RNA sequencing, in vivo and in vitro statin treatment, NFκB1 p50 nuclear translocation assays, CD47 expression assays, phagocytosis assays, atherosclerosis mouse models\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway identified (NFκB1 p50), in vivo and in vitro validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35990913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD47 expression is critical for CAR T-cell survival in vivo; CD47-knockout CAR T cells are sensitized to macrophage-mediated phagocytosis and fail to expand and persist in vivo despite potent in vitro activity; a CD47 variant (CD47 Q31P/47E) engages SIRPα and resists blockade by anti-CD47 antibodies, protecting adoptively transferred T cells from macrophage clearance while enabling macrophage recruitment to tumors.\",\n      \"method\": \"CD47 knockout in T cells, xenograft models, in vitro phagocytosis assays, CD47 Q31P engineered variant, adoptive transfer experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with mechanistic rescue via engineered variant, in vivo and in vitro orthogonal validation, identifies macrophage phagocytosis as mechanism of T cell clearance\",\n      \"pmids\": [\"38750365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Extracellular vesicles (exosomes) released from CD47-overexpressing cells can transfer CD47 to the surface of recipient cells ('cross-dressing'), enabling the cross-dressed CD47 to interact with SIRPα and inhibit phagocytosis; however, unlike autogenous CD47, ligation of cross-dressed CD47 does not induce cell death.\",\n      \"method\": \"Exosome isolation, flow cytometry for surface CD47, SIRPα binding assays, phagocytosis assays, cell death assays comparing autogenous vs. cross-dressed CD47\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional distinction between autogenous and cross-dressed CD47 established with multiple assays, single lab\",\n      \"pmids\": [\"36454036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Macrophage-specific SIRPα loss (but not global CD47 deletion) attenuates atherosclerosis by stimulating efferocytosis, reducing cholesterol accumulation, promoting lipid efflux, and inducing M2 polarization; conversely, myeloid cell-specific CD47 deletion inhibits efferocytosis, impairs cholesterol efflux, augments inflammation, and increases atherosclerosis, demonstrating cell-specific and opposite roles for CD47 vs. SIRPα in myeloid cells.\",\n      \"method\": \"Myeloid cell-specific and global conditional knockout mice, efferocytosis assays, cholesterol efflux assays, macrophage polarization, atherosclerosis mouse models\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-specific genetic KO models revealing opposite functional roles, multiple mechanistic readouts, replicated with different genetic strategies\",\n      \"pmids\": [\"34940829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TSP1 inhibits lymphangiogenesis through CD47 activation in lymphatic endothelial cells (LECs): TSP1 inhibits VEGF-C-induced AKT and eNOS activation and attenuates NO production; CD47 silencing in LECs prevents TSP1's effects on lymphangiogenic AKT-eNOS signaling; LEC-specific Cd47 knockout mice show reduced atherosclerosis and increased lymphatic vessel density.\",\n      \"method\": \"LEC-specific Cd47 KO mice (Cd47ΔLEC), AAV8-PCSK9 atherosclerosis model, in vitro LEC assays, siRNA, Western blot for AKT/eNOS, Matrigel plug assay, immunostaining\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-specific KO with in vivo phenotype, mechanistic pathway (AKT-eNOS) identified by siRNA and in vitro assays, multiple orthogonal methods\",\n      \"pmids\": [\"37259865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD47 associates with TLR2 in macrophages; CD47 blocking leads to decreased intracellular P. gingivalis survival dependent on bacterial major fimbriae; P. gingivalis infection induces increased TSP-1 expression and secretion, which broadly suppresses neutrophil bactericidal activity; CD47-TLR2 co-signaling induces TSP-1 to suppress neutrophil activity.\",\n      \"method\": \"Co-immunoprecipitation of CD47 and TLR2, anti-CD47 antibody blockade, CD47 knockout mice, intracellular survival assays, TSP-1 expression/secretion measurements\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing CD47-TLR2 association, KO mice for in vivo validation, functional bactericidal assays, single lab\",\n      \"pmids\": [\"39536084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Thrombospondin-1 (TSP-1) signaling through CD47 inhibits Th17 differentiation and promotes Treg differentiation from CD4+ T cells; TSP-1 functions as a negative regulator of T cell activation, with CD47 as the receptor; siRNA knockdown of TSP-1 in T cells and moDCs confirms this negative regulatory role.\",\n      \"method\": \"Th17/Treg differentiation assays, exogenous TSP-1 treatment, siRNA knockdown of TSP-1, immunofluorescence, RT-PCR in patient samples\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional differentiation assays, siRNA confirmation, patient and in vitro data, single lab\",\n      \"pmids\": [\"31214201\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD47 is a ubiquitously expressed transmembrane receptor that functions as a 'don't eat me' signal by binding SIRPα on myeloid and NK cells, activating SHP-1/SHP-2 (via SENP8-mediated SHP2 deneddylation) to inhibit phagocytosis; it also serves as a high-affinity signaling receptor for thrombospondin-1 that modulates integrin function, Gi protein signaling, autophagy, nitric oxide/eNOS pathways, and T cell differentiation; its expression is transcriptionally regulated by MYC, NFκB, IFN-γ/JAK/STAT1/IRF1, and ZEB1, and post-translationally regulated by EGFR-c-Src-mediated Y288 phosphorylation that blocks TRIM21-dependent polyubiquitylation and degradation, while it also associates with Fas to augment apoptosis and with TLR2 to modulate innate immune responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD47 is a ubiquitously expressed transmembrane receptor that functions as a self-recognition signal restraining phagocytic and immune clearance of cells [#0, #1]. Its canonical activity is to bind the inhibitory receptor SIRPα on splenic and myeloid phagocytes, marking red blood cells and other targets as 'self' and preventing their engulfment [#0]; this engagement is species- and cell-type specific and operates in a threshold-dependent manner that can be overridden by target rigidity-driven myosin-II activation at the phagocytic synapse [#3, #5]. Downstream of CD47-liganded SIRPα, the protein tyrosine phosphatases SHP-1 and SHP-2 are recruited [#4], and productive inhibitory signaling requires SENP8-mediated deneddylation of SHP2 at K358/K364 to relieve its autoinhibited conformation and permit substrate dephosphorylation at the phagocytic cup [#14]. This 'don't eat me' axis governs efferocytosis in diverse settings: it limits clearance of apoptotic and senescent cells in atherosclerosis [#9, #12, #19], restrains developmental microglial synaptic pruning [#10], and counteracts NK-cell cytotoxicity through SIRPα on activated NK cells [#11]. CD47 is also a high-affinity receptor for thrombospondin-1, through which it organizes a supramolecular complex with integrins, heterotrimeric Gi proteins, and cholesterol to modulate integrin function [#1], suppresses AKT-eNOS-dependent lymphangiogenesis [#20], inhibits Th17 and promotes Treg differentiation [#22], and regulates autophagic flux to control radiosensitivity [#8]; it further associates with Fas to augment apoptotic signaling [#2] and with TLR2 to drive TSP-1-dependent suppression of innate antibacterial activity [#21]. CD47 abundance is transcriptionally driven by MYC, IFN-γ via JAK1/STAT1/IRF1, and NFκB1 p50 [#6, #15, #16], and stabilized post-translationally by EGFR-c-Src-mediated Y288 phosphorylation that blocks TRIM21-dependent K99/102 polyubiquitylation and proteasomal degradation [#13]. Therapeutically, CD47 blockade requires dendritic-cell cross-priming and STING-dependent cytosolic DNA sensing rather than macrophage phagocytosis alone for antitumor T-cell responses [#7], and CD47 expression is essential for the persistence of adoptively transferred CAR T cells in vivo [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established CD47's foundational role as a self-marker: it was unknown how cells avoid phagocytic clearance, and CD47-null RBCs demonstrated that CD47-SIRPα engagement is required to prevent splenic macrophage destruction.\",\n      \"evidence\": \"In vivo adoptive transfer of CD47-null vs. wild-type mouse RBCs with macrophage phagocytosis assays\",\n      \"pmids\": [\"10856220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the intracellular signaling steps downstream of SIRPα\", \"Limited to RBC clearance in spleen\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined CD47 as a multifunctional receptor beyond self-recognition by identifying thrombospondin as a ligand and placing CD47 in a complex with integrins, Gi proteins, and cholesterol that modulates integrin function.\",\n      \"evidence\": \"Biochemical reconstitution, peptide agonist assays, and co-immunoprecipitation of complex components\",\n      \"pmids\": [\"11306274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Abstract-level summary of prior biochemistry, not a single primary dataset\", \"Stoichiometry and architecture of the supramolecular complex undefined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected CD47 to apoptotic signaling, showing it physically associates with Fas and is required for efficient Fas-mediated death, expanding CD47 function from anti-phagocytic to pro-apoptotic.\",\n      \"evidence\": \"CD47-knockout Jurkat cells with re-expression rescue, reciprocal Fas/CD47 Co-IP, and primary T cells from CD47-null mice\",\n      \"pmids\": [\"15917238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which CD47 couples to caspase activation unresolved\", \"Relationship to SIRPα signaling not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Quantified the CD47-SIRPα interaction's species and cell-type specificity, explaining why phagocytes do not adhere to RBCs under physiological conditions despite CD47 display.\",\n      \"evidence\": \"SIRPα1 binding assays, atomic force microscopy, centrifugation-based adhesion, and antibody inhibition\",\n      \"pmids\": [\"16291597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab biophysical characterization\", \"Functional consequence of weak MSC binding not pursued\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the inhibitory effectors of the axis, establishing that SIRPα recruits SHP-1 and SHP-2 and that CD47-SIRPα is a bidirectional system regulating migration and phagocytosis.\",\n      \"evidence\": \"Biochemical binding assays, structural analysis, and functional phagocytosis assays (review synthesis)\",\n      \"pmids\": [\"19144521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the regulatory steps controlling SHP-2 activation\", \"SIRPβ non-binding mechanism unexplained\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a thrombospondin/CD47-linked cytoprotection pathway, showing CD47 loss or blockade activates autophagic flux that mediates radioprotection of T and endothelial cells.\",\n      \"evidence\": \"CD47-null cells with re-expression, siRNA/pharmacological autophagy inhibition, EM, flow cytometry, and Western blot\",\n      \"pmids\": [\"22874555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling link between CD47 and autophagy machinery not defined\", \"Whether SIRPα or TSP1 mediates the effect unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed CD47 under direct oncogenic transcriptional control, showing MYC binds the Cd47 promoter and that CD47 contributes to MYC-driven immune evasion.\",\n      \"evidence\": \"ChIP of MYC at Cd47/Pd-l1 promoters, inducible MYC mouse tumors, and CD47 enforced-expression rescue\",\n      \"pmids\": [\"26966191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address other transcriptional inputs\", \"Relative contribution of CD47 vs. PD-L1 to evasion not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Redefined the cellular basis of CD47-blockade therapy, demonstrating it requires dendritic-cell cross-priming and STING-dependent DNA sensing rather than macrophage phagocytosis alone.\",\n      \"evidence\": \"Syngeneic tumor models with T cell-deficient mice, STING/MyD88/TRIF knockouts, and macrophage/DC depletion\",\n      \"pmids\": [\"26322579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Source of cytosolic DNA activating STING not identified\", \"How CD47 blockade triggers DC priming mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended the anti-efferocytosis role to cardiovascular disease, identifying TNF-α-driven CD47 upregulation as a barrier to apoptotic cell clearance in atherosclerosis reversible by CD47 blockade.\",\n      \"evidence\": \"Multiple atherosclerosis mouse models, anti-CD47 antibody treatment, and efferocytosis assays\",\n      \"pmids\": [\"27437576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factor downstream of TNF-α not defined here\", \"Cell-type-specific contributions not separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a neurodevelopmental function, showing CD47-SIRPα protects active synapses from excessive microglial pruning in an activity-dependent manner.\",\n      \"evidence\": \"CD47 knockout mice, microglial engulfment assays, electrophysiology, and confocal imaging of the retinogeniculate system\",\n      \"pmids\": [\"30308165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How neuronal activity regulates synaptic CD47 levels unknown\", \"Microglial SHP signaling in pruning not directly tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established transcriptional and innate-immune extensions of CD47 regulation: IFN-γ induces CD47 via JAK1/STAT1/IRF1 to strengthen SIRPα binding, and NK cells use IL-2-induced SIRPα to read target CD47.\",\n      \"evidence\": \"siRNA and JAK inhibitor studies with phagocytosis assays (IFN-γ); NK SIRPα characterization with CD47-overexpressing targets and cytotoxicity assays\",\n      \"pmids\": [\"34171557\", \"33416832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pathway epistasis for the IFN-γ axis\", \"NK SIRPα threshold-setting mechanism not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved cell-specific and context-specific roles in atherosclerosis and senescence: myeloid CD47 and SIRPα have opposite effects, statins suppress CD47 via NFκB1 p50, and senescent cells exploit QPCT/L-modified CD47 to block efferocytosis.\",\n      \"evidence\": \"Cell-specific and global conditional knockout mice, statin treatment with NFκB1 p50 translocation assays, senescent cell models with QPCT/L inhibition, and efferocytosis assays\",\n      \"pmids\": [\"34940829\", \"35990913\", \"36459066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing CD47 vs. SIRPα myeloid outcomes incomplete\", \"QPCT/L modification site on CD47 not fully mapped in these studies\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed CD47 can act in trans via exosomal transfer, with cross-dressed CD47 inhibiting phagocytosis through SIRPα but failing to transmit the pro-death signal of autogenous CD47.\",\n      \"evidence\": \"Exosome isolation, surface CD47 flow cytometry, SIRPα binding, and comparative phagocytosis and cell-death assays\",\n      \"pmids\": [\"36454036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for the death-signaling difference unknown\", \"Physiological prevalence of cross-dressing untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined post-translational stabilization of CD47, showing EGFR-c-Src Y288 phosphorylation blocks TRIM21-mediated K99/102 polyubiquitylation and degradation, controlling surface CD47 and phagocytosis.\",\n      \"evidence\": \"Co-IP, Y288F and K99/102R knock-in mutagenesis, in vitro kinase and ubiquitylation assays, phagocytosis assays, and in vivo brain tumor models\",\n      \"pmids\": [\"37541303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals coupling EGFR activity to CD47 in vivo not fully mapped\", \"Whether TRIM21 acts on other CD47 pools unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered a NEDD8 regulatory layer in inhibitory signaling, showing SHP2 is constitutively neddylated and that CD47-SIRPα-triggered SENP8 deneddylation is required to activate SHP2 at the phagocytic cup.\",\n      \"evidence\": \"Mass spectrometry mapping of neddylation sites, K358/K364 mutagenesis, SENP8 siRNA/KO, and substrate dephosphorylation and phagocytosis assays\",\n      \"pmids\": [\"36626230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SIRPα engagement activates SENP8 not defined\", \"Role of SHP-1 neddylation not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked TSP1-CD47 signaling to lymphatic biology, showing CD47 mediates TSP1 inhibition of VEGF-C-driven AKT-eNOS signaling and lymphangiogenesis with consequences for atherosclerosis.\",\n      \"evidence\": \"LEC-specific Cd47 knockout mice, AAV8-PCSK9 atherosclerosis model, siRNA, AKT/eNOS Western blots, and Matrigel plug assays\",\n      \"pmids\": [\"37259865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between CD47 and AKT/eNOS not fully defined\", \"Contribution relative to SIRPα-mediated efferocytosis unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that CD47 expression is essential for adoptive T-cell persistence and that an engineered CD47 variant can protect cells from clearance while permitting macrophage recruitment, with TLR2 co-signaling identified as an additional CD47 partnership.\",\n      \"evidence\": \"CD47 KO in T cells, xenograft and adoptive transfer models, the CD47 Q31P/47E variant (CAR T study); CD47-TLR2 Co-IP, KO mice, and bactericidal assays (TLR2 study)\",\n      \"pmids\": [\"38750365\", \"39536084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term safety of engineered CD47 variants untested\", \"Mechanism of CD47-TLR2 co-signaling to TSP-1 induction incompletely defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CD47's many context-specific functions—SIRPα inhibition, Fas-coupled apoptosis, TSP1-Gi/integrin signaling, autophagy, and TLR2 co-signaling—are mechanistically partitioned within a single receptor remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model coupling the distinct ligand-engaged states\", \"Lack of data on how cell type dictates which CD47 output dominates\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 7, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 20]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [13, 14]}\n    ],\n    \"complexes\": [\"CD47-SIRPα signaling complex\", \"CD47-integrin-Gi protein supramolecular complex\"],\n    \"partners\": [\"SIRPA\", \"THBS1\", \"FAS\", \"TLR2\", \"SRC\", \"TRIM21\", \"SHP-2 (PTPN11)\", \"SHP-1 (PTPN6)\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win"}}