Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: CD47 is a multi-pass transmembrane protein localized to the plasma membrane. This is well-established from early characterization studies and confirmed by multiple structural and functional studies (PMID:7691831, PMID:7998989). Reason: Plasma membrane localization is a core property of CD47 function. The protein must be at the cell surface to engage SIRPalpha on opposing cells and to interact with thrombospondin-1. UniProt confirms "Cell membrane; Multi-pass membrane protein". Supporting Evidence: PMID:7691831 Integrin Associated Protein (IAP) is a 50-kD membrane protein which copurifies with the integrin alpha v beta 3 from placenta file:human/CD47/CD47-deep-research-falcon.md model: Edison Scientific Literature
GO:0022409 positive regulation of cell-cell adhesion	IBA GO_REF:0000033	ACCEPT	Summary: CD47 mediates cell-cell adhesion through its interactions with SIRPalpha and SIRPgamma on opposing cells (PMID:11509594, PMID:15383453). The CD47-SIRPbeta2 interaction promotes T cell adhesion to antigen-presenting cells. Reason: Cell-cell adhesion mediation is experimentally validated. The CD47-SIRP interactions physically bridge cells and this is a core function of the protein. Supporting Evidence: PMID:15383453 SIRPbeta2 is expressed on T cells and activated natural killer (NK) cells and, like SIRPalpha, binds CD47, mediating cell-cell adhesion PMID:11509594 CD47/integrin-associated protein, a ubiquitous multispan transmembrane protein highly expressed on T cells, interacts with signal-regulator protein (SIRP)-alpha
GO:0050729 positive regulation of inflammatory response	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: CD47 signaling is involved in modulating inflammatory responses, particularly through its effects on cytokine production and dendritic cell function (PMID:11509594). The deep research notes that CD47-SIRPalpha and TSP1-CD47 axes can modulate inflammatory tone. Reason: While CD47 can modulate inflammatory responses, this is a downstream consequence of its core phagocytosis checkpoint function, not the primary function. The annotation is valid but represents a non-core pleiotropic effect. Supporting Evidence: PMID:11509594 Proinflammatory molecules, including IFN-gamma and IL-12, play a crucial role in the elimination of causative agents
GO:0050766 positive regulation of phagocytosis	IBA GO_REF:0000033	MODIFY	Summary: This annotation is MISLEADING. CD47 is fundamentally a NEGATIVE regulator of phagocytosis - the "don't eat me" signal. When CD47 engages SIRPalpha on macrophages, it INHIBITS phagocytosis. Blocking CD47 or the CD47-SIRPalpha axis PROMOTES phagocytosis (PMID:11509594, deep research). Reason: CD47's core function is as an inhibitory checkpoint that prevents phagocytosis. The annotation to "positive regulation of phagocytosis" appears to be an error or over-annotation. The ISS annotation (GO:0050765, negative regulation) is correct. The positive regulation may have been inferred incorrectly from studies where CD47 blockade increases phagocytosis. Proposed replacements: negative regulation of phagocytosis Supporting Evidence: PMID:11509594 CD47 on T cells and its cognate receptor SIRP-alpha on DC define a novel regulatory pathway that may be involved in the maintenance of homeostasis by preventing the escalation of the inflammatory immune response
GO:0070053 thrombospondin receptor activity	IBA GO_REF:0000033	ACCEPT	Summary: CD47 is a well-established receptor for the C-terminal cell-binding domain of thrombospondin-1 (TSP1). This was demonstrated by affinity labeling, antibody blocking, and functional assays (PMID:8550562, PMID:19004835). Reason: Thrombospondin receptor activity is a core molecular function of CD47. The interaction with TSP1 modulates important signaling pathways including nitric oxide signaling and integrin function. Supporting Evidence: PMID:8550562 IAP (CD47) as a receptor for the CBD of TS1 and suggest a mechanism for the well established effects of the CBD on cell motility PMID:8550562 Cell-binding peptides based on the sequence RFYVVM from the CBD of TS1 affinity label a 52-kDa cell surface glycoprotein, which we show is integrin-associated protein (IAP or CD47)
GO:0070062 extracellular exosome	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: CD47 has been detected in extracellular exosomes. This may reflect the ubiquitous expression of CD47 on cell membranes that become incorporated into exosomes. Reason: While CD47 may be present in exosomes, this is not a core localization for its primary phagocytosis checkpoint function. The plasma membrane localization is the functionally critical one.
GO:0034113 heterotypic cell-cell adhesion	IEA GO_REF:0000108	ACCEPT	Summary: CD47 mediates heterotypic cell-cell adhesion through trans interactions with SIRP family members on different cell types (e.g., T cells expressing CD47 binding to SIRPalpha on dendritic cells or macrophages). Reason: This is an accurate annotation. The CD47-SIRPalpha/SIRPgamma interactions mediate adhesion between different cell types, which is central to its immune checkpoint function. Supporting Evidence: PMID:11509594 CD47/integrin-associated protein... interacts with signal-regulator protein (SIRP)-alpha, an immunoreceptor tyrosine-based inhibition motif-containing molecule selectively expressed on myelomonocytic cells
GO:0001525 angiogenesis	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: CD47-TSP1 signaling has anti-angiogenic effects through inhibition of VEGF and nitric oxide signaling. CD47 plays a role in suppressing angiogenesis (PMID:32679764, deep research). Reason: While CD47 does modulate angiogenesis through TSP1 signaling, this is a downstream consequence of TSP1-CD47 interaction rather than the core phagocytosis checkpoint function. The annotation is valid but represents a pleiotropic effect of the TSP1 signaling axis.
GO:0002684 positive regulation of immune system process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: CD47 modulates immune responses through multiple mechanisms including the SIRPalpha checkpoint and T cell costimulation via SIRPbeta2/gamma. Reason: This is a very general term. CD47 has complex effects on immune processes - it can both inhibit (via SIRPalpha checkpoint) and promote (via T cell costimulation) immune responses depending on context. The annotation is too general to be informative about core function.
GO:0005886 plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate of IBA annotation. CD47 is a plasma membrane protein - this is well established. Reason: Plasma membrane localization is correct and represents core localization for CD47 function.
GO:0006915 apoptotic process	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: This annotation is an OVER-ANNOTATION and MISLEADING. CD47's core function is as a phagocytosis checkpoint. When CD47 is lost or blocked, cells are cleared by phagocytes - this appears as "cell death" but is NOT apoptosis. The cells are engulfed by macrophages, not dying by apoptotic program. While CD47 can augment FAS-mediated apoptosis (PMID:15917238), this is a secondary/modulatory effect, not its core function. Reason: CD47 is fundamentally a "don't eat me" signal that prevents phagocytosis. Loss of CD47 leads to phagocytic clearance, not apoptosis. The annotation to "apoptotic process" is fundamentally misleading about the protein's function. The keyword-based mapping from Swiss-Prot "Apoptosis" is inappropriate because CD47's relationship to cell death is indirect - it modulates whether cells get cleared by phagocytes, not whether they undergo intrinsic apoptotic cell death. Supporting Evidence: PMID:15917238 CD47 associates with Fas upon its activation and augments Fas-mediated apoptosis
GO:0006954 inflammatory response	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: CD47 modulates inflammatory responses through its effects on cytokine production and immune cell activation (PMID:11509594). Reason: CD47 does participate in inflammatory response modulation, but this is downstream of its core checkpoint function, not the primary function.
GO:0007155 cell adhesion	IEA GO_REF:0000043	ACCEPT	Summary: CD47 mediates cell adhesion through SIRP interactions and integrin associations. This is supported by multiple studies. Reason: Cell adhesion is a core function of CD47, enabling the physical interaction between cells required for the phagocytosis checkpoint. Supporting Evidence: PMID:15383453 SIRPbeta2 is expressed on T cells... and, like SIRPalpha, binds CD47, mediating cell-cell adhesion
GO:0022409 positive regulation of cell-cell adhesion	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate of IBA annotation. CD47 promotes cell-cell adhesion through SIRP interactions. Reason: Cell-cell adhesion is a validated function of CD47.
GO:0050729 positive regulation of inflammatory response	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Duplicate of IBA annotation. CD47 modulates inflammatory responses. Reason: This is a pleiotropic effect, not the core function.
GO:0050766 positive regulation of phagocytosis	IEA GO_REF:0000002	MODIFY	Summary: This is INCORRECT. CD47 is a NEGATIVE regulator of phagocytosis, not a positive regulator. Reason: CD47's core function is inhibiting phagocytosis via the SIRPalpha checkpoint. This annotation is fundamentally wrong. Proposed replacements: negative regulation of phagocytosis
GO:0070053 thrombospondin receptor activity	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate of IBA annotation. CD47 is a TSP1 receptor. Reason: Thrombospondin receptor activity is a core function.
GO:0098609 cell-cell adhesion	IEA GO_REF:0000117	ACCEPT	Summary: CD47 mediates cell-cell adhesion through SIRP interactions. Reason: Cell-cell adhesion is a core function of CD47.
GO:0005515 protein binding	IPI PMID:15383453 Adhesion of human T cells to antigen-presenting cells throug...	MODIFY	Summary: This study demonstrates CD47 binding to SIRPbeta2 (SIRPgamma), which mediates T cell adhesion to antigen-presenting cells and costimulates T-cell proliferation. A more specific term should be used. Reason: "Protein binding" is uninformative. The actual binding partner (SIRPgamma/SIRPbeta2) is characterized. Should use a more specific molecular function term such as "signaling receptor binding" or the specific cell-cell adhesion mediator function. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:15383453 SIRPbeta2 is expressed on T cells and activated natural killer (NK) cells and, like SIRPalpha, binds CD47, mediating cell-cell adhesion
GO:0005515 protein binding	IPI PMID:17070842 Functional elements on SIRPalpha IgV domain mediate cell sur...	MODIFY	Summary: This study characterizes the SIRPalpha-CD47 binding interaction at the molecular level, identifying key residues on SIRPalpha required for CD47 binding. Reason: "Protein binding" is uninformative. The interaction with SIRPalpha is well-characterized and more specific terms should be used. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:17070842 binding of SIRPalpha with CD47... through the extracellular IgV domain regulates important leukocyte functions including macrophage recognition, leukocyte adhesion and transmigration
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	REMOVE	Summary: High-throughput interactome study. Generic protein binding. Reason: "Protein binding" from high-throughput studies provides no functional information. Should be removed in favor of more specific annotations. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network.
GO:0005515 protein binding	IPI PMID:32822567 Human IgSF Cell-Surface Interactome	REMOVE	Summary: IgSF cell-surface interactome study. Generic protein binding. Reason: High-throughput generic binding annotations are uninformative. Supporting Evidence: PMID:32822567 A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks	REMOVE	Summary: Proteome-scale interactome study. Generic protein binding. Reason: High-throughput generic binding annotations are uninformative. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:35922511 A physical wiring diagram for the human immune system.	REMOVE	Summary: Physical wiring diagram study. Generic protein binding. Reason: High-throughput generic binding annotations are uninformative. Supporting Evidence: PMID:35922511 Aug 3. A physical wiring diagram for the human immune system.
GO:0005886 plasma membrane	IDA GO_REF:0000052	ACCEPT	Summary: Plasma membrane localization based on immunofluorescence data. Reason: Core localization confirmed by direct experimental evidence.
GO:0005515 protein binding	IPI PMID:15917238 CD47 augments Fas/CD95-mediated apoptosis	MODIFY	Summary: This study shows CD47 interacts with FAS/CD95 upon Fas activation, augmenting Fas-mediated apoptosis. Reason: The binding partner (FAS) is specific and characterized. A more informative term should be used. However, this is a secondary function of CD47. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:15917238 CH11 induces association of Fas and CD47
GO:0070051 fibrinogen binding	IDA PMID:22079249 Integrin-associated protein (CD47) is a putative mediator fo...	KEEP AS NON CORE	Summary: CD47 was identified as a putative mediator for soluble fibrinogen interaction with human red blood cells (PMID:22079249). Reason: Fibrinogen binding has been demonstrated but this is not a core function of CD47. It may relate to the integrin-associated functions. Supporting Evidence: PMID:22079249 Integrin-associated protein (CD47) is a putative mediator for soluble fibrinogen interaction with human red blood cells membrane
GO:0005515 protein binding	IPI PMID:19004835 Differential interactions of thrombospondin-1, -2, and -4 wi...	MODIFY	Summary: This study characterizes differential interactions of thrombospondin-1, -2, and -4 with CD47. CD47 binds TSP1 most strongly. Reason: The binding to thrombospondin is well-characterized. The thrombospondin receptor activity annotation (GO:0070053) is more appropriate. Proposed replacements: thrombospondin receptor activity Supporting Evidence: PMID:19004835 Differential interactions of thrombospondin-1, -2, and -4 with CD47 and effects on cGMP signaling and ischemic injury responses
GO:0005515 protein binding	IPI PMID:8550562 Integrin-associated protein is a receptor for the C-terminal...	MODIFY	Summary: Original identification of CD47 as the thrombospondin receptor. Reason: The specific thrombospondin receptor activity term is more appropriate. Proposed replacements: thrombospondin receptor activity Supporting Evidence: PMID:8550562 Integrin-associated protein is a receptor for the C-terminal domain of thrombospondin
GO:0070053 thrombospondin receptor activity	IDA PMID:8550562 Integrin-associated protein is a receptor for the C-terminal...	ACCEPT	Summary: Direct experimental demonstration that CD47/IAP is the receptor for thrombospondin C-terminal cell-binding domain (PMID:8550562). Reason: Core molecular function of CD47 with strong experimental support. Supporting Evidence: PMID:8550562 IAP (CD47) as a receptor for the CBD of TS1
GO:0050765 negative regulation of phagocytosis	ISS GO_REF:0000024	ACCEPT	Summary: CD47 engagement of SIRPalpha delivers a "don't eat me" signal that inhibits phagocytosis. This is the CORE function of CD47. Reason: This is the primary, core function of CD47 as an innate immune checkpoint. The CD47-SIRPalpha axis is the central "don't eat me" signal. Supporting Evidence: PMID:11509594 CD47 on T cells and its cognate receptor SIRP-alpha on DC define a novel regulatory pathway that may be involved in the maintenance of homeostasis
GO:0060368 regulation of Fc receptor mediated stimulatory signaling pathway	ISS PMID:21401967 Myelin down-regulates myelin phagocytosis by microglia and m...	ACCEPT	Summary: CD47-SIRPalpha interaction down-regulates Fc receptor signaling in phagocytes, contributing to the "don't eat me" signal. Reason: This is related to the core phagocytosis checkpoint function. The CD47-SIRPalpha axis inhibits Fc receptor-mediated phagocytosis. Supporting Evidence: PMID:21401967 Myelin down-regulates myelin phagocytosis by microglia and macrophages through interactions between CD47 on myelin and SIRPα (signal regulatory protein-α) on phagocytes.
GO:2000439 positive regulation of monocyte extravasation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: CD47 has been implicated in monocyte extravasation through its interactions with SIRPalpha and effects on cell migration. Reason: This is a secondary effect related to cell adhesion functions, not the core phagocytosis checkpoint function.
GO:1904669 ATP export	IDA PMID:24022490 CR1-mediated ATP release by human red blood cells promotes C...	KEEP AS NON CORE	Summary: CD47 has been implicated in CR1-mediated ATP release by human red blood cells. Reason: ATP export is a specialized function in red blood cells, not the core immune checkpoint function of CD47. Supporting Evidence: PMID:24022490 2013 Sep 10. CR1-mediated ATP release by human red blood cells promotes CR1 clustering and modulates the immune transfer process.
GO:0009986 cell surface	IDA PMID:11509594 Bidirectional negative regulation of human T and dendritic c...	ACCEPT	Summary: CD47 is expressed on the cell surface where it engages SIRPalpha in trans. Confirmed by this study on T and dendritic cells. Reason: Cell surface localization is essential for CD47's checkpoint function. Supporting Evidence: PMID:11509594 CD47/integrin-associated protein, a ubiquitous multispan transmembrane protein highly expressed on T cells
GO:0032649 regulation of type II interferon production	IMP PMID:11509594 Bidirectional negative regulation of human T and dendritic c...	KEEP AS NON CORE	Summary: CD47-SIRPalpha engagement modulates IFN-gamma production. CD47-Fc decreases IFN-gamma production in allogeneic MLR (PMID:11509594). Reason: Cytokine regulation is a downstream consequence of the CD47-SIRPalpha checkpoint, not the core function. Supporting Evidence: PMID:11509594 CD47-Fc decreases IFN-gamma production after priming and impairs the development of a Th1 response
GO:0032653 regulation of interleukin-10 production	IMP PMID:11509594 Bidirectional negative regulation of human T and dendritic c...	KEEP AS NON CORE	Summary: CD47-SIRPalpha engagement modulates IL-10 production. Reason: Cytokine regulation is a downstream effect, not core function. Supporting Evidence: PMID:11509594 Bidirectional negative regulation of human T and dendritic cells by CD47 and its cognate receptor signal-regulator protein-alpha: down-regulation of IL-12 responsiveness and inhibition of dendritic cell activation.
GO:0032655 regulation of interleukin-12 production	IMP PMID:11509594 Bidirectional negative regulation of human T and dendritic c...	KEEP AS NON CORE	Summary: CD47 ligation down-regulates IL-12 responsiveness of T cells (PMID:11509594). Reason: Cytokine regulation is a downstream effect, not core function. Supporting Evidence: PMID:11509594 CD47 ligation by CD47 mAb or L-SIRP-alpha transfectants inhibits IL-12R expression and down-regulates IL-12 responsiveness of activated CD4(+) and CD8(+) adult T cells
GO:0032675 regulation of interleukin-6 production	IMP PMID:11509594 Bidirectional negative regulation of human T and dendritic c...	KEEP AS NON CORE	Summary: CD47-SIRPalpha engagement modulates IL-6 production. Reason: Cytokine regulation is a downstream effect, not core function. Supporting Evidence: PMID:11509594 Bidirectional negative regulation of human T and dendritic cells by CD47 and its cognate receptor signal-regulator protein-alpha: down-regulation of IL-12 responsiveness and inhibition of dendritic cell activation.
GO:0032680 regulation of tumor necrosis factor production	IMP PMID:11509594 Bidirectional negative regulation of human T and dendritic c...	KEEP AS NON CORE	Summary: CD47-SIRPalpha engagement modulates TNF production. Reason: Cytokine regulation is a downstream effect, not core function. Supporting Evidence: PMID:11509594 Bidirectional negative regulation of human T and dendritic cells by CD47 and its cognate receptor signal-regulator protein-alpha: down-regulation of IL-12 responsiveness and inhibition of dendritic cell activation.
GO:0071349 cellular response to interleukin-12	IMP PMID:11509594 Bidirectional negative regulation of human T and dendritic c...	KEEP AS NON CORE	Summary: CD47 ligation down-regulates IL-12 responsiveness of T cells (PMID:11509594). Reason: This is downstream signaling modulation, not core function. Supporting Evidence: PMID:11509594 CD47 ligation by CD47 mAb or L-SIRP-alpha transfectants inhibits IL-12R expression and down-regulates IL-12 responsiveness
GO:0098632 cell-cell adhesion mediator activity	IPI PMID:11509594 Bidirectional negative regulation of human T and dendritic c...	ACCEPT	Summary: CD47 mediates cell-cell adhesion through its interactions with SIRPalpha and other SIRP family members. Reason: Cell-cell adhesion mediator activity is a well-supported core molecular function of CD47. Supporting Evidence: PMID:11509594 CD47/integrin-associated protein... interacts with signal-regulator protein (SIRP)-alpha
GO:0045428 regulation of nitric oxide biosynthetic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: TSP1-CD47 signaling inhibits NO signaling, which has effects on vascular function (UniProt, deep research). Reason: This is mediated by TSP1-CD47 signaling, which is a secondary axis distinct from the core phagocytosis checkpoint function.
GO:0086080 protein binding involved in heterotypic cell-cell adhesion	ISS GO_REF:0000024	ACCEPT	Summary: CD47 binds SIRP family members on opposing cells to mediate heterotypic cell-cell adhesion. Reason: This is a well-supported molecular function of CD47 that is central to its immune checkpoint activity.
GO:0009986 cell surface	ISS GO_REF:0000024	ACCEPT	Summary: Duplicate localization annotation. CD47 is on the cell surface. Reason: Core localization is well-established.
GO:0016477 cell migration	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: CD47 is involved in cell migration, likely through its integrin associations and TSP1 signaling. Reason: Cell migration is a downstream effect of CD47's adhesion and signaling functions, not its core checkpoint function.
GO:0051496 positive regulation of stress fiber assembly	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: CD47 signaling can affect cytoskeletal organization. Reason: This is a downstream effect of CD47 signaling, not core function.
GO:0071346 cellular response to type II interferon	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: CD47 expression is induced by IFN-gamma signaling. Reason: This describes regulation of CD47, not its core function.
GO:0071347 cellular response to interleukin-1	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: CD47 may respond to IL-1 signaling. Reason: This describes regulation of CD47, not its core function.
GO:0009986 cell surface	NAS PMID:25795378 SIRP/CD47 signaling in neurological disorders	ACCEPT	Summary: Review of SIRP/CD47 signaling confirms cell surface localization. Reason: Core localization confirmed by review. Supporting Evidence: PMID:25795378 2015 Mar 17. SIRP/CD47 signaling in neurological disorders.
GO:0005515 protein binding	IPI PMID:24026300 Inflammation-induced proteolytic processing of the SIRPα cyt...	MODIFY	Summary: Study on SIRPalpha proteolytic processing and CD47 interaction. Reason: More specific binding terms should be used. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:24026300 Inflammation-induced proteolytic processing of the SIRPα cytoplasmic ITIM in neutrophils propagates a proinflammatory state.
GO:0035579 specific granule membrane	TAS Reactome:R-HSA-6799350	KEEP AS NON CORE	Summary: CD47 is present on specific granule membranes in neutrophils, where it can be mobilized to the cell surface. Reason: This is a cell-type specific localization in neutrophils, not the core localization for CD47's checkpoint function.
GO:0070821 tertiary granule membrane	TAS Reactome:R-HSA-6798747	KEEP AS NON CORE	Summary: CD47 is present on tertiary granule membranes in neutrophils. Reason: Cell-type specific localization in neutrophils.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-202703	ACCEPT	Summary: Reactome annotation for CD47 binding SIRP. Confirms plasma membrane localization. Reason: Core localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2426259	ACCEPT	Summary: Reactome annotation for COMP binding to CD47. Confirms plasma membrane localization. Reason: Core localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-391151	ACCEPT	Summary: Reactome pathway annotation for SIRPalpha-CD47 signaling. Reason: Core localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-391152	ACCEPT	Summary: Reactome pathway annotation. Reason: Core localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-391153	ACCEPT	Summary: Reactome pathway annotation. Reason: Core localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-391157	ACCEPT	Summary: Reactome pathway annotation. Reason: Core localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-391158	ACCEPT	Summary: Reactome annotation for SIRPalpha binding CD47. Reason: Core localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-391168	ACCEPT	Summary: Reactome annotation for SIRPgamma binding CD47. Reason: Core localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6798747	ACCEPT	Summary: Reactome pathway annotation. Reason: Core localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6799350	ACCEPT	Summary: Reactome pathway annotation. Reason: Core localization.
GO:0070053 thrombospondin receptor activity	IPI PMID:15700281 Insulin-like growth factor binding protein-5 (IGFBP-5) inter...	ACCEPT	Summary: Study showing IGFBP-5 interacts with TSP1 to modulate IGF-I actions through CD47. Reason: Supports CD47's role as thrombospondin receptor. Supporting Evidence: PMID:15700281 Insulin-like growth factor binding protein-5 (IGFBP-5) interacts with thrombospondin-1 to induce negative regulatory effects on IGF-I actions.
GO:0008284 positive regulation of cell population proliferation	IDA PMID:15383453 Adhesion of human T cells to antigen-presenting cells throug...	KEEP AS NON CORE	Summary: CD47 engagement by SIRPbeta2 costimulates T-cell proliferation (PMID:15383453). Reason: T cell costimulation is a secondary function of CD47 through SIRP interactions, not the core phagocytosis checkpoint function. Supporting Evidence: PMID:15383453 engagement of SIRPbeta2 on T cells by CD47 on antigen-presenting cells results in enhanced antigen-specific T-cell proliferation
GO:0022409 positive regulation of cell-cell adhesion	IDA PMID:15383453 Adhesion of human T cells to antigen-presenting cells throug...	ACCEPT	Summary: CD47-SIRPbeta2 interaction promotes cell-cell adhesion (PMID:15383453). Reason: Cell-cell adhesion promotion is a well-supported function. Supporting Evidence: PMID:15383453 Here, we show that SIRPbeta2 is expressed on T cells and activated natural killer (NK) cells and, like SIRPalpha, binds CD47, mediating cell-cell adhesion
GO:0050870 positive regulation of T cell activation	IDA PMID:15383453 Adhesion of human T cells to antigen-presenting cells throug...	KEEP AS NON CORE	Summary: CD47-SIRPbeta2 interaction costimulates T cell activation (PMID:15383453). Reason: T cell costimulation is a secondary function, not the core phagocytosis checkpoint function. Supporting Evidence: PMID:15383453 engagement of SIRPbeta2 on T cells by CD47 on antigen-presenting cells results in enhanced antigen-specific T-cell proliferation
GO:0005886 plasma membrane	TAS PMID:7998989 Isolation and characterization of CD47 glycoprotein	ACCEPT	Summary: Original characterization of CD47 confirms plasma membrane localization. Reason: Core localization. Supporting Evidence: PMID:7998989 Isolation and characterization of CD47 glycoprotein: a multispanning membrane protein which is the same as integrin-associated protein (IAP) and the ovarian tumour marker OA3.
GO:0005886 plasma membrane	TAS PMID:10429193 A CD9, alphaIIbbeta3, integrin-associated protein, and GPIb/...	ACCEPT	Summary: Study on platelet surface complexes confirms CD47 at plasma membrane. Reason: Core localization. Supporting Evidence: PMID:10429193 A CD9, alphaIIbbeta3, integrin-associated protein, and GPIb/V/IX complex on the surface of human platelets is influenced by alphaIIbbeta3 conformational states.
GO:0007229 integrin-mediated signaling pathway	TAS PMID:8294396 Rh-related antigen CD47 is the signal-transducer integrin-as...	KEEP AS NON CORE	Summary: CD47 was originally identified as integrin-associated protein (IAP) and participates in integrin-mediated signaling. Reason: Integrin association is a secondary function of CD47, though historically important. The primary function is the SIRPalpha phagocytosis checkpoint. Supporting Evidence: PMID:8294396 Rh-related antigen CD47 is the signal-transducer integrin-associated protein.

Core Functions

CD47 on target cells binds SIRPalpha on macrophages/phagocytes, recruiting SHP-1/SHP-2 phosphatases to inhibit phagocytosis. This is the primary innate immune checkpoint function of CD47 - the "don't eat me" signal.

Molecular Function:

cell-cell adhesion mediator activity

Directly Involved In:

negative regulation of phagocytosis

Cellular Locations:

cell surface

CD47 is the receptor for the C-terminal cell-binding domain of TSP1, modulating integrin function and vascular signaling (including NO signaling).

Molecular Function:

thrombospondin receptor activity

Cellular Locations:

plasma membrane

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on inter-ontology links

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:7691831

Molecular cloning of integrin-associated protein

CD47/IAP is a multi-pass membrane protein that associates with integrins

PMID:7998989

Isolation and characterization of CD47 glycoprotein

CD47 is identical to IAP and OA3 tumor marker
Multi-spanning membrane protein

PMID:8294396

Rh-related antigen CD47 is the signal-transducer integrin-associated protein

CD47 is IAP and participates in integrin signaling

PMID:8550562

Integrin-associated protein is a receptor for the C-terminal domain of thrombospondin

CD47/IAP is the receptor for thrombospondin-1 C-terminal domain
Mediates chemotaxis to TSP1

PMID:10429193

A CD9, alphaIIbbeta3, integrin-associated protein, and GPIb/V/IX complex on the surface of human platelets is influenced by alphaIIbbeta3 conformational states.

CD47 is in complex with integrins on platelets

"A noncovalently associated complex comprising of CD9, the fibrinogen (Fg) receptor alphaIIbbeta3, integrin-associated protein (IAP), and glycoprotein (GP) Ib/V/IX complex was isolated from Chaps-solubilized human platelets"

PMID:11509594

Bidirectional negative regulation of human T and dendritic cells by CD47 and its cognate receptor signal-regulator protein-alpha: down-regulation of IL-12 responsiveness and inhibition of dendritic cell activation.

CD47-SIRPalpha interaction is a negative regulatory pathway

"CD47 on T cells and its cognate receptor SIRP-alpha on DC define a novel regulatory pathway that may be involved in the maintenance of homeostasis by preventing the escalation of the inflammatory immune response"
Inhibits dendritic cell maturation and cytokine production

"SIRP-alpha engagement by CD47-Fc prevents the phenotypic and functional maturation of immature DC and still inhibits cytokine production by mature DC"
Down-regulates IL-12 responsiveness of T cells

"CD47 ligation by CD47 mAb or L-SIRP-alpha transfectants inhibits IL-12R expression and down-regulates IL-12 responsiveness of activated CD4(+) and CD8(+) adult T cells"

PMID:15383453

Adhesion of human T cells to antigen-presenting cells through SIRPbeta2-CD47 interaction costimulates T-cell proliferation.

SIRPbeta2/gamma binds CD47

"Here, we show that SIRPbeta2 is expressed on T cells and activated natural killer (NK) cells and, like SIRPalpha, binds CD47, mediating cell-cell adhesion"
Mediates cell-cell adhesion

"SIRPbeta2 is expressed on T cells and activated natural killer (NK) cells and, like SIRPalpha, binds CD47, mediating cell-cell adhesion"
Costimulates T cell proliferation

"engagement of SIRPbeta2 on T cells by CD47 on antigen-presenting cells results in enhanced antigen-specific T-cell proliferation"

PMID:15700281

Insulin-like growth factor binding protein-5 (IGFBP-5) interacts with thrombospondin-1 to induce negative regulatory effects on IGF-I actions.

IGFBP-5 modulates TSP1-CD47 interactions

"IGFBP-5 inhibits the binding of TS-1 to IAP, and this results in an alteration of the ability of TS-1 to modulate the disruption of the IAP/SHPS-1 interaction"

PMID:15917238

CD47 augments Fas/CD95-mediated apoptosis

CD47 associates with FAS upon activation
Augments FAS-mediated apoptosis (secondary function)

PMID:17070842

Functional elements on SIRPalpha IgV domain mediate cell surface binding to CD47

Defines key residues for SIRPalpha-CD47 binding

PMID:19004835

Differential interactions of thrombospondin-1, -2, and -4 with CD47 and effects on cGMP signaling and ischemic injury responses.

TSP1 binds CD47 with highest affinity

"high affinity interaction with CD47 appears to be relatively specific for the signature domain of TSP1"
Affects cGMP signaling

"Thrombospondin-1 regulates nitric oxide (NO) signaling in vascular cells via CD47"

PMID:21401967

Myelin down-regulates myelin phagocytosis by microglia and macrophages through interactions between CD47 on myelin and SIRPα (signal regulatory protein-α) on phagocytes.

CD47-SIRPalpha axis inhibits phagocytosis

"Myelin down-regulates its own phagocytosis through CD47-SIRPα interactions"

PMID:22079249

Integrin-associated protein (CD47) is a putative mediator for soluble fibrinogen interaction with human red blood cells membrane.

CD47 mediates fibrinogen-RBC interaction

"Our results support a specific and age-dependent interaction of soluble fibrinogen with human RBC membrane; additionally we present CD47 as a putative mediator in this process"

PMID:24022490

CR1-mediated ATP release by human red blood cells promotes CR1 clustering and modulates the immune transfer process.

PMID:24026300

Inflammation-induced proteolytic processing of the SIRPα cytoplasmic ITIM in neutrophils propagates a proinflammatory state.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:25795378

SIRP/CD47 signaling in neurological disorders

PMID:32679764

CD47 Promotes Age-Associated Deterioration in Angiogenesis

CD47 suppresses angiogenesis
Role in metabolic dysregulation during aging

PMID:32822567

Human IgSF Cell-Surface Interactome

PMID:33961781

Dual proteome-scale networks

PMID:35922511

A physical wiring diagram for the human immune system.

Reactome:R-HSA-202703

CD47 binds SIRP

Reactome:R-HSA-2426259

COMP binds Integrin alpha5beta1, Integrin alphaVbeta3, CD47

Reactome:R-HSA-391151

p-4Y-SIRPA:CD47:SKAP2 binds FYB

Reactome:R-HSA-391152

p-4Y-SIRPA:CD47 binds PTK2B

Reactome:R-HSA-391153

p-4Y-SIRPA:CD47 binds GRB2-1

Reactome:R-HSA-391157

p-4Y-SIRPA:CD47 binds SKAP2

Reactome:R-HSA-391158

SIRP alpha binds CD47

Reactome:R-HSA-391168

SIRP gamma binds CD47

Reactome:R-HSA-6798747

Exocytosis of tertiary granule membrane proteins

Reactome:R-HSA-6799350

Exocytosis of specific granule membrane proteins

file:human/CD47/CD47-deep-research-falcon.md

Deep research report on CD47

📚 Additional Documentation

Deep Research Falcon

(CD47-deep-research-falcon.md)

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surface determinant protein OA3; AltName: Full=Integrin-associated protein; Short=IAP;
AltName: Full=Protein MER6; AltName: CD_antigen=CD47; Flags: Precursor;'
gene_info: Name=CD47; Synonyms=MER6;
organism_full: Homo sapiens (Human).
protein_family: Not specified in UniProt
protein_domains: CD47. (IPR006704); CD47-like_TM. (IPR013147); CD47_Vset. (IPR013270);
Ig-like_dom. (IPR007110); Ig-like_dom_sf. (IPR036179)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q08722
Protein Description: RecName: Full=Leukocyte surface antigen CD47; AltName: Full=Antigenic surface determinant protein OA3; AltName: Full=Integrin-associated protein; Short=IAP; AltName: Full=Protein MER6; AltName: CD_antigen=CD47; Flags: Precursor;
Gene Information: Name=CD47; Synonyms=MER6;
Organism (full): Homo sapiens (Human).
Protein Family: Not specified in UniProt
Key Domains: CD47. (IPR006704); CD47-like_TM. (IPR013147); CD47_Vset. (IPR013270); Ig-like_dom. (IPR007110); Ig-like_dom_sf. (IPR036179)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "CD47" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'CD47' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene CD47 (gene ID: CD47, UniProt: Q08722) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q08722
Protein Description: RecName: Full=Leukocyte surface antigen CD47; AltName: Full=Antigenic surface determinant protein OA3; AltName: Full=Integrin-associated protein; Short=IAP; AltName: Full=Protein MER6; AltName: CD_antigen=CD47; Flags: Precursor;
Gene Information: Name=CD47; Synonyms=MER6;
Organism (full): Homo sapiens (Human).
Protein Family: Not specified in UniProt
Key Domains: CD47. (IPR006704); CD47-like_TM. (IPR013147); CD47_Vset. (IPR013270); Ig-like_dom. (IPR007110); Ig-like_dom_sf. (IPR036179)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "CD47" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene CD47 (gene ID: CD47, UniProt: Q08722) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan and verification
- Identity checks: The target is human CD47 (UniProt Q08722), also known as integrin-associated protein (IAP) and leukocyte surface antigen CD47. CD47 is a widely expressed plasma-membrane protein with an extracellular Ig-like domain that binds SIRPα and thrombospondin-1 (TSP1), consistent with the provided UniProt identity and domain annotations. No conflicting symbols were encountered in the evidence; all sources refer to human CD47 as an innate immune checkpoint ligand and integrin-associated protein (no organismal ambiguity). (isenberg2024toleratingcd47 pages 1-3, skrobek2023structuralcharacterizationof pages 46-49)

Comprehensive research report

1) Key concepts and definitions (current understanding)
- Molecular identity and localization: CD47 is a ubiquitously expressed cell-surface receptor on human cells, originally identified as integrin-associated protein (IAP). It resides on the outer plasma membrane and forms membrane clusters impacting signaling and phagocytosis. (Isenberg & Montero 2024; URL: https://doi.org/10.1002/ctm2.1584). (isenberg2024toleratingcd47 pages 1-3)
- Principal ligands and complexes: The extracellular Ig-like domain of CD47 binds SIRPα on myeloid cells in trans, establishing an innate immune checkpoint that suppresses phagocytosis. CD47 also binds TSP1 with high affinity and can interact in cis with multiple β integrins (αVβ3, αIIbβ3, α2β1, α4β1, α6β1, α5β1), and co-associates with receptors including VEGFR2, FAS, CD14, and others, shaping diverse downstream signaling outcomes. (Skrobek 2023; URL: https://doi.org/10.5282/edoc.32156. Isenberg & Montero 2024). (skrobek2023structuralcharacterizationof pages 46-49, isenberg2024toleratingcd47 pages 1-3)
- Core checkpoint mechanism (CD47–SIRPα): Upon CD47–SIRPα engagement, SIRPα ITIMs recruit SHP-1 and SHP-2 phosphatases, which dephosphorylate myosin IIA and other substrates to inhibit phagocytic synapse formation and engulfment (“don’t-eat-me” signal). (Skrobek 2023). (skrobek2023structuralcharacterizationof pages 46-49)
- TSP1–CD47 signaling: TSP1 binding to CD47 modulates vascular and metabolic signaling, notably inhibiting nitric oxide (NO) signaling and VEGF signaling, constricting blood vessels and exerting anti-angiogenic effects; it can promote ROS/oxidative stress and cellular senescence in specific contexts. (Skrobek 2023; Isenberg & Montero 2024; URLs: https://doi.org/10.5282/edoc.32156; https://doi.org/10.1002/ctm2.1584). (skrobek2023structuralcharacterizationof pages 46-49, isenberg2024toleratingcd47 pages 8-9)

2) Recent developments and latest research (2023–2024)
- Updated conceptual framing: Editorial analyses emphasize that CD47 sits at a junction of multiple receptor–ligand networks (SIRPα, TSP1, integrins, VEGFR2), complicating therapeutic modulation and necessitating attention to on-target, non-SIRPα effects when designing inhibitors. Program halts and trial discontinuations have prompted re-evaluation of strategy, dose, and combinations. (Isenberg & Montero 2024; URL: https://doi.org/10.1002/ctm2.1584). (isenberg2024toleratingcd47 pages 1-3, isenberg2024toleratingcd47 pages 8-9)
- Engineering/selectivity strategies to mitigate anemia: 2023 reviews summarize approaches to reduce RBC binding/toxicity, including tumor-selective anti-CD47 antibodies, SIRPα-targeting decoys/antibodies that avoid RBCs, and blockade of CD47 pyroglutamylation via QPCTL inhibition to weaken CD47–SIRPα without affecting mature RBCs. (Liu et al. 2023; URL: https://doi.org/10.1038/s41392-023-01365-z). (liu2023emergingphagocytosischeckpoints pages 18-19)
- Quantitative updates from hematologic malignancy trials (selected): A 2024 review compiled efficacy and safety readouts across several anti-CD47 programs:
- Magrolimab + azacitidine in higher-risk MDS (phase 1): ORR 75%, CR 33%; anemia risk mitigated by priming dose; later, phase 3 ENHANCE program halted in 2023 due to lack of survival benefit in AML subsets and broader strategic concerns. (Xu et al. 2024; URL: https://doi.org/10.3389/fimmu.2024.1348852). (xu2024opportunitiesandchallenges pages 2-4, xu2024opportunitiesandchallenges pages 10-11)
- Magrolimab + rituximab in NHL: ORR 40%/CR 33% in DLBCL (n=15) and ORR 71%/CR 43% in follicular lymphoma (n=7) in early studies; multi-agent combinations reported ORR ~51.5%, CR ~39.4%, median DOR ~18 months in selected settings. (Xu et al. 2024; URL: https://doi.org/10.3389/fimmu.2024.1348852). (xu2024opportunitiesandchallenges pages 2-4)
- Letaplimab + azacitidine (MDS): ORR 82.2%, CR 31.1%, with anemia in ~48%. Lemzoparlimab + azacitidine: ORR 82.1%. Ligufalimab (AK117): in AML/MDS cohorts, multiple grade ≥3 cytopenias; among 20 evaluable, 9 CR + 2 CRi; in MDS, 48.1% CR in 27 evaluable and 22.2% grade ≥3 anemia. (Xu et al. 2024). (xu2024opportunitiesandchallenges pages 2-4)
- Evorpacept (ALX148): MDS/AML program (e.g., ASPEN-02) terminated in Aug 2023 for insufficient added benefit versus azacitidine; ongoing/alternative solid tumor combinations continue outside MDS. (Xu et al. 2024; Jiang et al. 2024; URLs: https://doi.org/10.3389/fimmu.2024.1348852; https://doi.org/10.3389/fonc.2024.1378647). (xu2024opportunitiesandchallenges pages 2-4, xu2024opportunitiesandchallenges pages 10-11)
- Mechanistic modeling: Membrane-biophysical studies in 2023 described cooperative, membrane-mediated clustering and interactions in CD47–SIRPα adhesion systems, complementing microscopy data and extending quantitative understanding for therapeutic design. (Li et al. 2023; URL: https://doi.org/10.3390/membranes13110871). ()

3) Current applications and real-world implementations
- Oncology (hematologic): Anti-CD47 antibodies (e.g., magrolimab) and SIRPα-based decoys/antibodies are being advanced mainly in MDS/AML and B-cell lymphomas, often in combination with hypomethylating agents or anti-CD20 antibodies to exploit enhanced antibody-dependent phagocytosis and innate–adaptive crosstalk. Early-phase activity has been observed, though late-phase readouts have been mixed, leading to program reprioritizations in 2023. (Xu et al. 2024; Jiang et al. 2024; URLs above). (xu2024opportunitiesandchallenges pages 2-4, xu2024opportunitiesandchallenges pages 10-11)
- Solid tumors: Combination strategies (e.g., with anti-EGFR or anti-HER2 antibodies) remain under exploration; strategic reassessments followed 2023 terminations in MDS, but solid tumor development continues in selected combinations and platform trials. (Jiang et al. 2024; Isenberg & Montero 2024; URL: https://doi.org/10.3389/fonc.2024.1378647; https://doi.org/10.1002/ctm2.1584). (xu2024opportunitiesandchallenges pages 10-11, isenberg2024toleratingcd47 pages 1-3)
- Vascular biology/cardiometabolic disease (mechanistic application): Recent studies reinforce that TSP1–CD47 signaling inhibits NO–cGMP and VEGF signaling, supporting investigational concepts for modulating perfusion, angiogenesis, and inflammatory tone; however, clinical translation outside oncology remains exploratory. (Skrobek 2023; Isenberg & Montero 2024). (skrobek2023structuralcharacterizationof pages 46-49, isenberg2024toleratingcd47 pages 8-9)

4) Expert opinions and analysis (authoritative sources)
- Strategic reassessment of CD47 targeting: Editorial commentary argues that CD47’s pleiotropy and multi-receptor hub function explain divergent clinical outcomes and on-target toxicities; future success likely requires agent-specific pharmacology (e.g., epitope, Fc design), refined dosing (priming, step-up), and rational combinations that consider both SIRPα-dependent and TSP1/integrin/VEGFR2 co-signaling. (Isenberg & Montero 2024; URL: https://doi.org/10.1002/ctm2.1584). (isenberg2024toleratingcd47 pages 1-3, isenberg2024toleratingcd47 pages 8-9)
- Industry landscape (2023–2024): Reviews summarize the halting of phase 3 ENHANCE (magrolimab + azacitidine in HR‑MDS) in July 2023 and termination of evorpacept MDS program in August 2023, underscoring feasibility challenges and the need for improved patient selection and biomarkers (e.g., TP53 status, macrophage/TME contexture). (Jiang et al. 2024; Xu et al. 2024). (xu2024opportunitiesandchallenges pages 10-11, xu2024opportunitiesandchallenges pages 2-4)
- Engineering recommendations: Reviews highlight RBC-sparing strategies (SIRPα-focused agents, tumor-selective antibodies, QPCTL inhibition) as crucial to balancing efficacy and safety in upcoming trials. (Liu et al. 2023; URL: https://doi.org/10.1038/s41392-023-01365-z). (liu2023emergingphagocytosischeckpoints pages 18-19)

5) Relevant statistics and data from recent studies (selected)
- HR-MDS (magrolimab + azacitidine, early-phase): ORR 75%, CR 33% (phase 1). (Xu et al. 2024). (xu2024opportunitiesandchallenges pages 2-4)
- NHL combinations (magrolimab + rituximab): DLBCL cohort ORR 40%/CR 33% (n=15); FL cohort ORR 71%/CR 43% (n=7). (Xu et al. 2024). (xu2024opportunitiesandchallenges pages 2-4)
- Multi-agent regimens (selected settings): ORR ~51.5%, CR ~39.4%, median DOR ~18 months; median OS not reached at reporting. (Xu et al. 2024). (xu2024opportunitiesandchallenges pages 2-4)
- Safety signals: Anemia is a prominent, mechanism-based toxicity due to RBC CD47; mitigation via priming doses and RBC-sparing designs is reported across clinical programs. (Xu et al. 2024; Liu et al. 2023). (xu2024opportunitiesandchallenges pages 2-4, liu2023emergingphagocytosischeckpoints pages 18-19)

Mechanistic detail and pathway roles
- CD47–SIRPα phagocytosis checkpoint: CD47 on target cells engages SIRPα on macrophages; SIRPα ITIMs recruit SHP‑1/SHP‑2, which dephosphorylate myosin IIA, reducing contractility and engulfment, thereby suppressing phagocytosis. This checkpoint integrates with other myeloid checkpoints (e.g., PD‑L1/MHC‑I axes) and can be overcome by blockade or by pro-phagocytic receptor activation. (Skrobek 2023; Liu et al. 2023; URL: https://doi.org/10.5282/edoc.32156; https://doi.org/10.1038/s41392-023-01365-z). (skrobek2023structuralcharacterizationof pages 46-49, liu2023emergingphagocytosischeckpoints pages 18-19)
- TSP1–CD47 vascular and metabolic signaling: TSP1 ligation of CD47 inhibits NO–cGMP signaling (limiting vasodilation) and decreases VEGF signaling, anti-angiogenic overall; it can promote ROS and senescence, with implications for ischemia, atherosclerosis, and tissue stress responses. (Skrobek 2023; Isenberg & Montero 2024). (skrobek2023structuralcharacterizationof pages 46-49, isenberg2024toleratingcd47 pages 8-9)
- Integrin associations and inside-out signaling: CD47’s cis association with multiple integrins (e.g., αIIbβ3) links TSP1–CD47 engagement to integrin activation via Gi, SYK, FAK, and Src, aligning with its original designation as IAP and supporting roles in adhesion and platelet biology. (Skrobek 2023). (skrobek2023structuralcharacterizationof pages 46-49)

Structural insights (recent)
- Structural and biophysical efforts: Attempts using cryo-EM and nanobody complexes to characterize full-length human CD47 and its complexes are reported; CD47 forms membrane clusters and engages multiple partners, but high-resolution, full-length structures remain technically challenging. These efforts guide epitope- and interface-focused therapeutic design even when atomic-resolution data are incomplete. (Skrobek 2023; URL: https://doi.org/10.5282/edoc.32156. Isenberg & Montero 2024). (skrobek2023structuralcharacterizationof pages 46-49, isenberg2024toleratingcd47 pages 1-3)

Clinical landscape synopsis (2023–2024)
- Programs and outcomes: After early promising activity, magrolimab’s phase 3 ENHANCE program in MDS was halted in 2023; AML development concluded with limited expected survival benefit in TP53‑mutant disease. Evorpacept’s MDS/AML program was terminated for lack of added benefit, though other solid-tumor combinations continue. Several alternative anti‑CD47 and SIRPα‑directed agents report high response rates in early MDS cohorts but share hematologic toxicities that require mitigation. (Jiang et al. 2024; Xu et al. 2024; URLs above). (xu2024opportunitiesandchallenges pages 10-11, xu2024opportunitiesandchallenges pages 2-4)
- Safety and translational considerations: Anemia attributable to RBC CD47 remains the principal on‑target toxicity; strategies include priming/step dosing, RBC‑sparing epitope selection, SIRPα‑centric agents, Fc engineering, and modulation of CD47–SIRPα maturation (e.g., QPCTL). (Liu et al. 2023; Xu et al. 2024). (liu2023emergingphagocytosischeckpoints pages 18-19, xu2024opportunitiesandchallenges pages 2-4)

Notes on verification and domains
- The literature aligns with the UniProt description: CD47 is an Ig superfamily protein with a V-set Ig-like extracellular domain, a multi-pass transmembrane region, and a short cytoplasmic tail; the functionally salient domains and binding partners (SIRPα, TSP1, integrins) are consistent with domain annotations provided. No conflicting gene symbol usage or non-human ortholog confusion was found. (Isenberg & Montero 2024; Skrobek 2023). (isenberg2024toleratingcd47 pages 1-3, skrobek2023structuralcharacterizationof pages 46-49)

References within text (URLs/dates provided above) are supported by the following sources: Isenberg & Montero 2024 (Clinical and Translational Medicine), Skrobek 2023 (Dissertation), Xu et al. 2024 (Frontiers in Immunology), Liu et al. 2023 (Signal Transduction and Targeted Therapy), Jiang et al. 2024 (Frontiers in Oncology). Citations are indicated after each corresponding statement. (isenberg2024toleratingcd47 pages 1-3, skrobek2023structuralcharacterizationof pages 46-49, xu2024opportunitiesandchallenges pages 2-4, liu2023emergingphagocytosischeckpoints pages 18-19, xu2024opportunitiesandchallenges pages 10-11)

References

(isenberg2024toleratingcd47 pages 1-3): Jeffrey S. Isenberg and Enrique Montero. Tolerating cd47. Clinical and Translational Medicine, Feb 2024. URL: https://doi.org/10.1002/ctm2.1584, doi:10.1002/ctm2.1584. This article has 16 citations and is from a peer-reviewed journal.
(skrobek2023structuralcharacterizationof pages 46-49): Blazej Skrobek. Structural characterization of cd47 and sting in complex with the activating nanobody. Dissertation, Jan 2023. URL: https://doi.org/10.5282/edoc.32156, doi:10.5282/edoc.32156. This article has 0 citations.
(isenberg2024toleratingcd47 pages 8-9): Jeffrey S. Isenberg and Enrique Montero. Tolerating cd47. Clinical and Translational Medicine, Feb 2024. URL: https://doi.org/10.1002/ctm2.1584, doi:10.1002/ctm2.1584. This article has 16 citations and is from a peer-reviewed journal.
(liu2023emergingphagocytosischeckpoints pages 18-19): Yue-Ying Liu, Yanjin Wang, Yanrong Yang, Linjun Weng, Qi Wu, Jin Zhang, Pengcheng Zhao, L. Fang, Yufeng Shi, and Ping Wang. Emerging phagocytosis checkpoints in cancer immunotherapy. Signal Transduction and Targeted Therapy, Mar 2023. URL: https://doi.org/10.1038/s41392-023-01365-z, doi:10.1038/s41392-023-01365-z. This article has 226 citations and is from a peer-reviewed journal.
(xu2024opportunitiesandchallenges pages 2-4): Yilan Xu, Panruo Jiang, Zhenyan Xu, and Haige Ye. Opportunities and challenges for anti-cd47 antibodies in hematological malignancies. Frontiers in Immunology, Feb 2024. URL: https://doi.org/10.3389/fimmu.2024.1348852, doi:10.3389/fimmu.2024.1348852. This article has 31 citations and is from a peer-reviewed journal.
(xu2024opportunitiesandchallenges pages 10-11): Yilan Xu, Panruo Jiang, Zhenyan Xu, and Haige Ye. Opportunities and challenges for anti-cd47 antibodies in hematological malignancies. Frontiers in Immunology, Feb 2024. URL: https://doi.org/10.3389/fimmu.2024.1348852, doi:10.3389/fimmu.2024.1348852. This article has 31 citations and is from a peer-reviewed journal.

Citations

skrobek2023structuralcharacterizationof pages 46-49
liu2023emergingphagocytosischeckpoints pages 18-19
xu2024opportunitiesandchallenges pages 2-4
xu2024opportunitiesandchallenges pages 10-11
https://doi.org/10.1002/ctm2.1584
https://doi.org/10.5282/edoc.32156.
https://doi.org/10.5282/edoc.32156;
https://doi.org/10.1038/s41392-023-01365-z
https://doi.org/10.3389/fimmu.2024.1348852
https://doi.org/10.3389/fimmu.2024.1348852;
https://doi.org/10.3389/fonc.2024.1378647
https://doi.org/10.3390/membranes13110871
https://doi.org/10.3389/fonc.2024.1378647;
https://doi.org/10.1002/ctm2.1584,
https://doi.org/10.5282/edoc.32156,
https://doi.org/10.1038/s41392-023-01365-z,
https://doi.org/10.3389/fimmu.2024.1348852,

📄 View Raw YAML

id: Q08722
gene_symbol: CD47
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  CD47 (also known as integrin-associated protein, IAP) is a ubiquitously expressed
  cell surface receptor that functions as an innate immune checkpoint - the "don't
  eat me"
  signal. The core function of CD47 is to bind SIRPalpha on myeloid cells (macrophages,
  dendritic cells) in trans, which recruits SHP-1/SHP-2 phosphatases to inhibit phagocytosis.
  This CD47-SIRPalpha axis is critical for self-recognition and prevents inappropriate
  phagocytic clearance of healthy cells. CD47 also binds thrombospondin-1 (TSP1) to
  modulate
  vascular signaling, including inhibition of nitric oxide signaling. Additionally,
  CD47
  associates with multiple integrins (alphaVbeta3, alphaIIbbeta3, etc.) to modulate
  integrin-mediated signaling and cell adhesion. The protein contains an extracellular
  Ig-like V-type domain and five transmembrane helices.
existing_annotations:
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CD47 is a multi-pass transmembrane protein localized to the plasma membrane.
        This is well-established from early characterization studies and confirmed
        by
        multiple structural and functional studies (PMID:7691831, PMID:7998989).
      action: ACCEPT
      reason: >-
        Plasma membrane localization is a core property of CD47 function. The protein
        must be at the cell surface to engage SIRPalpha on opposing cells and to interact
        with thrombospondin-1. UniProt confirms "Cell membrane; Multi-pass membrane
        protein".
      supported_by:
        - reference_id: PMID:7691831
          supporting_text: "Integrin Associated Protein (IAP) is a 50-kD membrane
            protein which copurifies with the integrin alpha v beta 3 from placenta"
        - reference_id: file:human/CD47/CD47-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0022409
      label: positive regulation of cell-cell adhesion
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CD47 mediates cell-cell adhesion through its interactions with SIRPalpha
        and SIRPgamma on opposing cells (PMID:11509594, PMID:15383453). The
        CD47-SIRPbeta2 interaction promotes T cell adhesion to antigen-presenting
        cells.
      action: ACCEPT
      reason: >-
        Cell-cell adhesion mediation is experimentally validated. The CD47-SIRP
        interactions physically bridge cells and this is a core function of the protein.
      supported_by:
        - reference_id: PMID:15383453
          supporting_text: "SIRPbeta2 is expressed on T cells and activated natural
            killer (NK) cells and, like SIRPalpha, binds CD47, mediating cell-cell
            adhesion"
        - reference_id: PMID:11509594
          supporting_text: "CD47/integrin-associated protein, a ubiquitous multispan
            transmembrane protein highly expressed on T cells, interacts with signal-regulator
            protein (SIRP)-alpha"
  - term:
      id: GO:0050729
      label: positive regulation of inflammatory response
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CD47 signaling is involved in modulating inflammatory responses, particularly
        through its effects on cytokine production and dendritic cell function (PMID:11509594).
        The deep research notes that CD47-SIRPalpha and TSP1-CD47 axes can modulate
        inflammatory tone.
      action: KEEP_AS_NON_CORE
      reason: >-
        While CD47 can modulate inflammatory responses, this is a downstream consequence
        of its core phagocytosis checkpoint function, not the primary function. The
        annotation is valid but represents a non-core pleiotropic effect.
      supported_by:
        - reference_id: PMID:11509594
          supporting_text: "Proinflammatory molecules, including IFN-gamma and IL-12,
            play a crucial role in the elimination of causative agents"
  - term:
      id: GO:0050766
      label: positive regulation of phagocytosis
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        This annotation is MISLEADING. CD47 is fundamentally a NEGATIVE regulator
        of phagocytosis - the "don't eat me" signal. When CD47 engages SIRPalpha on
        macrophages, it INHIBITS phagocytosis. Blocking CD47 or the CD47-SIRPalpha
        axis PROMOTES phagocytosis (PMID:11509594, deep research).
      action: MODIFY
      reason: >-
        CD47's core function is as an inhibitory checkpoint that prevents phagocytosis.
        The annotation to "positive regulation of phagocytosis" appears to be an error
        or over-annotation. The ISS annotation (GO:0050765, negative regulation) is
        correct. The positive regulation may have been inferred incorrectly from
        studies where CD47 blockade increases phagocytosis.
      proposed_replacement_terms:
        - id: GO:0050765
          label: negative regulation of phagocytosis
      supported_by:
        - reference_id: PMID:11509594
          supporting_text: "CD47 on T cells and its cognate receptor SIRP-alpha on
            DC define a novel regulatory pathway that may be involved in the maintenance
            of homeostasis by preventing the escalation of the inflammatory immune
            response"
  - term:
      id: GO:0070053
      label: thrombospondin receptor activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CD47 is a well-established receptor for the C-terminal cell-binding domain
        of thrombospondin-1 (TSP1). This was demonstrated by affinity labeling,
        antibody blocking, and functional assays (PMID:8550562, PMID:19004835).
      action: ACCEPT
      reason: >-
        Thrombospondin receptor activity is a core molecular function of CD47.
        The interaction with TSP1 modulates important signaling pathways including
        nitric oxide signaling and integrin function.
      supported_by:
        - reference_id: PMID:8550562
          supporting_text: "IAP (CD47) as a receptor for the CBD of TS1 and suggest
            a mechanism for the well established effects of the CBD on cell motility"
        - reference_id: PMID:8550562
          supporting_text: "Cell-binding peptides based on the sequence RFYVVM from
            the CBD of TS1 affinity label a 52-kDa cell surface glycoprotein, which
            we show is integrin-associated protein (IAP or CD47)"
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CD47 has been detected in extracellular exosomes. This may reflect the
        ubiquitous expression of CD47 on cell membranes that become incorporated
        into exosomes.
      action: KEEP_AS_NON_CORE
      reason: >-
        While CD47 may be present in exosomes, this is not a core localization
        for its primary phagocytosis checkpoint function. The plasma membrane
        localization is the functionally critical one.
  - term:
      id: GO:0034113
      label: heterotypic cell-cell adhesion
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: >-
        CD47 mediates heterotypic cell-cell adhesion through trans interactions
        with SIRP family members on different cell types (e.g., T cells expressing
        CD47 binding to SIRPalpha on dendritic cells or macrophages).
      action: ACCEPT
      reason: >-
        This is an accurate annotation. The CD47-SIRPalpha/SIRPgamma interactions
        mediate adhesion between different cell types, which is central to its
        immune checkpoint function.
      supported_by:
        - reference_id: PMID:11509594
          supporting_text: "CD47/integrin-associated protein... interacts with signal-regulator
            protein (SIRP)-alpha, an immunoreceptor tyrosine-based inhibition motif-containing
            molecule selectively expressed on myelomonocytic cells"
  - term:
      id: GO:0001525
      label: angiogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        CD47-TSP1 signaling has anti-angiogenic effects through inhibition of
        VEGF and nitric oxide signaling. CD47 plays a role in suppressing
        angiogenesis (PMID:32679764, deep research).
      action: KEEP_AS_NON_CORE
      reason: >-
        While CD47 does modulate angiogenesis through TSP1 signaling, this is
        a downstream consequence of TSP1-CD47 interaction rather than the core
        phagocytosis checkpoint function. The annotation is valid but represents
        a pleiotropic effect of the TSP1 signaling axis.
  - term:
      id: GO:0002684
      label: positive regulation of immune system process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        CD47 modulates immune responses through multiple mechanisms including
        the SIRPalpha checkpoint and T cell costimulation via SIRPbeta2/gamma.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a very general term. CD47 has complex effects on immune processes
        -
        it can both inhibit (via SIRPalpha checkpoint) and promote (via T cell
        costimulation) immune responses depending on context. The annotation
        is too general to be informative about core function.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Duplicate of IBA annotation. CD47 is a plasma membrane protein - this
        is well established.
      action: ACCEPT
      reason: >-
        Plasma membrane localization is correct and represents core localization
        for CD47 function.
  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        This annotation is an OVER-ANNOTATION and MISLEADING. CD47's core function
        is as a phagocytosis checkpoint. When CD47 is lost or blocked, cells are
        cleared by phagocytes - this appears as "cell death" but is NOT apoptosis.
        The cells are engulfed by macrophages, not dying by apoptotic program.
        While CD47 can augment FAS-mediated apoptosis (PMID:15917238), this is a
        secondary/modulatory effect, not its core function.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        CD47 is fundamentally a "don't eat me" signal that prevents phagocytosis.
        Loss of CD47 leads to phagocytic clearance, not apoptosis. The annotation
        to "apoptotic process" is fundamentally misleading about the protein's
        function. The keyword-based mapping from Swiss-Prot "Apoptosis" is
        inappropriate because CD47's relationship to cell death is indirect -
        it modulates whether cells get cleared by phagocytes, not whether they
        undergo intrinsic apoptotic cell death.
      supported_by:
        - reference_id: PMID:15917238
          supporting_text: "CD47 associates with Fas upon its activation and augments
            Fas-mediated apoptosis"
  - term:
      id: GO:0006954
      label: inflammatory response
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        CD47 modulates inflammatory responses through its effects on cytokine
        production and immune cell activation (PMID:11509594).
      action: KEEP_AS_NON_CORE
      reason: >-
        CD47 does participate in inflammatory response modulation, but this is
        downstream of its core checkpoint function, not the primary function.
  - term:
      id: GO:0007155
      label: cell adhesion
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        CD47 mediates cell adhesion through SIRP interactions and integrin
        associations. This is supported by multiple studies.
      action: ACCEPT
      reason: >-
        Cell adhesion is a core function of CD47, enabling the physical
        interaction between cells required for the phagocytosis checkpoint.
      supported_by:
        - reference_id: PMID:15383453
          supporting_text: "SIRPbeta2 is expressed on T cells... and, like SIRPalpha,
            binds CD47, mediating cell-cell adhesion"
  - term:
      id: GO:0022409
      label: positive regulation of cell-cell adhesion
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        Duplicate of IBA annotation. CD47 promotes cell-cell adhesion through
        SIRP interactions.
      action: ACCEPT
      reason: >-
        Cell-cell adhesion is a validated function of CD47.
  - term:
      id: GO:0050729
      label: positive regulation of inflammatory response
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        Duplicate of IBA annotation. CD47 modulates inflammatory responses.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a pleiotropic effect, not the core function.
  - term:
      id: GO:0050766
      label: positive regulation of phagocytosis
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        This is INCORRECT. CD47 is a NEGATIVE regulator of phagocytosis,
        not a positive regulator.
      action: MODIFY
      reason: >-
        CD47's core function is inhibiting phagocytosis via the SIRPalpha checkpoint.
        This annotation is fundamentally wrong.
      proposed_replacement_terms:
        - id: GO:0050765
          label: negative regulation of phagocytosis
  - term:
      id: GO:0070053
      label: thrombospondin receptor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        Duplicate of IBA annotation. CD47 is a TSP1 receptor.
      action: ACCEPT
      reason: >-
        Thrombospondin receptor activity is a core function.
  - term:
      id: GO:0098609
      label: cell-cell adhesion
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        CD47 mediates cell-cell adhesion through SIRP interactions.
      action: ACCEPT
      reason: >-
        Cell-cell adhesion is a core function of CD47.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15383453
    review:
      summary: >-
        This study demonstrates CD47 binding to SIRPbeta2 (SIRPgamma), which
        mediates T cell adhesion to antigen-presenting cells and costimulates
        T-cell proliferation. A more specific term should be used.
      action: MODIFY
      reason: >-
        "Protein binding" is uninformative. The actual binding partner (SIRPgamma/SIRPbeta2)
        is characterized. Should use a more specific molecular function term such
        as
        "signaling receptor binding" or the specific cell-cell adhesion mediator function.
      proposed_replacement_terms:
        - id: GO:0005102
          label: signaling receptor binding
      supported_by:
        - reference_id: PMID:15383453
          supporting_text: "SIRPbeta2 is expressed on T cells and activated natural
            killer (NK) cells and, like SIRPalpha, binds CD47, mediating cell-cell
            adhesion"
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17070842
    review:
      summary: >-
        This study characterizes the SIRPalpha-CD47 binding interaction at the
        molecular level, identifying key residues on SIRPalpha required for
        CD47 binding.
      action: MODIFY
      reason: >-
        "Protein binding" is uninformative. The interaction with SIRPalpha is
        well-characterized and more specific terms should be used.
      proposed_replacement_terms:
        - id: GO:0005102
          label: signaling receptor binding
      supported_by:
        - reference_id: PMID:17070842
          supporting_text: "binding of SIRPalpha with CD47... through the extracellular
            IgV domain regulates important leukocyte functions including macrophage
            recognition, leukocyte adhesion and transmigration"
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25416956
    review:
      summary: >-
        High-throughput interactome study. Generic protein binding.
      action: REMOVE
      reason: >-
        "Protein binding" from high-throughput studies provides no functional
        information. Should be removed in favor of more specific annotations.
      supported_by:
        - reference_id: PMID:25416956
          supporting_text: A proteome-scale map of the human interactome 
            network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32822567
    review:
      summary: >-
        IgSF cell-surface interactome study. Generic protein binding.
      action: REMOVE
      reason: >-
        High-throughput generic binding annotations are uninformative.
      supported_by:
        - reference_id: PMID:32822567
          supporting_text: A Human IgSF Cell-Surface Interactome Reveals a 
            Complex Network of Protein-Protein Interactions.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: >-
        Proteome-scale interactome study. Generic protein binding.
      action: REMOVE
      reason: >-
        High-throughput generic binding annotations are uninformative.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
            cell-specific remodeling of the human interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35922511
    review:
      summary: >-
        Physical wiring diagram study. Generic protein binding.
      action: REMOVE
      reason: >-
        High-throughput generic binding annotations are uninformative.
      supported_by:
        - reference_id: PMID:35922511
          supporting_text: Aug 3. A physical wiring diagram for the human immune
            system.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        Plasma membrane localization based on immunofluorescence data.
      action: ACCEPT
      reason: >-
        Core localization confirmed by direct experimental evidence.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15917238
    review:
      summary: >-
        This study shows CD47 interacts with FAS/CD95 upon Fas activation,
        augmenting Fas-mediated apoptosis.
      action: MODIFY
      reason: >-
        The binding partner (FAS) is specific and characterized. A more
        informative term should be used. However, this is a secondary
        function of CD47.
      proposed_replacement_terms:
        - id: GO:0005102
          label: signaling receptor binding
      supported_by:
        - reference_id: PMID:15917238
          supporting_text: "CH11 induces association of Fas and CD47"
  - term:
      id: GO:0070051
      label: fibrinogen binding
    evidence_type: IDA
    original_reference_id: PMID:22079249
    review:
      summary: >-
        CD47 was identified as a putative mediator for soluble fibrinogen
        interaction with human red blood cells (PMID:22079249).
      action: KEEP_AS_NON_CORE
      reason: >-
        Fibrinogen binding has been demonstrated but this is not a core
        function of CD47. It may relate to the integrin-associated functions.
      supported_by:
        - reference_id: PMID:22079249
          supporting_text: "Integrin-associated protein (CD47) is a putative mediator
            for soluble fibrinogen interaction with human red blood cells membrane"
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19004835
    review:
      summary: >-
        This study characterizes differential interactions of thrombospondin-1,
        -2, and -4 with CD47. CD47 binds TSP1 most strongly.
      action: MODIFY
      reason: >-
        The binding to thrombospondin is well-characterized. The thrombospondin
        receptor activity annotation (GO:0070053) is more appropriate.
      proposed_replacement_terms:
        - id: GO:0070053
          label: thrombospondin receptor activity
      supported_by:
        - reference_id: PMID:19004835
          supporting_text: "Differential interactions of thrombospondin-1, -2, and
            -4 with CD47 and effects on cGMP signaling and ischemic injury responses"
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:8550562
    review:
      summary: >-
        Original identification of CD47 as the thrombospondin receptor.
      action: MODIFY
      reason: >-
        The specific thrombospondin receptor activity term is more appropriate.
      proposed_replacement_terms:
        - id: GO:0070053
          label: thrombospondin receptor activity
      supported_by:
        - reference_id: PMID:8550562
          supporting_text: "Integrin-associated protein is a receptor for the C-terminal
            domain of thrombospondin"
  - term:
      id: GO:0070053
      label: thrombospondin receptor activity
    evidence_type: IDA
    original_reference_id: PMID:8550562
    review:
      summary: >-
        Direct experimental demonstration that CD47/IAP is the receptor for
        thrombospondin C-terminal cell-binding domain (PMID:8550562).
      action: ACCEPT
      reason: >-
        Core molecular function of CD47 with strong experimental support.
      supported_by:
        - reference_id: PMID:8550562
          supporting_text: "IAP (CD47) as a receptor for the CBD of TS1"
  - term:
      id: GO:0050765
      label: negative regulation of phagocytosis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CD47 engagement of SIRPalpha delivers a "don't eat me" signal that
        inhibits phagocytosis. This is the CORE function of CD47.
      action: ACCEPT
      reason: >-
        This is the primary, core function of CD47 as an innate immune checkpoint.
        The CD47-SIRPalpha axis is the central "don't eat me" signal.
      supported_by:
        - reference_id: PMID:11509594
          supporting_text: "CD47 on T cells and its cognate receptor SIRP-alpha on
            DC define a novel regulatory pathway that may be involved in the maintenance
            of homeostasis"
  - term:
      id: GO:0060368
      label: regulation of Fc receptor mediated stimulatory signaling pathway
    evidence_type: ISS
    original_reference_id: PMID:21401967
    review:
      summary: >-
        CD47-SIRPalpha interaction down-regulates Fc receptor signaling in
        phagocytes, contributing to the "don't eat me" signal.
      action: ACCEPT
      reason: >-
        This is related to the core phagocytosis checkpoint function. The
        CD47-SIRPalpha axis inhibits Fc receptor-mediated phagocytosis.
      supported_by:
        - reference_id: PMID:21401967
          supporting_text: Myelin down-regulates myelin phagocytosis by 
            microglia and macrophages through interactions between CD47 on 
            myelin and SIRPα (signal regulatory protein-α) on phagocytes.
  - term:
      id: GO:2000439
      label: positive regulation of monocyte extravasation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CD47 has been implicated in monocyte extravasation through its
        interactions with SIRPalpha and effects on cell migration.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a secondary effect related to cell adhesion functions, not
        the core phagocytosis checkpoint function.
  - term:
      id: GO:1904669
      label: ATP export
    evidence_type: IDA
    original_reference_id: PMID:24022490
    review:
      summary: >-
        CD47 has been implicated in CR1-mediated ATP release by human red
        blood cells.
      action: KEEP_AS_NON_CORE
      reason: >-
        ATP export is a specialized function in red blood cells, not the
        core immune checkpoint function of CD47.
      supported_by:
        - reference_id: PMID:24022490
          supporting_text: 2013 Sep 10. CR1-mediated ATP release by human red 
            blood cells promotes CR1 clustering and modulates the immune 
            transfer process.
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: IDA
    original_reference_id: PMID:11509594
    review:
      summary: >-
        CD47 is expressed on the cell surface where it engages SIRPalpha
        in trans. Confirmed by this study on T and dendritic cells.
      action: ACCEPT
      reason: >-
        Cell surface localization is essential for CD47's checkpoint function.
      supported_by:
        - reference_id: PMID:11509594
          supporting_text: "CD47/integrin-associated protein, a ubiquitous multispan
            transmembrane protein highly expressed on T cells"
  - term:
      id: GO:0032649
      label: regulation of type II interferon production
    evidence_type: IMP
    original_reference_id: PMID:11509594
    review:
      summary: >-
        CD47-SIRPalpha engagement modulates IFN-gamma production. CD47-Fc
        decreases IFN-gamma production in allogeneic MLR (PMID:11509594).
      action: KEEP_AS_NON_CORE
      reason: >-
        Cytokine regulation is a downstream consequence of the CD47-SIRPalpha
        checkpoint, not the core function.
      supported_by:
        - reference_id: PMID:11509594
          supporting_text: "CD47-Fc decreases IFN-gamma production after priming and
            impairs the development of a Th1 response"
  - term:
      id: GO:0032653
      label: regulation of interleukin-10 production
    evidence_type: IMP
    original_reference_id: PMID:11509594
    review:
      summary: >-
        CD47-SIRPalpha engagement modulates IL-10 production.
      action: KEEP_AS_NON_CORE
      reason: >-
        Cytokine regulation is a downstream effect, not core function.
      supported_by:
        - reference_id: PMID:11509594
          supporting_text: 'Bidirectional negative regulation of human T and dendritic
            cells by CD47 and its cognate receptor signal-regulator protein-alpha:
            down-regulation of IL-12 responsiveness and inhibition of dendritic cell
            activation.'
  - term:
      id: GO:0032655
      label: regulation of interleukin-12 production
    evidence_type: IMP
    original_reference_id: PMID:11509594
    review:
      summary: >-
        CD47 ligation down-regulates IL-12 responsiveness of T cells
        (PMID:11509594).
      action: KEEP_AS_NON_CORE
      reason: >-
        Cytokine regulation is a downstream effect, not core function.
      supported_by:
        - reference_id: PMID:11509594
          supporting_text: "CD47 ligation by CD47 mAb or L-SIRP-alpha transfectants
            inhibits IL-12R expression and down-regulates IL-12 responsiveness of
            activated CD4(+) and CD8(+) adult T cells"
  - term:
      id: GO:0032675
      label: regulation of interleukin-6 production
    evidence_type: IMP
    original_reference_id: PMID:11509594
    review:
      summary: >-
        CD47-SIRPalpha engagement modulates IL-6 production.
      action: KEEP_AS_NON_CORE
      reason: >-
        Cytokine regulation is a downstream effect, not core function.
      supported_by:
        - reference_id: PMID:11509594
          supporting_text: 'Bidirectional negative regulation of human T and dendritic
            cells by CD47 and its cognate receptor signal-regulator protein-alpha:
            down-regulation of IL-12 responsiveness and inhibition of dendritic cell
            activation.'
  - term:
      id: GO:0032680
      label: regulation of tumor necrosis factor production
    evidence_type: IMP
    original_reference_id: PMID:11509594
    review:
      summary: >-
        CD47-SIRPalpha engagement modulates TNF production.
      action: KEEP_AS_NON_CORE
      reason: >-
        Cytokine regulation is a downstream effect, not core function.
      supported_by:
        - reference_id: PMID:11509594
          supporting_text: 'Bidirectional negative regulation of human T and dendritic
            cells by CD47 and its cognate receptor signal-regulator protein-alpha:
            down-regulation of IL-12 responsiveness and inhibition of dendritic cell
            activation.'
  - term:
      id: GO:0071349
      label: cellular response to interleukin-12
    evidence_type: IMP
    original_reference_id: PMID:11509594
    review:
      summary: >-
        CD47 ligation down-regulates IL-12 responsiveness of T cells
        (PMID:11509594).
      action: KEEP_AS_NON_CORE
      reason: >-
        This is downstream signaling modulation, not core function.
      supported_by:
        - reference_id: PMID:11509594
          supporting_text: "CD47 ligation by CD47 mAb or L-SIRP-alpha transfectants
            inhibits IL-12R expression and down-regulates IL-12 responsiveness"
  - term:
      id: GO:0098632
      label: cell-cell adhesion mediator activity
    evidence_type: IPI
    original_reference_id: PMID:11509594
    review:
      summary: >-
        CD47 mediates cell-cell adhesion through its interactions with
        SIRPalpha and other SIRP family members.
      action: ACCEPT
      reason: >-
        Cell-cell adhesion mediator activity is a well-supported core molecular
        function of CD47.
      supported_by:
        - reference_id: PMID:11509594
          supporting_text: "CD47/integrin-associated protein... interacts with signal-regulator
            protein (SIRP)-alpha"
  - term:
      id: GO:0045428
      label: regulation of nitric oxide biosynthetic process
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        TSP1-CD47 signaling inhibits NO signaling, which has effects on
        vascular function (UniProt, deep research).
      action: KEEP_AS_NON_CORE
      reason: >-
        This is mediated by TSP1-CD47 signaling, which is a secondary axis
        distinct from the core phagocytosis checkpoint function.
  - term:
      id: GO:0086080
      label: protein binding involved in heterotypic cell-cell adhesion
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CD47 binds SIRP family members on opposing cells to mediate heterotypic
        cell-cell adhesion.
      action: ACCEPT
      reason: >-
        This is a well-supported molecular function of CD47 that is central
        to its immune checkpoint activity.
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Duplicate localization annotation. CD47 is on the cell surface.
      action: ACCEPT
      reason: >-
        Core localization is well-established.
  - term:
      id: GO:0016477
      label: cell migration
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CD47 is involved in cell migration, likely through its integrin
        associations and TSP1 signaling.
      action: KEEP_AS_NON_CORE
      reason: >-
        Cell migration is a downstream effect of CD47's adhesion and signaling
        functions, not its core checkpoint function.
  - term:
      id: GO:0051496
      label: positive regulation of stress fiber assembly
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CD47 signaling can affect cytoskeletal organization.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a downstream effect of CD47 signaling, not core function.
  - term:
      id: GO:0071346
      label: cellular response to type II interferon
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CD47 expression is induced by IFN-gamma signaling.
      action: KEEP_AS_NON_CORE
      reason: >-
        This describes regulation of CD47, not its core function.
  - term:
      id: GO:0071347
      label: cellular response to interleukin-1
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        CD47 may respond to IL-1 signaling.
      action: KEEP_AS_NON_CORE
      reason: >-
        This describes regulation of CD47, not its core function.
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: NAS
    original_reference_id: PMID:25795378
    review:
      summary: >-
        Review of SIRP/CD47 signaling confirms cell surface localization.
      action: ACCEPT
      reason: >-
        Core localization confirmed by review.
      supported_by:
        - reference_id: PMID:25795378
          supporting_text: 2015 Mar 17. SIRP/CD47 signaling in neurological 
            disorders.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24026300
    review:
      summary: >-
        Study on SIRPalpha proteolytic processing and CD47 interaction.
      action: MODIFY
      reason: >-
        More specific binding terms should be used.
      proposed_replacement_terms:
        - id: GO:0005102
          label: signaling receptor binding
      supported_by:
        - reference_id: PMID:24026300
          supporting_text: Inflammation-induced proteolytic processing of the 
            SIRPα cytoplasmic ITIM in neutrophils propagates a proinflammatory 
            state.
  - term:
      id: GO:0035579
      label: specific granule membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6799350
    review:
      summary: >-
        CD47 is present on specific granule membranes in neutrophils,
        where it can be mobilized to the cell surface.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a cell-type specific localization in neutrophils, not
        the core localization for CD47's checkpoint function.
  - term:
      id: GO:0070821
      label: tertiary granule membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6798747
    review:
      summary: >-
        CD47 is present on tertiary granule membranes in neutrophils.
      action: KEEP_AS_NON_CORE
      reason: >-
        Cell-type specific localization in neutrophils.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-202703
    review:
      summary: >-
        Reactome annotation for CD47 binding SIRP. Confirms plasma membrane
        localization.
      action: ACCEPT
      reason: >-
        Core localization.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2426259
    review:
      summary: >-
        Reactome annotation for COMP binding to CD47. Confirms plasma
        membrane localization.
      action: ACCEPT
      reason: >-
        Core localization.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-391151
    review:
      summary: >-
        Reactome pathway annotation for SIRPalpha-CD47 signaling.
      action: ACCEPT
      reason: >-
        Core localization.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-391152
    review:
      summary: >-
        Reactome pathway annotation.
      action: ACCEPT
      reason: >-
        Core localization.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-391153
    review:
      summary: >-
        Reactome pathway annotation.
      action: ACCEPT
      reason: >-
        Core localization.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-391157
    review:
      summary: >-
        Reactome pathway annotation.
      action: ACCEPT
      reason: >-
        Core localization.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-391158
    review:
      summary: >-
        Reactome annotation for SIRPalpha binding CD47.
      action: ACCEPT
      reason: >-
        Core localization.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-391168
    review:
      summary: >-
        Reactome annotation for SIRPgamma binding CD47.
      action: ACCEPT
      reason: >-
        Core localization.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6798747
    review:
      summary: >-
        Reactome pathway annotation.
      action: ACCEPT
      reason: >-
        Core localization.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6799350
    review:
      summary: >-
        Reactome pathway annotation.
      action: ACCEPT
      reason: >-
        Core localization.
  - term:
      id: GO:0070053
      label: thrombospondin receptor activity
    evidence_type: IPI
    original_reference_id: PMID:15700281
    review:
      summary: >-
        Study showing IGFBP-5 interacts with TSP1 to modulate IGF-I actions
        through CD47.
      action: ACCEPT
      reason: >-
        Supports CD47's role as thrombospondin receptor.
      supported_by:
        - reference_id: PMID:15700281
          supporting_text: Insulin-like growth factor binding protein-5 
            (IGFBP-5) interacts with thrombospondin-1 to induce negative 
            regulatory effects on IGF-I actions.
  - term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
    evidence_type: IDA
    original_reference_id: PMID:15383453
    review:
      summary: >-
        CD47 engagement by SIRPbeta2 costimulates T-cell proliferation
        (PMID:15383453).
      action: KEEP_AS_NON_CORE
      reason: >-
        T cell costimulation is a secondary function of CD47 through SIRP
        interactions, not the core phagocytosis checkpoint function.
      supported_by:
        - reference_id: PMID:15383453
          supporting_text: "engagement of SIRPbeta2 on T cells by CD47 on antigen-presenting
            cells results in enhanced antigen-specific T-cell proliferation"
  - term:
      id: GO:0022409
      label: positive regulation of cell-cell adhesion
    evidence_type: IDA
    original_reference_id: PMID:15383453
    review:
      summary: >-
        CD47-SIRPbeta2 interaction promotes cell-cell adhesion (PMID:15383453).
      action: ACCEPT
      reason: >-
        Cell-cell adhesion promotion is a well-supported function.
      supported_by:
        - reference_id: PMID:15383453
          supporting_text: "Here, we show that SIRPbeta2 is expressed on T cells and
            activated natural killer (NK) cells and, like SIRPalpha, binds CD47, mediating
            cell-cell adhesion"
  - term:
      id: GO:0050870
      label: positive regulation of T cell activation
    evidence_type: IDA
    original_reference_id: PMID:15383453
    review:
      summary: >-
        CD47-SIRPbeta2 interaction costimulates T cell activation (PMID:15383453).
      action: KEEP_AS_NON_CORE
      reason: >-
        T cell costimulation is a secondary function, not the core
        phagocytosis checkpoint function.
      supported_by:
        - reference_id: PMID:15383453
          supporting_text: "engagement of SIRPbeta2 on T cells by CD47 on antigen-presenting
            cells results in enhanced antigen-specific T-cell proliferation"
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: PMID:7998989
    review:
      summary: >-
        Original characterization of CD47 confirms plasma membrane localization.
      action: ACCEPT
      reason: >-
        Core localization.
      supported_by:
        - reference_id: PMID:7998989
          supporting_text: 'Isolation and characterization of CD47 glycoprotein: a
            multispanning membrane protein which is the same as integrin-associated
            protein (IAP) and the ovarian tumour marker OA3.'
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: PMID:10429193
    review:
      summary: >-
        Study on platelet surface complexes confirms CD47 at plasma membrane.
      action: ACCEPT
      reason: >-
        Core localization.
      supported_by:
        - reference_id: PMID:10429193
          supporting_text: A CD9, alphaIIbbeta3, integrin-associated protein, 
            and GPIb/V/IX complex on the surface of human platelets is 
            influenced by alphaIIbbeta3 conformational states.
  - term:
      id: GO:0007229
      label: integrin-mediated signaling pathway
    evidence_type: TAS
    original_reference_id: PMID:8294396
    review:
      summary: >-
        CD47 was originally identified as integrin-associated protein (IAP)
        and participates in integrin-mediated signaling.
      action: KEEP_AS_NON_CORE
      reason: >-
        Integrin association is a secondary function of CD47, though historically
        important. The primary function is the SIRPalpha phagocytosis checkpoint.
      supported_by:
        - reference_id: PMID:8294396
          supporting_text: Rh-related antigen CD47 is the signal-transducer 
            integrin-associated protein.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000108
    title: Automatic assignment of GO terms using logical inference, based on 
      inter-ontology links
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:7691831
    title: Molecular cloning of integrin-associated protein
    findings:
      - statement: CD47/IAP is a multi-pass membrane protein that associates 
          with integrins
  - id: PMID:7998989
    title: Isolation and characterization of CD47 glycoprotein
    findings:
      - statement: CD47 is identical to IAP and OA3 tumor marker
      - statement: Multi-spanning membrane protein
  - id: PMID:8294396
    title: Rh-related antigen CD47 is the signal-transducer integrin-associated 
      protein
    findings:
      - statement: CD47 is IAP and participates in integrin signaling
  - id: PMID:8550562
    title: Integrin-associated protein is a receptor for the C-terminal domain 
      of thrombospondin
    findings:
      - statement: CD47/IAP is the receptor for thrombospondin-1 C-terminal 
          domain
      - statement: Mediates chemotaxis to TSP1
  - id: PMID:10429193
    title: A CD9, alphaIIbbeta3, integrin-associated protein, and GPIb/V/IX 
      complex on the surface of human platelets is influenced by alphaIIbbeta3 
      conformational states.
    findings:
      - statement: CD47 is in complex with integrins on platelets
        supporting_text: "A noncovalently associated complex comprising of CD9, the
          fibrinogen (Fg) receptor alphaIIbbeta3, integrin-associated protein (IAP),
          and glycoprotein (GP) Ib/V/IX complex was isolated from Chaps-solubilized
          human platelets"
  - id: PMID:11509594
    title: "Bidirectional negative regulation of human T and dendritic cells by CD47
      and its cognate receptor signal-regulator protein-alpha: down-regulation of
      IL-12 responsiveness and inhibition of dendritic cell activation."
    findings:
      - statement: CD47-SIRPalpha interaction is a negative regulatory pathway
        supporting_text: "CD47 on T cells and its cognate receptor SIRP-alpha on DC
          define a novel regulatory pathway that may be involved in the maintenance
          of homeostasis by preventing the escalation of the inflammatory immune response"
      - statement: Inhibits dendritic cell maturation and cytokine production
        supporting_text: "SIRP-alpha engagement by CD47-Fc prevents the phenotypic
          and functional maturation of immature DC and still inhibits cytokine production
          by mature DC"
      - statement: Down-regulates IL-12 responsiveness of T cells
        supporting_text: "CD47 ligation by CD47 mAb or L-SIRP-alpha transfectants
          inhibits IL-12R expression and down-regulates IL-12 responsiveness of activated
          CD4(+) and CD8(+) adult T cells"
  - id: PMID:15383453
    title: Adhesion of human T cells to antigen-presenting cells through 
      SIRPbeta2-CD47 interaction costimulates T-cell proliferation.
    findings:
      - statement: SIRPbeta2/gamma binds CD47
        supporting_text: "Here, we show that SIRPbeta2 is expressed on T cells and
          activated natural killer (NK) cells and, like SIRPalpha, binds CD47, mediating
          cell-cell adhesion"
      - statement: Mediates cell-cell adhesion
        supporting_text: "SIRPbeta2 is expressed on T cells and activated natural
          killer (NK) cells and, like SIRPalpha, binds CD47, mediating cell-cell adhesion"
      - statement: Costimulates T cell proliferation
        supporting_text: "engagement of SIRPbeta2 on T cells by CD47 on antigen-presenting
          cells results in enhanced antigen-specific T-cell proliferation"
  - id: PMID:15700281
    title: Insulin-like growth factor binding protein-5 (IGFBP-5) interacts with
      thrombospondin-1 to induce negative regulatory effects on IGF-I actions.
    findings:
      - statement: IGFBP-5 modulates TSP1-CD47 interactions
        supporting_text: "IGFBP-5 inhibits the binding of TS-1 to IAP, and this results
          in an alteration of the ability of TS-1 to modulate the disruption of the
          IAP/SHPS-1 interaction"
  - id: PMID:15917238
    title: CD47 augments Fas/CD95-mediated apoptosis
    findings:
      - statement: CD47 associates with FAS upon activation
      - statement: Augments FAS-mediated apoptosis (secondary function)
  - id: PMID:17070842
    title: Functional elements on SIRPalpha IgV domain mediate cell surface 
      binding to CD47
    findings:
      - statement: Defines key residues for SIRPalpha-CD47 binding
  - id: PMID:19004835
    title: Differential interactions of thrombospondin-1, -2, and -4 with CD47 
      and effects on cGMP signaling and ischemic injury responses.
    findings:
      - statement: TSP1 binds CD47 with highest affinity
        supporting_text: "high affinity interaction with CD47 appears to be relatively
          specific for the signature domain of TSP1"
      - statement: Affects cGMP signaling
        supporting_text: "Thrombospondin-1 regulates nitric oxide (NO) signaling in
          vascular cells via CD47"
  - id: PMID:21401967
    title: "Myelin down-regulates myelin phagocytosis by microglia and macrophages
      through interactions between CD47 on myelin and SIRPα (signal regulatory protein-α)
      on phagocytes."
    findings:
      - statement: CD47-SIRPalpha axis inhibits phagocytosis
        supporting_text: "Myelin down-regulates its own phagocytosis through CD47-SIRPα
          interactions"
  - id: PMID:22079249
    title: Integrin-associated protein (CD47) is a putative mediator for soluble
      fibrinogen interaction with human red blood cells membrane.
    findings:
      - statement: CD47 mediates fibrinogen-RBC interaction
        supporting_text: "Our results support a specific and age-dependent interaction
          of soluble fibrinogen with human RBC membrane; additionally we present CD47
          as a putative mediator in this process"
  - id: PMID:24022490
    title: CR1-mediated ATP release by human red blood cells promotes CR1 
      clustering and modulates the immune transfer process.
    findings: []
  - id: PMID:24026300
    title: "Inflammation-induced proteolytic processing of the SIRPα cytoplasmic ITIM
      in neutrophils propagates a proinflammatory state."
    findings: []
  - id: PMID:25416956
    title: A proteome-scale map of the human interactome network.
    findings: []
  - id: PMID:25795378
    title: SIRP/CD47 signaling in neurological disorders
    findings: []
  - id: PMID:32679764
    title: CD47 Promotes Age-Associated Deterioration in Angiogenesis
    findings:
      - statement: CD47 suppresses angiogenesis
      - statement: Role in metabolic dysregulation during aging
  - id: PMID:32822567
    title: Human IgSF Cell-Surface Interactome
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks
    findings: []
  - id: PMID:35922511
    title: A physical wiring diagram for the human immune system.
    findings: []
  - id: Reactome:R-HSA-202703
    title: CD47 binds SIRP
    findings: []
  - id: Reactome:R-HSA-2426259
    title: COMP binds Integrin alpha5beta1, Integrin alphaVbeta3, CD47
    findings: []
  - id: Reactome:R-HSA-391151
    title: p-4Y-SIRPA:CD47:SKAP2 binds FYB
    findings: []
  - id: Reactome:R-HSA-391152
    title: p-4Y-SIRPA:CD47 binds PTK2B
    findings: []
  - id: Reactome:R-HSA-391153
    title: p-4Y-SIRPA:CD47 binds GRB2-1
    findings: []
  - id: Reactome:R-HSA-391157
    title: p-4Y-SIRPA:CD47 binds SKAP2
    findings: []
  - id: Reactome:R-HSA-391158
    title: SIRP alpha binds CD47
    findings: []
  - id: Reactome:R-HSA-391168
    title: SIRP gamma binds CD47
    findings: []
  - id: Reactome:R-HSA-6798747
    title: Exocytosis of tertiary granule membrane proteins
    findings: []
  - id: Reactome:R-HSA-6799350
    title: Exocytosis of specific granule membrane proteins
    findings: []
  - id: file:human/CD47/CD47-deep-research-falcon.md
    title: Deep research report on CD47
    findings: []
core_functions:
  - description: >-
      CD47 on target cells binds SIRPalpha on macrophages/phagocytes, recruiting
      SHP-1/SHP-2 phosphatases to inhibit phagocytosis. This is the primary innate
      immune checkpoint function of CD47 - the "don't eat me" signal.
    molecular_function:
      id: GO:0098632
      label: cell-cell adhesion mediator activity
    directly_involved_in:
      - id: GO:0050765
        label: negative regulation of phagocytosis
    locations:
      - id: GO:0009986
        label: cell surface
  - description: >-
      CD47 is the receptor for the C-terminal cell-binding domain of TSP1,
      modulating integrin function and vascular signaling (including NO signaling).
    molecular_function:
      id: GO:0070053
      label: thrombospondin receptor activity
    locations:
      - id: GO:0005886
        label: plasma membrane

CD47

Gene Description

Existing Annotations Review

Core Functions

CD47 on target cells binds SIRPalpha on macrophages/phagocytes, recruiting SHP-1/SHP-2 phosphatases to inhibit phagocytosis. This is the primary innate immune checkpoint function of CD47 - the "don't eat me" signal.

CD47 is the receptor for the C-terminal cell-binding domain of TSP1, modulating integrin function and vascular signaling (including NO signaling).

References

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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