THBS1

UniProt ID: P07996
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

Thrombospondin-1 is a secreted matricellular glycoprotein that mediates cell-matrix interactions and modulates key signaling pathways (angiogenic, TGF-beta, NO/cGMP) in the extracellular environment. It functions as a negative regulator of angiogenesis via CD36 receptor engagement, an activator of latent TGF-beta1, and an inhibitor of nitric oxide signaling via CD47. TSP1 is stored in platelet alpha granules and released upon activation, where it promotes hemostasis and vasoconstriction.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0031012 extracellular matrix
IBA
GO_REF:0000033 		ACCEPT
Summary: TSP1 is a well-established component of the extracellular matrix. The deep research confirms that TSP1 is "secreted into the ECM or circulation" and "associates with the ECM and cell surfaces by binding to proteoglycans and integrins" [PMID:6341993]. This is a core localization for TSP1.
Reason: Strong phylogenetic and experimental evidence supports TSP1 localization to the extracellular matrix. TSP1 is a matricellular protein that functions in the ECM to regulate cell-matrix interactions.
Supporting Evidence:
file:human/THBS1/THBS1-deep-research-openai.md
TSP1 is a secreted protein that predominantly functions in the extracellular space and matrix. Within tissues, TSP1 often associates with the ECM and cell surfaces by binding to proteoglycans and integrins.
file:human/THBS1/THBS1-deep-research-falcon.md
a secreted matricellular (ECM-associated) glycoprotein in the Group A thrombospondin subfamily that forms trimers in the extracellular space
GO:0016525 negative regulation of angiogenesis
IBA
GO_REF:0000033 		ACCEPT
Summary: Negative regulation of angiogenesis is one of the best-documented core functions of TSP1. The protein was first identified as a potent angiogenesis inhibitor in 1990. TSP1 suppresses endothelial cell proliferation, migration, survival, and can induce endothelial apoptosis via CD36 receptor engagement [PMID:10613822].
Reason: This represents a core function of TSP1. The IBA annotation is well-supported by extensive experimental evidence showing TSP1 inhibits angiogenesis through CD36-mediated signaling and sequestration of pro-angiogenic factors like VEGF and FGF-2.
Supporting Evidence:
file:human/THBS1/THBS1-deep-research-openai.md
TSP1 directly suppresses endothelial cell proliferation, migration, and survival, thereby blocking the growth of new capillaries. It can even induce endothelial apoptosis when present at sufficient levels.
file:human/THBS1/THBS1-deep-research-falcon.md
THBS1 binds CD36 (via TSRs) and contributes to platelet and vascular effects; CD36 is also part of anti-angiogenic signaling.
GO:0001525 angiogenesis
IEA
GO_REF:0000043 		ACCEPT
Summary: TSP1 is involved in angiogenesis, though primarily as a negative regulator. The broader term "angiogenesis" is appropriate as TSP1 modulates this process. However, a more specific term (negative regulation of angiogenesis) better captures its function.
Reason: While the more specific term "negative regulation of angiogenesis" is more accurate, this broader term is not incorrect. TSP1 is indeed involved in angiogenesis as a key regulator. The IEA annotation from keyword mapping is acceptable.
GO:0001937 negative regulation of endothelial cell proliferation
IEA
GO_REF:0000117 		ACCEPT
Summary: TSP1 inhibits endothelial cell proliferation as part of its anti-angiogenic function. This is well-documented through multiple mechanisms including CD36-mediated signaling and inhibition of growth factor signaling [PMID:10613822, PMID:17596205].
Reason: This is a well-supported aspect of TSP1's anti-angiogenic function. Multiple studies demonstrate TSP1 suppresses endothelial cell proliferation through CD36 engagement and growth factor sequestration.
GO:0002684 positive regulation of immune system process
IEA
GO_REF:0000117 		MARK AS OVER ANNOTATED
Summary: TSP1 has complex effects on the immune system. Evidence suggests TSP1 primarily has immunosuppressive effects - negatively regulating cytokine production through CD47 and CD36 interactions [PMID:14568985]. However, it can also amplify certain inflammatory responses in specific contexts.
Reason: This annotation is too broad and somewhat misleading. TSP1's predominant role is immunosuppressive - it negatively regulates IL-12, TNF-alpha, and IL-10 production through CD47/CD36 signaling and limits T-cell/NK cell activation. While TSP1 can enhance certain immune responses in specific contexts, this broad positive regulation term does not accurately capture TSP1's function.
GO:0005509 calcium ion binding
IEA
GO_REF:0000002 		ACCEPT
Summary: TSP1 contains multiple calcium-binding sites, particularly within its type 3 repeats. Calcium binding is essential for TSP1 structure and function, affecting its conformation and ligand-binding properties. The UniProt record documents calcium-binding sites throughout the protein.
Reason: Calcium binding is a well-documented property of TSP1. The type 3 repeat region contains multiple calcium-binding loops that are critical for protein structure and function. This is supported by structural studies and InterPro domain analysis.
GO:0005576 extracellular region
IEA
GO_REF:0000120 		ACCEPT
Summary: TSP1 is a secreted protein that functions in the extracellular region. It is synthesized with a signal peptide and released from cells into the ECM or circulation.
Reason: This is a core localization for TSP1 as a secreted matricellular protein. The protein is synthesized with a signal peptide and released into the extracellular space.
Supporting Evidence:
file:human/THBS1/THBS1-deep-research-falcon.md
thrombospondins as secreted extracellular glycoproteins that are typically low at baseline and induced after tissue damage; THBS1 (TSP-1) is a Group A thrombospondin acting at the cell surface/ECM interface.
GO:0005783 endoplasmic reticulum
IEA
GO_REF:0000120 		ACCEPT
Summary: TSP1 transits through the ER as part of its secretory pathway. The ER lumen is where TSP1 undergoes post-translational modifications including glycosylation and disulfide bond formation prior to secretion.
Reason: As a secreted protein, TSP1 transits through the ER during biosynthesis. This is a transit compartment rather than a site of function, but the annotation is accurate for localization purposes.
GO:0006915 apoptotic process
IEA
GO_REF:0000043 		ACCEPT
Summary: TSP1 is involved in apoptosis, particularly in inducing apoptosis of endothelial cells via CD36 signaling as part of its anti-angiogenic function [PMID:10613822]. TSP1 can also promote or protect against apoptosis depending on context and receptor.
Reason: TSP1 is clearly involved in apoptotic processes. It induces endothelial cell apoptosis through CD36-mediated signaling (key to anti-angiogenic function) but can also signal survival through calreticulin/LRP1. The broad term is appropriate.
GO:0006954 inflammatory response
IEA
GO_REF:0000120 		ACCEPT
Summary: TSP1 is involved in modulating the inflammatory response. TSP1 null mice show persistent multi-organ inflammation, indicating TSP1 normally helps resolve inflammation. TSP1 activates TGF-beta1 (immunosuppressive) and negatively regulates cytokine production through CD47/CD36 [PMID:14568985].
Reason: TSP1 plays important roles in inflammatory responses, primarily as an immunosuppressive/anti-inflammatory mediator. The annotation is appropriate though it does not capture the directional effect.
GO:0006986 response to unfolded protein
IEA
GO_REF:0000043 		KEEP AS NON CORE
Summary: This annotation appears to derive from UniProt keyword mapping. TSP1 expression may be induced under ER stress conditions, but there is limited direct evidence that TSP1 is a primary component of the unfolded protein response.
Reason: While TSP1 may be induced during ER stress, this is not a core function. The annotation is likely based on induction rather than direct mechanistic involvement in the UPR pathway.
GO:0007155 cell adhesion
IEA
GO_REF:0000120 		ACCEPT
Summary: TSP1 is an adhesive glycoprotein that mediates cell-matrix and cell-cell adhesion. It binds integrins, proteoglycans, and other ECM components to influence cell attachment and migration. The N-terminal domain binds calreticulin/LRP1 to modulate focal adhesion dynamics [deep research].
Reason: Cell adhesion is a well-documented function of TSP1 as an adhesive glycoprotein. TSP1 binds multiple integrins and ECM components to mediate cell-matrix interactions.
GO:0008201 heparin binding
IEA
GO_REF:0000120 		ACCEPT
Summary: TSP1 binds heparin and heparan sulfate proteoglycans through its N-terminal domain. This binding is important for TSP1 localization in the ECM and for some of its biological activities [PMID:101549].
Reason: Heparin binding is a well-documented property of TSP1. The N-terminal domain contains a heparin-binding region that mediates interactions with glycosaminoglycans.
GO:0009986 cell surface
IEA
GO_REF:0000044 		ACCEPT
Summary: TSP1 can associate with the cell surface through binding to membrane receptors (CD36, CD47, integrins) and proteoglycans. Upon release from platelets, TSP1 binds to platelet surfaces in a Ca2+-dependent manner [PMID:6777381].
Reason: Cell surface association is well-documented for TSP1. The secreted protein binds to various cell surface receptors and can accumulate on cell membranes.
GO:0010810 regulation of cell-substrate adhesion
IEA
GO_REF:0000117 		ACCEPT
Summary: TSP1 modulates cell-substrate adhesion through its interactions with integrins and the calreticulin/LRP1 complex. The N-terminal domain can trigger focal adhesion disassembly and promote cell motility [deep research].
Reason: TSP1 regulates cell-substrate adhesion as part of its matricellular function. It can both promote and inhibit adhesion depending on context and receptor engagement.
GO:0016529 sarcoplasmic reticulum
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: This annotation may derive from UniProt subcellular location mapping. TSP1 is primarily known as an extracellular/secreted protein. Localization to SR may relate to expression in muscle cells during biosynthesis.
Reason: Sarcoplasmic reticulum localization is not a well-established or primary site for TSP1 function. The protein primarily functions in the extracellular space.
GO:0030335 positive regulation of cell migration
IEA
GO_REF:0000117 		ACCEPT
Summary: TSP1 can promote cell migration in certain contexts. Through calreticulin/LRP1 engagement, TSP1 triggers focal adhesion disassembly and promotes cell motility. It can also stimulate migration of fibroblasts and some tumor cells [PMID:18555217].
Reason: TSP1 has documented pro-migratory effects in specific cellular contexts, particularly through calreticulin/LRP1 signaling that promotes focal adhesion turnover. However, effects on migration are cell-type dependent.
GO:0030511 positive regulation of transforming growth factor beta receptor signaling pathway
IEA
GO_REF:0000117 		ACCEPT
Summary: TSP1 activates latent TGF-beta1 through direct binding via sequences in its type-1 repeats. This releases active TGF-beta1 which can then signal through TGF-beta receptors. This is a core function of TSP1 [deep research].
Reason: This is a well-established core function of TSP1. TSP1 is necessary to activate TGF-beta1 in vivo, and TSP1-null mice phenocopy aspects of TGF-beta1 null mice with multi-organ inflammation.
Supporting Evidence:
file:human/THBS1/THBS1-deep-research-falcon.md
Multiple 2023–2024 sources characterize THBS1/TSP‑1 as a major mediator/activator of latent TGF‑β. This function positions THBS1 upstream of profibrotic and immunoregulatory programs (e.g., Smad signaling and downstream ECM remodeling).
GO:0031012 extracellular matrix
IEA
GO_REF:0000117 		ACCEPT
Summary: Duplicate of the IBA annotation. TSP1 is a well-established ECM component.
Reason: Same term as IBA annotation - TSP1 localization to ECM is well supported.
GO:0031091 platelet alpha granule
IEA
GO_REF:0000117 		ACCEPT
Summary: TSP1 was originally discovered in platelets where it is stored in alpha granules and released upon platelet activation (e.g., by thrombin) [PMID:101549, deep research]. This is a primary storage site for TSP1.
Reason: Platelet alpha granule is a core localization for TSP1. The protein was first characterized from platelets and alpha granule storage is well-documented.
GO:0048514 blood vessel morphogenesis
IEA
GO_REF:0000117 		ACCEPT
Summary: TSP1 is involved in blood vessel morphogenesis, primarily as a negative regulator that limits vessel growth. It affects vessel density in normal tissues and curtails tumor neovascularization [PMID:10613822].
Reason: TSP1 clearly participates in blood vessel morphogenesis through its anti-angiogenic activities. The annotation is appropriate for this core function.
GO:0050840 extracellular matrix binding
IEA
GO_REF:0000117 		ACCEPT
Summary: TSP1 binds to multiple ECM components including fibronectin, fibrinogen, collagen (especially type V), laminin, and proteoglycans [PMID:6489349, PMID:6693501].
Reason: ECM binding is well-documented for TSP1. The protein interacts with numerous matrix components as part of its matricellular function.
GO:0050921 positive regulation of chemotaxis
IEA
GO_REF:0000117 		ACCEPT
Summary: TSP1 can promote chemotaxis of certain cell types, including macrophages and some endothelial cells, depending on context and receptor engagement [PMID:18555217].
Reason: TSP1 has documented chemotactic effects, particularly for monocytes/macrophages. The annotation is supported by experimental evidence.
GO:0005515 protein binding
IPI
PMID:15864306
A functional SNP in CILP, encoding cartilage intermediate la... 		MARK AS OVER ANNOTATED
Summary: This IPI annotation indicates TSP1 binds to CILP (cartilage intermediate layer protein). TSP1 interacts with numerous proteins, so binding to CILP is plausible but "protein binding" is too generic.
Reason: Generic "protein binding" annotations provide limited functional insight. While TSP1 does bind many proteins, more specific molecular function terms are preferred. The paper focuses on CILP SNP effects on disc disease susceptibility.
Supporting Evidence:
PMID:15864306
A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease.
GO:0005515 protein binding
IPI
PMID:18042364
TSG-6 binds via its CUB_C domain to the cell-binding domain ... 		MARK AS OVER ANNOTATED
Summary: This annotation relates to TSG-6 binding to fibronectin - the relevance to TSP1 is unclear from the title. TSP1 does bind fibronectin but this reference appears to be about TSG-6.
Reason: Generic "protein binding" provides limited information. The reference title mentions TSG-6, not TSP1 directly. TSP1-fibronectin binding is documented elsewhere (PMID:6489349).
Supporting Evidence:
PMID:18042364
TSG-6 binds via its CUB_C domain to the cell-binding domain of fibronectin and increases fibronectin matrix assembly.
GO:0005515 protein binding
IPI
PMID:19542224
The first draft of the endostatin interaction network. 		MARK AS OVER ANNOTATED
Summary: This annotation comes from an endostatin interaction network study. TSP1 may interact with endostatin or related proteins, but "protein binding" is too generic to be informative.
Reason: Generic protein binding annotation from an interactome study. While TSP1 interacts with many proteins, this annotation adds limited functional insight.
Supporting Evidence:
PMID:19542224
The first draft of the endostatin interaction network.
GO:0005515 protein binding
IPI
PMID:24117177
Extended interaction network of procollagen C-proteinase enh... 		MARK AS OVER ANNOTATED
Summary: This annotation derives from a study of procollagen C-proteinase enhancer-1 interactions in the ECM, indicating TSP1 participates in this interaction network.
Reason: Generic protein binding from an interaction network study. TSP1 is known to interact with many ECM proteins, but "protein binding" provides limited functional insight.
Supporting Evidence:
PMID:24117177
Extended interaction network of procollagen C-proteinase enhancer-1 in the extracellular matrix.
GO:0005615 extracellular space
IEA
GO_REF:0000120 		ACCEPT
Summary: TSP1 is secreted into the extracellular space where it functions. This is a core localization for this matricellular protein.
Reason: Extracellular space is a core localization for TSP1 as a secreted protein that functions outside the cell.
GO:0009612 response to mechanical stimulus
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: TSP1 expression may be induced by mechanical stimuli in certain tissues. This is plausible given TSP1's roles in wound healing and tissue remodeling.
Reason: While TSP1 may respond to mechanical stimuli, this is not a primary or well-characterized function. The annotation is likely based on expression data rather than direct functional involvement.
GO:0016525 negative regulation of angiogenesis
IEA
GO_REF:0000120 		ACCEPT
Summary: Duplicate of IBA annotation - negative regulation of angiogenesis is a core function of TSP1.
Reason: Same term as IBA annotation. This is a well-established core function of TSP1.
GO:0033574 response to testosterone
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: TSP1 expression may be regulated by testosterone in certain tissues. This is not a core function but may be relevant in specific physiological contexts.
Reason: Hormonal regulation of TSP1 expression is not a primary function. This likely reflects expression data from specific tissue contexts.
GO:0050431 transforming growth factor beta binding
IEA
GO_REF:0000107 		ACCEPT
Summary: TSP1 binds latent TGF-beta1 through its type-1 repeats (TSRs), which is essential for activating latent TGF-beta. The LSKL sequence in TSP1 binds the latency-associated peptide of TGF-beta [deep research].
Reason: TGF-beta binding is a core molecular function of TSP1. The type-1 repeats mediate binding to latent TGF-beta1 and its subsequent activation.
Supporting Evidence:
file:human/THBS1/THBS1-deep-research-falcon.md
TSRs are necessary for binding latent TGF‑β and CD36
GO:0071356 cellular response to tumor necrosis factor
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: TSP1 expression may be induced by TNF-alpha, and TSP1 in turn can regulate TNF-alpha production by dendritic cells [PMID:14568985].
Reason: While TSP1 may respond to TNF signaling, this is not a core function. The more relevant annotation is TSP1's effect on regulating TNF production.
GO:0071363 cellular response to growth factor stimulus
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: TSP1 expression is regulated by various growth factors and TSP1 modulates growth factor signaling (VEGF, FGF-2, TGF-beta). This broad term captures TSP1's involvement in growth factor responses.
Reason: While accurate, this is a very broad term. TSP1's specific roles in sequestering VEGF/FGF-2 and activating TGF-beta are more informative.
GO:0071636 positive regulation of transforming growth factor beta production
IEA
GO_REF:0000107 		MODIFY
Summary: TSP1 activates latent TGF-beta1 (converting inactive to active form) rather than increasing TGF-beta production per se. This annotation may conflate activation with production.
Reason: TSP1 activates pre-existing latent TGF-beta1 rather than inducing its production. A more accurate term would be related to TGF-beta activation or signaling pathway regulation.
GO:0141151 negative regulation of nitric oxide-cGMP mediated signal transduction
IDA
PMID:19004835
Differential interactions of thrombospondin-1, -2, and -4 wi... 		ACCEPT
Summary: TSP1 binding to CD47 inhibits NO-stimulated cGMP production in vascular cells. This is a well-established core function of TSP1 that affects vascular tone and platelet reactivity [PMID:19004835, deep research].
Reason: This is a core function of TSP1. TSP1-CD47 signaling antagonizes NO-cGMP signaling, leading to vasoconstriction and enhanced platelet activation. This mechanism is critical for hemostasis.
Supporting Evidence:
PMID:19004835
Differential interactions of thrombospondin-1, -2, and -4 with CD47 and effects on cGMP signaling and ischemic injury responses.
file:human/THBS1/THBS1-deep-research-falcon.md
THBS1 binds CD47 (via CTD) and triggers signaling that suppresses nitric oxide (NO) pathway effects.
GO:0072378 blood coagulation, fibrin clot formation
IDA
PMID:3997886
Incorporation of thrombospondin into fibrin clots. 		ACCEPT
Summary: TSP1 is incorporated into fibrin clots and contributes to hemostasis. Released from activated platelets, TSP1 helps stabilize clots by binding fibrinogen and fibrin [PMID:3997886].
Reason: TSP1 participation in fibrin clot formation is well-documented. The protein binds fibrinogen/fibrin and is incorporated into clots, contributing to hemostasis.
Supporting Evidence:
PMID:3997886
Incorporation of thrombospondin into fibrin clots.
file:human/THBS1/THBS1-deep-research-falcon.md
THBS1 is described as a major component of platelet α‑granules and is rapidly released at injury sites, supporting platelet activation, vasoconstriction, and thrombus formation
GO:0031012 extracellular matrix
HDA
PMID:23658023
Comparative proteomic analysis of supportive and unsupportiv... 		ACCEPT
Summary: Proteomic identification of TSP1 in ECM preparations. Consistent with its known localization as a matricellular protein.
Reason: High-throughput proteomic evidence supporting TSP1 localization in ECM. Consistent with extensive prior evidence.
Supporting Evidence:
PMID:23658023
Comparative proteomic analysis of supportive and unsupportive extracellular matrix substrates for human embryonic stem cell maintenance.
GO:0043410 positive regulation of MAPK cascade
IMP
PMID:17413041
Interaction of alpha9beta1 integrin with thrombospondin-1 pr... 		ACCEPT
Summary: TSP1 interaction with alpha9beta1 integrin can activate MAPK signaling. This is context-dependent - through different receptors TSP1 can have opposing effects on MAPK signaling [PMID:17413041].
Reason: TSP1 can positively regulate MAPK cascade through integrin engagement. This is part of its complex signaling effects that are receptor-dependent.
Supporting Evidence:
PMID:17413041
Interaction of alpha9beta1 integrin with thrombospondin-1 promotes angiogenesis.
GO:0016525 negative regulation of angiogenesis
IDA
PMID:10613822
Signals leading to apoptosis-dependent inhibition of neovasc... 		ACCEPT
Summary: Direct experimental evidence from a landmark paper showing TSP1 inhibits angiogenesis through CD36-mediated endothelial cell apoptosis. TSP1 induced apoptosis at tumor margins in vivo [PMID:10613822].
Reason: High-quality experimental evidence supporting TSP1's anti-angiogenic function. The study demonstrated the CD36-p59fyn-caspase-3-p38 MAPK signaling cascade leading to endothelial apoptosis.
Supporting Evidence:
PMID:10613822
Thrombospondin-1 (TSP-1) is a naturally occurring inhibitor of angiogenesis that limits vessel density in normal tissues and curtails tumor growth.
GO:0032693 negative regulation of interleukin-10 production
IDA
PMID:14568985
Thrombospondin 1 is an autocrine negative regulator of human... 		ACCEPT
Summary: PMID:14568985 demonstrated that endogenous TSP produced by dendritic cells negatively regulates IL-10 production through CD47 and CD36 interactions. Anti-TSP antibodies enhanced IL-10 synthesis.
Reason: Direct experimental evidence showing TSP1 negatively regulates IL-10 production by dendritic cells. This is part of TSP1's immunomodulatory function.
Supporting Evidence:
PMID:14568985
The endogenous TSP produced during early DC activation negatively regulates IL-12, TNF-alpha, and IL-10 release through its interactions with CD47 and CD36.
GO:0032695 negative regulation of interleukin-12 production
IDA
PMID:14568985
Thrombospondin 1 is an autocrine negative regulator of human... 		ACCEPT
Summary: PMID:14568985 showed that endogenous TSP negatively regulates IL-12 production by dendritic cells. Blocking TSP-CD47/CD36 interactions enhanced IL-12 synthesis.
Reason: Direct experimental evidence demonstrating TSP1 negatively regulates IL-12 production. This contributes to TSP1's immunosuppressive function.
Supporting Evidence:
PMID:14568985
The endogenous TSP produced during early DC activation negatively regulates IL-12, TNF-alpha, and IL-10 release through its interactions with CD47 and CD36.
GO:0032720 negative regulation of tumor necrosis factor production
IDA
PMID:14568985
Thrombospondin 1 is an autocrine negative regulator of human... 		ACCEPT
Summary: PMID:14568985 demonstrated that endogenous TSP negatively regulates TNF-alpha production by dendritic cells through CD47 and CD36 receptor engagement.
Reason: Direct experimental evidence showing TSP1 negatively regulates TNF-alpha production. Part of TSP1's anti-inflammatory/immunosuppressive function.
Supporting Evidence:
PMID:14568985
The endogenous TSP produced during early DC activation negatively regulates IL-12, TNF-alpha, and IL-10 release through its interactions with CD47 and CD36.
GO:0005515 protein binding
IPI
PMID:19004835
Differential interactions of thrombospondin-1, -2, and -4 wi... 		MARK AS OVER ANNOTATED
Summary: This IPI documents TSP1 interaction with CD47. The specific binding to CD47 is well-characterized but "protein binding" is too generic.
Reason: TSP1-CD47 binding is real and functionally important, but "protein binding" is uninformative. More specific receptor binding terms would be preferable.
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:24511121
Thrombospondin-1 activation of signal-regulatory protein-Ξ± s... 		MARK AS OVER ANNOTATED
Summary: IPI documents TSP1 interaction with SIRPalpha. This represents a specific receptor interaction but "protein binding" is too generic.
Reason: TSP1-SIRPalpha binding is documented but "protein binding" is uninformative.
Supporting Evidence:
PMID:24511121
Thrombospondin-1 activation of signal-regulatory protein-Ξ± stimulates reactive oxygen species production and promotes renal ischemia reperfusion injury.
GO:2000379 positive regulation of reactive oxygen species metabolic process
IDA
PMID:24511121
Thrombospondin-1 activation of signal-regulatory protein-Ξ± s... 		KEEP AS NON CORE
Summary: TSP1 activation of SIRPalpha stimulates ROS production. This is documented in the context of renal ischemia-reperfusion injury [PMID:24511121].
Reason: While TSP1 can stimulate ROS production through SIRPalpha signaling, this is a context-dependent effect rather than a core function of the protein.
Supporting Evidence:
PMID:24511121
Thrombospondin-1 activation of signal-regulatory protein-Ξ± stimulates reactive oxygen species production and promotes renal ischemia reperfusion injury.
GO:0001968 fibronectin binding
IDA
PMID:6489349
Thrombospondin interactions with fibronectin and fibrinogen.... 		ACCEPT
Summary: TSP1 directly binds fibronectin. This interaction is well-characterized and relevant to TSP1's ECM functions [PMID:6489349].
Reason: Fibronectin binding is a well-documented molecular function of TSP1, contributing to its role in ECM organization and cell adhesion.
Supporting Evidence:
PMID:6489349
Thrombospondin interactions with fibronectin and fibrinogen.
GO:0005515 protein binding
IPI
PMID:2478219
An integrin receptor on normal and thrombasthenic platelets ... 		MARK AS OVER ANNOTATED
Summary: IPI documenting TSP1 binding to integrin receptors on platelets. The specific integrin binding is more informative than generic protein binding.
Reason: This documents integrin binding which is real but "protein binding" is too generic. The integrin binding annotation is more informative.
Supporting Evidence:
PMID:2478219
An integrin receptor on normal and thrombasthenic platelets that binds thrombospondin.
GO:0005515 protein binding
IPI
PMID:8550562
Integrin-associated protein is a receptor for the C-terminal... 		MARK AS OVER ANNOTATED
Summary: IPI documenting TSP1 binding to CD47 (integrin-associated protein). This is a critical receptor interaction for TSP1's vascular signaling functions.
Reason: TSP1-CD47 binding is critically important for TSP1 function but "protein binding" is uninformative. A CD47 receptor binding term would be more specific.
Supporting Evidence:
PMID:8550562
Integrin-associated protein is a receptor for the C-terminal domain of thrombospondin.
GO:0031012 extracellular matrix
IDA
PMID:18285447
Extracellular matrix retention of thrombospondin 1 is contro... 		ACCEPT
Summary: Direct evidence for TSP1 localization in the ECM. The study characterized how TSP1's C-terminal region controls its retention in the ECM.
Reason: Direct experimental evidence for TSP1 ECM localization, consistent with its established role as a matricellular protein.
Supporting Evidence:
PMID:18285447
Extracellular matrix retention of thrombospondin 1 is controlled by its conserved C-terminal region.
GO:0070051 fibrinogen binding
IDA
PMID:6489349
Thrombospondin interactions with fibronectin and fibrinogen.... 		ACCEPT
Summary: TSP1 directly binds fibrinogen. This interaction is important for TSP1's role in hemostasis and clot formation [PMID:6489349].
Reason: Fibrinogen binding is a well-documented molecular function of TSP1, relevant to its role in hemostasis and clot stabilization.
Supporting Evidence:
PMID:6489349
Thrombospondin interactions with fibronectin and fibrinogen.
GO:0005201 extracellular matrix structural constituent
RCA
PMID:23979707
SILAC-based proteomics of human primary endothelial cell mor... 		MODIFY
Summary: TSP1 was identified in ECM proteomics. However, TSP1 is a matricellular protein (regulatory) rather than a structural constituent of ECM.
Reason: TSP1 is a matricellular protein that modulates cell-matrix interactions rather than forming structural fibers. "ECM structural constituent" implies a structural role that is not accurate for TSP1.
Proposed replacements: extracellular matrix
Supporting Evidence:
PMID:23979707
SILAC-based proteomics of human primary endothelial cell morphogenesis unveils tumor angiogenic markers.
GO:0016525 negative regulation of angiogenesis
IDA
PMID:23896411
Thrombospondin-1 modulates VEGF signaling via CD36 by recrui... 		ACCEPT
Summary: TSP1 inhibits angiogenesis by modulating VEGF signaling through CD36. The study showed TSP1 recruits SHP-1 phosphatase to VEGFR2, attenuating VEGF signaling [PMID:23896411].
Reason: Strong experimental evidence for TSP1's anti-angiogenic mechanism involving CD36-mediated attenuation of VEGF receptor signaling.
Supporting Evidence:
PMID:23896411
Thrombospondin-1 modulates VEGF signaling via CD36 by recruiting SHP-1 to VEGFR2 complex in microvascular endothelial cells.
GO:0031012 extracellular matrix
IDA
PMID:6341993
Cultured human fibroblasts synthesize and secrete thrombospo... 		ACCEPT
Summary: Classic study demonstrating fibroblasts synthesize TSP1 and incorporate it into the ECM [PMID:6341993]. Foundational evidence for TSP1 ECM localization.
Reason: Direct experimental evidence for TSP1 secretion and incorporation into ECM by fibroblasts.
Supporting Evidence:
PMID:6341993
Cultured human fibroblasts synthesize and secrete thrombospondin and incorporate it into extracellular matrix.
GO:0038060 nitric oxide-cGMP-mediated signaling
IDA
PMID:17416590
Thrombospondin-1 inhibits nitric oxide signaling via CD36 by... 		ACCEPT
Summary: TSP1 is involved in NO-cGMP signaling, specifically as an inhibitor of this pathway. TSP1 inhibits NO signaling via CD36 by inhibiting myristic acid uptake required for eNOS myristoylation [PMID:17416590].
Reason: TSP1 participates in NO-cGMP signaling as a negative regulator. The annotation captures TSP1's involvement in this pathway.
Supporting Evidence:
PMID:17416590
Thrombospondin-1 inhibits nitric oxide signaling via CD36 by inhibiting myristic acid uptake.
GO:0002020 protease binding
IPI
PMID:7679575
Characterization of the antiplasmin activity of human thromb... 		ACCEPT
Summary: TSP1 binds plasmin and has antiplasmin activity. This contributes to regulation of fibrinolysis [PMID:7679575].
Reason: TSP1 binding to plasmin is well-documented and functionally relevant to its role in regulating fibrinolysis.
Supporting Evidence:
PMID:7679575
Characterization of the antiplasmin activity of human thrombospondin-1 in solution.
GO:0004866 endopeptidase inhibitor activity
IDA
PMID:7679575
Characterization of the antiplasmin activity of human thromb... 		ACCEPT
Summary: TSP1 has antiplasmin activity, inhibiting the serine protease plasmin. This contributes to regulation of fibrinolysis [PMID:7679575].
Reason: TSP1's endopeptidase inhibitor activity against plasmin is documented and functionally relevant.
Supporting Evidence:
PMID:7679575
Characterization of the antiplasmin activity of human thrombospondin-1 in solution.
GO:0042803 protein homodimerization activity
IPI
PMID:7679575
Characterization of the antiplasmin activity of human thromb... 		MODIFY
Summary: TSP1 forms homotrimers (not homodimers). The term "homodimerization" may be inaccurate - TSP1 is a homotrimeric protein.
Reason: TSP1 forms homotrimers via disulfide bonds in the coiled-coil region, not homodimers. A more accurate term would reflect homo-oligomerization.
Proposed replacements: protein homooligomerization
Supporting Evidence:
PMID:7679575
Characterization of the antiplasmin activity of human thrombospondin-1 in solution.
GO:0001968 fibronectin binding
IDA
PMID:18042364
TSG-6 binds via its CUB_C domain to the cell-binding domain ... 		ACCEPT
Summary: The reference title mentions TSG-6, not TSP1 directly. TSP1 fibronectin binding is well-documented elsewhere (PMID:6489349). This annotation may be misattributed.
Reason: TSP1 fibronectin binding is well-established from other studies even if this specific reference may be misattributed.
Supporting Evidence:
PMID:18042364
TSG-6 binds via its CUB_C domain to the cell-binding domain of fibronectin and increases fibronectin matrix assembly.
GO:0008285 negative regulation of cell population proliferation
IDA
PMID:17596205
Novel antiangiogenic pathway of thrombospondin-1 mediated by... 		ACCEPT
Summary: TSP1 inhibits cell proliferation, particularly of endothelial cells, as part of its anti-angiogenic mechanism. The study revealed cell cycle suppression as a mechanism [PMID:17596205].
Reason: TSP1's anti-proliferative effect on endothelial cells is well-documented and contributes to its anti-angiogenic function.
Supporting Evidence:
PMID:17596205
Novel antiangiogenic pathway of thrombospondin-1 mediated by suppression of the cell cycle.
GO:0005201 extracellular matrix structural constituent
HDA
PMID:28344315
Proteomic characterization of human multiple myeloma bone ma... 		MODIFY
Summary: TSP1 identified in ECM proteomics. However, TSP1 is matricellular (regulatory) rather than a structural ECM constituent.
Reason: TSP1 is not a structural ECM component. It modulates cell-matrix interactions but does not form structural fibers. Localization term is more appropriate.
Proposed replacements: extracellular matrix
Supporting Evidence:
PMID:28344315
Proteomic characterization of human multiple myeloma bone marrow extracellular matrix.
GO:0005201 extracellular matrix structural constituent
RCA
PMID:28327460
Comprehensive proteomic characterization of stem cell-derive... 		MODIFY
Summary: TSP1 identified in ECM proteomics. TSP1 is matricellular rather than structural.
Reason: TSP1 is not a structural ECM component.
Proposed replacements: extracellular matrix
Supporting Evidence:
PMID:28327460
Comprehensive proteomic characterization of stem cell-derived extracellular matrices.
GO:0031012 extracellular matrix
HDA
PMID:28327460
Comprehensive proteomic characterization of stem cell-derive... 		ACCEPT
Summary: Proteomic evidence for TSP1 in ECM. Consistent with its established localization.
Reason: HDA evidence supporting TSP1 ECM localization.
Supporting Evidence:
PMID:28327460
Comprehensive proteomic characterization of stem cell-derived extracellular matrices.
GO:0031012 extracellular matrix
HDA
PMID:28344315
Proteomic characterization of human multiple myeloma bone ma... 		ACCEPT
Summary: Proteomic evidence for TSP1 in ECM from bone marrow samples.
Reason: HDA evidence supporting TSP1 ECM localization.
Supporting Evidence:
PMID:28344315
Proteomic characterization of human multiple myeloma bone marrow extracellular matrix.
GO:0005201 extracellular matrix structural constituent
ISS
GO_REF:0000024 		MODIFY
Summary: TSP1 is a matricellular protein (regulatory) rather than a structural ECM component. This term is inaccurate for TSP1.
Reason: TSP1 modulates cell-matrix interactions but does not form structural fibers like collagens or elastin. ECM localization is accurate; structural role is not.
Proposed replacements: extracellular matrix
GO:0005201 extracellular matrix structural constituent
RCA
PMID:20551380
Proteomics characterization of extracellular space component... 		MODIFY
Summary: TSP1 identified in aorta ECM proteomics. TSP1 is matricellular, not structural.
Reason: TSP1 is not a structural ECM component.
Proposed replacements: extracellular matrix
Supporting Evidence:
PMID:20551380
Proteomics characterization of extracellular space components in the human aorta.
GO:0005576 extracellular region
HDA
PMID:27068509
Extracellular matrix remodelling in response to venous hyper... 		ACCEPT
Summary: Proteomic evidence for TSP1 in extracellular region from varicose vein samples.
Reason: HDA evidence supporting TSP1 extracellular localization.
Supporting Evidence:
PMID:27068509
Extracellular matrix remodelling in response to venous hypertension
GO:0005615 extracellular space
HDA
PMID:20551380
Proteomics characterization of extracellular space component... 		ACCEPT
Summary: Proteomic evidence for TSP1 in extracellular space from aorta samples.
Reason: HDA evidence supporting TSP1 extracellular localization.
Supporting Evidence:
PMID:20551380
Proteomics characterization of extracellular space components in the human aorta.
GO:0031012 extracellular matrix
HDA
PMID:20551380
Proteomics characterization of extracellular space component... 		ACCEPT
Summary: Proteomic evidence for TSP1 in ECM from aorta samples.
Reason: HDA evidence supporting TSP1 ECM localization.
Supporting Evidence:
PMID:20551380
Proteomics characterization of extracellular space components in the human aorta.
GO:1903671 negative regulation of sprouting angiogenesis
IGI
PMID:28124060
Bone morphogenetic protein 4 regulates microRNAs miR-494 and... 		ACCEPT
Summary: TSP1 inhibits sprouting angiogenesis. This study examined BMP4 regulation of miRNAs that affect endothelial function, with TSP1 involvement.
Reason: TSP1 inhibition of sprouting angiogenesis is consistent with its well-established anti-angiogenic function.
Supporting Evidence:
PMID:28124060
Bone morphogenetic protein 4 regulates microRNAs miR-494 and miR-126-5p in control of endothelial cell function in angiogenesis.
GO:0031012 extracellular matrix
ISS
PMID:22261194
Proteomics analysis of cardiac extracellular matrix remodeli... 		ACCEPT
Summary: Proteomic identification of TSP1 in cardiac ECM.
Reason: Evidence supporting TSP1 ECM localization from cardiac tissue.
Supporting Evidence:
PMID:22261194
Proteomics analysis of cardiac extracellular matrix remodeling in a porcine model of ischemia/reperfusion injury.
GO:0016525 negative regulation of angiogenesis
IMP
PMID:24177325
MicroRNA miR-27b rescues bone marrow-derived angiogenic cell... 		ACCEPT
Summary: Study examining miR-27b effects on angiogenesis and wound healing, with TSP1 as a target. Consistent with TSP1's anti-angiogenic role.
Reason: Supports TSP1's role in negative regulation of angiogenesis.
Supporting Evidence:
PMID:24177325
MicroRNA miR-27b rescues bone marrow-derived angiogenic cell function and accelerates wound healing in type 2 diabetes mellitus.
GO:0090051 negative regulation of cell migration involved in sprouting angiogenesis
IMP
PMID:25660232
miR-487b promotes human umbilical vein endothelial cell prol... 		ACCEPT
Summary: Study showing miR-487b targets THBS1 to promote endothelial cell migration, implying THBS1 normally inhibits this migration.
Reason: Consistent with TSP1's role in inhibiting endothelial cell migration as part of its anti-angiogenic function.
Supporting Evidence:
PMID:25660232
miR-487b promotes human umbilical vein endothelial cell proliferation, migration, invasion and tube formation through regulating THBS1.
GO:1903588 negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis
IMP
PMID:25660232
miR-487b promotes human umbilical vein endothelial cell prol... 		ACCEPT
Summary: Study showing miR-487b targets THBS1 to promote endothelial proliferation, implying THBS1 normally inhibits proliferation.
Reason: Consistent with TSP1's role in inhibiting endothelial cell proliferation.
Supporting Evidence:
PMID:25660232
miR-487b promotes human umbilical vein endothelial cell proliferation, migration, invasion and tube formation through regulating THBS1.
GO:0031012 extracellular matrix
HDA
PMID:23979707
SILAC-based proteomics of human primary endothelial cell mor... 		ACCEPT
Summary: Proteomic evidence for TSP1 in ECM from endothelial cell studies.
Reason: HDA evidence supporting TSP1 ECM localization.
Supporting Evidence:
PMID:23979707
SILAC-based proteomics of human primary endothelial cell morphogenesis unveils tumor angiogenic markers.
GO:0008284 positive regulation of cell population proliferation
IDA
PMID:24615654
Interleukin-18 may lead to benign prostatic hyperplasia via ... 		KEEP AS NON CORE
Summary: Study suggesting TSP1 may promote proliferation of prostatic smooth muscle cells. This is context-dependent - TSP1 can have opposing effects on proliferation depending on cell type.
Reason: TSP1's effect on proliferation is cell-type dependent. In endothelial cells it inhibits proliferation; in smooth muscle it may promote. Not a core function.
Supporting Evidence:
PMID:24615654
Interleukin-18 may lead to benign prostatic hyperplasia via thrombospondin-1 production in prostatic smooth muscle cells.
GO:0048661 positive regulation of smooth muscle cell proliferation
IDA
PMID:24615654
Interleukin-18 may lead to benign prostatic hyperplasia via ... 		KEEP AS NON CORE
Summary: Study suggesting TSP1 may promote smooth muscle cell proliferation in prostate tissue. Cell-type specific effect.
Reason: Context-dependent effect on smooth muscle cells. Not a core function of TSP1.
Supporting Evidence:
PMID:24615654
Interleukin-18 may lead to benign prostatic hyperplasia via thrombospondin-1 production in prostatic smooth muscle cells.
GO:0005615 extracellular space
IDA
PMID:26395742
Angiogenic microRNAs Linked to Incidence and Progression of ... 		ACCEPT
Summary: TSP1 is a secreted protein that localizes to the extracellular space. This study examined angiogenic miRNAs in diabetic retinopathy, where TSP1 would be present in the extracellular milieu.
Reason: Extracellular space is a core localization for TSP1 as a secreted matricellular protein.
Supporting Evidence:
PMID:26395742
Angiogenic microRNAs Linked to Incidence and Progression of Diabetic Retinopathy in Type 1 Diabetes.
GO:0005515 protein binding
IPI
PMID:26627825
Extracellular Fibrinogen-binding Protein (Efb) from Staphylo... 		MARK AS OVER ANNOTATED
Summary: This IPI documents TSP1 interaction with Staphylococcus aureus extracellular fibrinogen-binding protein (Efb). While TSP1 does bind fibrinogen and participate in platelet-leukocyte complexes, "protein binding" is too generic.
Reason: Generic "protein binding" provides limited functional insight. The study examines bacterial protein interactions in platelet biology.
Supporting Evidence:
PMID:26627825
Extracellular Fibrinogen-binding Protein (Efb) from Staphylococcus aureus Inhibits the Formation of Platelet-Leukocyte Complexes.
GO:0001937 negative regulation of endothelial cell proliferation
IDA
PMID:16150726
Thrombospondin-1 inhibits endothelial cell responses to nitr... 		ACCEPT
Summary: PMID:16150726 demonstrated that TSP1 inhibits NO-stimulated endothelial cell proliferation at picomolar concentrations. The study showed that "proliferation stimulated by 10 ΞΌM DETA/NO was inhibited by 50% at <22 pM TSP1" in multiple endothelial cell types.
Reason: Strong direct experimental evidence showing TSP1 inhibits endothelial cell proliferation via antagonism of NO/cGMP signaling. This is a core anti-angiogenic function of TSP1.
Supporting Evidence:
PMID:16150726
proliferation stimulated by 10 ΞΌM DETA/NO was inhibited by 50% at <22 pM TSP1
GO:0001953 negative regulation of cell-matrix adhesion
IDA
PMID:16150726
Thrombospondin-1 inhibits endothelial cell responses to nitr... 		ACCEPT
Summary: PMID:16150726 showed that TSP1 potently inhibits NO-stimulated endothelial cell adhesion to collagen substrates. Exogenous TSP1 at <2.2 pM abrogated NO-stimulated cell adhesion and reversed effects on cell spreading.
Reason: Direct experimental evidence showing TSP1 inhibits cell-matrix adhesion through antagonism of NO/cGMP signaling. This is mediated by the type-1 repeats (TSRs) via CD36.
Supporting Evidence:
PMID:16150726
Exogenous TSP1 at <2.2 pM abrogated the stimulation by NO of cell adhesion to collagen
GO:0010751 negative regulation of nitric oxide mediated signal transduction
IDA
PMID:16150726
Thrombospondin-1 inhibits endothelial cell responses to nitr... 		ACCEPT
Summary: PMID:16150726 demonstrated that TSP1 is a potent inhibitor of NO signaling. TSP1 inhibits NO-stimulated cGMP accumulation and downstream signaling. The study showed "Addition of 100 pM TSP1 prevented the NO-stimulated increase in cGMP."
Reason: This is a core function of TSP1. The study provided strong evidence that TSP1 inhibits NO signaling both upstream (cGMP synthesis) and downstream of cGMP. This is mediated via CD36 and the type-1 repeats.
Supporting Evidence:
PMID:16150726
Addition of 100 pM TSP1 prevented the NO-stimulated increase in cGMP
file:human/THBS1/THBS1-deep-research-falcon.md
THBS1-CD47 signaling antagonizes NO/cGMP-dependent signaling, with consequences for vascular smooth muscle relaxation/vasodilation and ischemic survival.
GO:0016525 negative regulation of angiogenesis
IDA
PMID:16150726
Thrombospondin-1 inhibits endothelial cell responses to nitr... 		ACCEPT
Summary: PMID:16150726 demonstrated TSP1 inhibits angiogenesis by antagonizing NO/cGMP signaling. TSP1-null muscle explants showed exaggerated angiogenic responses to NO that were reversed by adding exogenous TSP1.
Reason: Strong experimental evidence for TSP1's anti-angiogenic function through inhibition of NO-cGMP signaling in endothelial cells.
Supporting Evidence:
PMID:16150726
explants from mice lacking the angiogenesis inhibitor thrombospondin-1 (TSP1) exhibit exaggerated angiogenic responses to an exogenous NO donor, which could be reversed by providing exogenous TSP1
GO:2001027 negative regulation of endothelial cell chemotaxis
IDA
PMID:16150726
Thrombospondin-1 inhibits endothelial cell responses to nitr... 		ACCEPT
Summary: PMID:16150726 showed TSP1 potently inhibits NO-stimulated endothelial cell chemotaxis. "TSP1 inhibited HUVEC chemotaxis stimulated by 10 ΞΌM DETA/NO with an IC50 of 7 pM."
Reason: Strong direct experimental evidence showing TSP1 inhibits endothelial cell chemotaxis through antagonism of NO signaling via the type-1 repeats. This is a core anti-angiogenic function.
Supporting Evidence:
PMID:16150726
TSP1 inhibited HUVEC chemotaxis stimulated by 10 ΞΌM DETA/NO with an IC 50 of 7 pM
GO:0070062 extracellular exosome
HDA
PMID:23533145
In-depth proteomic analyses of exosomes isolated from expres... 		ACCEPT
Summary: Proteomic identification of TSP1 in exosomes from prostatic secretions. As a secreted protein, TSP1 can be incorporated into exosomes.
Reason: HDA evidence supporting TSP1 presence in extracellular exosomes. This is consistent with TSP1 being a secreted protein that can associate with various extracellular vesicles.
Supporting Evidence:
PMID:23533145
In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
GO:0005615 extracellular space
HDA
PMID:16502470
Human colostrum: identification of minor proteins in the aqu... 		ACCEPT
Summary: Proteomic identification of TSP1 in human colostrum, consistent with its presence in extracellular fluids as a secreted protein.
Reason: HDA evidence supporting TSP1 presence in extracellular space. Consistent with its known localization as a secreted protein.
Supporting Evidence:
PMID:16502470
Human colostrum: identification of minor proteins in the aqueous phase by proteomics.
GO:0005788 endoplasmic reticulum lumen
TAS
Reactome:R-HSA-5173005 		ACCEPT
Summary: TSP1 transits through the ER lumen during biosynthesis as a secreted protein. It undergoes post-translational modifications including glycosylation and disulfide bond formation in the ER.
Reason: As a secreted protein, TSP1 passes through the ER lumen during synthesis. Reactome evidence for secretory pathway transit.
GO:0005788 endoplasmic reticulum lumen
TAS
Reactome:R-HSA-5173192 		ACCEPT
Summary: Duplicate Reactome evidence for TSP1 transit through ER lumen during biosynthesis.
Reason: TSP1 passes through the ER lumen as part of the secretory pathway.
GO:0005788 endoplasmic reticulum lumen
TAS
Reactome:R-HSA-6785565 		ACCEPT
Summary: Reactome evidence for TSP1 presence in ER lumen during protein maturation and secretion.
Reason: TSP1 transits through the ER lumen as a secreted protein.
GO:0070062 extracellular exosome
HDA
PMID:19199708
Proteomic analysis of human parotid gland exosomes by multid... 		ACCEPT
Summary: Proteomic identification of TSP1 in parotid gland exosomes.
Reason: HDA evidence supporting TSP1 presence in extracellular exosomes. Consistent with TSP1 being a secreted protein.
Supporting Evidence:
PMID:19199708
Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).
GO:0070062 extracellular exosome
HDA
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exos... 		ACCEPT
Summary: Proteomic identification of TSP1 in urinary exosomes.
Reason: HDA evidence supporting TSP1 presence in extracellular exosomes.
Supporting Evidence:
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exosomes.
GO:0005783 endoplasmic reticulum
ISS
GO_REF:0000024 		ACCEPT
Summary: TSP1 transits through the ER during biosynthesis as a secreted protein. It is synthesized with a signal peptide and processed in the ER before secretion.
Reason: As a secreted protein, TSP1 passes through the ER during synthesis. This is a transit compartment, not a site of function.
GO:0016529 sarcoplasmic reticulum
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Sarcoplasmic reticulum localization is not a primary site for TSP1. This annotation may relate to ER localization in muscle cells during biosynthesis. TSP1 primarily functions extracellularly.
Reason: Not a primary site of TSP1 function. The protein is secreted and functions in the extracellular space.
GO:0034976 response to endoplasmic reticulum stress
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: TSP1 expression may be induced during ER stress, but this is not a well-characterized core function of TSP1.
Reason: While TSP1 may be upregulated during ER stress, response to ER stress is not a primary function. This is likely a secondary transcriptional effect rather than a direct mechanistic role.
GO:0048266 behavioral response to pain
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: TSP1 may have indirect effects on pain responses through its effects on inflammation and vascular function, but this is not a primary function of the protein.
Reason: Behavioral response to pain is not a well-characterized direct function of TSP1. Any effect would be indirect through its roles in inflammation or vascular regulation.
GO:1902043 positive regulation of extrinsic apoptotic signaling pathway via death domain receptors
IDA
PMID:18726995
Thrombospondin-1-induced apoptosis of brain microvascular en... 		ACCEPT
Summary: PMID:18726995 showed TSP1 induces apoptosis of brain microvascular endothelial cells through TNF-R1 (a death domain receptor). This is part of TSP1's anti-angiogenic mechanism.
Reason: Direct experimental evidence for TSP1 promoting extrinsic apoptosis via TNF-R1. This is consistent with TSP1's known pro-apoptotic effects on endothelial cells.
Supporting Evidence:
PMID:18726995
Thrombospondin-1-induced apoptosis of brain microvascular endothelial cells can be mediated by TNF-R1.
GO:2001237 negative regulation of extrinsic apoptotic signaling pathway
TAS
PMID:17879962
Syndecan-4 contributes to endothelial tubulogenesis through ... 		KEEP AS NON CORE
Summary: The N-terminal domain of TSP1 can promote cell survival through interactions with calreticulin/LRP1, which signals resistance to anoikis. This study shows syndecan-4 interactions with TSP1's N-terminal pro-angiogenic domain.
Reason: TSP1 can have both pro-apoptotic (via CD36) and anti-apoptotic (via calreticulin/LRP1) effects depending on the receptor engaged. The anti-apoptotic effect through the N-terminal domain is a context-dependent function.
Supporting Evidence:
PMID:17879962
Syndecan-4 contributes to endothelial tubulogenesis through interactions with two motifs inside the pro-angiogenic N-terminal domain of thrombospondin-1.
GO:0009986 cell surface
IDA
PMID:2435757
Isolation of the thrombospondin membrane receptor. 		ACCEPT
Summary: TSP1 binds to cell surface receptors and can accumulate on cell membranes. This classic study isolated the thrombospondin membrane receptor, demonstrating TSP1 cell surface association.
Reason: Direct experimental evidence for TSP1 association with cell surface through receptor binding. This is a core localization for TSP1 as it interacts with membrane receptors (CD36, CD47, integrins).
Supporting Evidence:
PMID:2435757
Isolation of the thrombospondin membrane receptor.
GO:0009986 cell surface
IDA
PMID:3084490
Interaction of thrombospondin with resting and stimulated hu... 		ACCEPT
Summary: Classic study showing TSP1 binds to platelet surfaces. Upon platelet activation, TSP1 is released from alpha granules and binds to the platelet cell surface.
Reason: Direct evidence for TSP1 association with platelet cell surface. This is a well-established localization for TSP1.
Supporting Evidence:
PMID:3084490
Interaction of thrombospondin with resting and stimulated human platelets.
GO:0009986 cell surface
IDA
PMID:6777381
Ca2+-mediated association of glycoprotein G (thrombinsensiti... 		ACCEPT
Summary: Classic study showing TSP1 (called glycoprotein G at the time) binds to platelet surfaces in a Ca2+-dependent manner.
Reason: Early foundational evidence for TSP1 association with platelet cell surface through calcium-dependent binding.
Supporting Evidence:
PMID:6777381
Ca2+-mediated association of glycoprotein G (thrombinsensitive protein, thrombospondin) with human platelets.
GO:2000353 positive regulation of endothelial cell apoptotic process
IDA
PMID:18726995
Thrombospondin-1-induced apoptosis of brain microvascular en... 		ACCEPT
Summary: PMID:18726995 showed TSP1 induces apoptosis of brain microvascular endothelial cells via TNF-R1 signaling. This is a key mechanism of TSP1's anti-angiogenic function.
Reason: Direct experimental evidence for TSP1 promoting endothelial cell apoptosis. This is a core anti-angiogenic function of TSP1, also demonstrated via CD36 in other studies [PMID:10613822].
Supporting Evidence:
PMID:18726995
Thrombospondin-1-induced apoptosis of brain microvascular endothelial cells can be mediated by TNF-R1.
GO:0031093 platelet alpha granule lumen
TAS
Reactome:R-HSA-481007 		ACCEPT
Summary: TSP1 is stored in platelet alpha granule lumen and released upon platelet activation. This is a well-established storage site.
Reason: Platelet alpha granule lumen is a core storage localization for TSP1. The protein was first characterized from platelets and this localization is well-documented.
Supporting Evidence:
file:human/THBS1/THBS1-deep-research-falcon.md
THBS1 is described as a major component of platelet Ξ±-granules and is rapidly released at injury sites
GO:0031093 platelet alpha granule lumen
TAS
Reactome:R-HSA-8936995 		ACCEPT
Summary: Duplicate Reactome evidence for TSP1 storage in platelet alpha granule lumen.
Reason: TSP1 storage in platelet alpha granules is well-established.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-265429 		ACCEPT
Summary: Reactome evidence for TSP1 localization in the extracellular region.
Reason: Extracellular region is a core localization for TSP1 as a secreted matricellular protein.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-349603 		ACCEPT
Summary: Reactome evidence for TSP1 in extracellular region.
Reason: Core localization for TSP1 as a secreted protein.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-382054 		ACCEPT
Summary: Reactome evidence for TSP1 in extracellular region.
Reason: Core localization for TSP1 as a secreted protein.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-481007 		ACCEPT
Summary: Reactome evidence for TSP1 in extracellular region.
Reason: Core localization for TSP1 as a secreted protein.
GO:0005576 extracellular region
TAS
Reactome:R-NUL-2731112 		ACCEPT
Summary: Reactome evidence for TSP1 in extracellular region.
Reason: Core localization for TSP1 as a secreted protein.
GO:0070062 extracellular exosome
HDA
PMID:21362503
Protein profile of exosomes from trabecular meshwork cells. 		ACCEPT
Summary: Proteomic identification of TSP1 in exosomes from trabecular meshwork cells.
Reason: HDA evidence supporting TSP1 presence in extracellular exosomes.
Supporting Evidence:
PMID:21362503
Protein profile of exosomes from trabecular meshwork cells.
GO:0006954 inflammatory response
IDA
PMID:23144964
Endogenous thrombospondin-1 regulates leukocyte recruitment ... 		ACCEPT
Summary: Study showing TSP1 regulates leukocyte recruitment and activation during systemic candidiasis, indicating TSP1 is involved in inflammatory responses. TSP1 accelerated death from infection.
Reason: Direct experimental evidence for TSP1 involvement in inflammatory response. TSP1 modulates inflammation through multiple mechanisms including TGF-beta activation and cytokine regulation.
Supporting Evidence:
PMID:23144964
Endogenous thrombospondin-1 regulates leukocyte recruitment and activation and accelerates death from systemic candidiasis.
GO:0017134 fibroblast growth factor binding
IDA
PMID:17996481
Fibroblast growth factor-2 binding to the thrombospondin-1 t... 		ACCEPT
Summary: PMID:17996481 demonstrated that FGF-2 binds to the type III repeats of TSP1. This binding sequesters FGF-2 and contributes to TSP1's anti-angiogenic function.
Reason: Direct experimental evidence for TSP1 binding FGF-2. This is a core molecular function that contributes to TSP1's anti-angiogenic activity by sequestering pro-angiogenic growth factors.
Supporting Evidence:
PMID:17996481
Fibroblast growth factor-2 binding to the thrombospondin-1 type III repeats, a novel antiangiogenic domain.
GO:0005515 protein binding
IPI
PMID:11134179
Histidine-rich glycoprotein inhibits the antiangiogenic effe... 		MARK AS OVER ANNOTATED
Summary: Study showing histidine-rich glycoprotein (HRG) binds TSP1 and inhibits its anti-angiogenic effect. While the interaction is documented, "protein binding" is too generic.
Reason: Generic "protein binding" provides limited functional insight. The specific TSP1-HRG interaction is documented but a more specific term would be more informative.
Supporting Evidence:
PMID:11134179
Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1.
GO:2000379 positive regulation of reactive oxygen species metabolic process
IDA
PMID:18757424
Thrombospondin 1 promotes tumor macrophage recruitment and e... 		KEEP AS NON CORE
Summary: TSP1 enhances tumor cell cytotoxicity through macrophage activation, which involves ROS production. This is a context-dependent effect in tumor microenvironments.
Reason: ROS regulation by TSP1 is context-dependent and secondary to its effects on macrophage activation, not a core function of the protein.
Supporting Evidence:
PMID:18757424
Thrombospondin 1 promotes tumor macrophage recruitment and enhances tumor cell cytotoxicity of differentiated U937 cells.
GO:0008201 heparin binding
IDA
PMID:8288588
Thrombospondin 3 is a developmentally regulated heparin bind... 		ACCEPT
Summary: Note: This reference is about thrombospondin-3 (THBS3), not THBS1. However, TSP1 does have heparin binding activity through its N-terminal domain, well-documented in other studies.
Reason: Heparin binding is a well-documented property of TSP1. The N-terminal domain contains a heparin-binding region. This annotation is valid for TSP1 even though the specific reference is about TSP3.
Supporting Evidence:
PMID:8288588
Thrombospondin 3 is a developmentally regulated heparin binding protein.
GO:0001786 phosphatidylserine binding
IDA
PMID:18940719
Phosphatidylserine-positive erythrocytes bind to immobilized... 		ACCEPT
Summary: Study showing that phosphatidylserine-exposing erythrocytes bind to TSP1 via its heparin-binding domain. This mediates clearance of damaged/apoptotic cells.
Reason: Direct experimental evidence for TSP1 binding phosphatidylserine. This function is relevant to TSP1's roles in hemostasis and clearance of apoptotic cells.
Supporting Evidence:
PMID:18940719
Phosphatidylserine-positive erythrocytes bind to immobilized and soluble thrombospondin-1 via its heparin-binding domain.
GO:0005515 protein binding
IPI
PMID:18688696
Calumenin but not reticulocalbin forms a Ca2+-dependent comp... 		MARK AS OVER ANNOTATED
Summary: Study showing calumenin forms a Ca2+-dependent complex with TSP1. While this interaction is documented, "protein binding" is too generic.
Reason: Generic "protein binding" provides limited functional insight. The specific TSP1-calumenin interaction is documented.
Supporting Evidence:
PMID:18688696
Calumenin but not reticulocalbin forms a Ca2+-dependent complex with thrombospondin-1.
GO:0009410 response to xenobiotic stimulus
IEP
PMID:19738618
Induction of thrombospondin-1 partially mediates the anti-an... 		KEEP AS NON CORE
Summary: TSP1 expression is induced by dexrazoxane (a xenobiotic drug), which contributes to the drug's anti-angiogenic activity.
Reason: TSP1 expression may be induced by xenobiotics, but this is not a core function. This is an IEP (expression pattern) annotation reflecting transcriptional regulation rather than direct function.
Supporting Evidence:
PMID:19738618
Induction of thrombospondin-1 partially mediates the anti-angiogenic activity of dexrazoxane.
GO:0016525 negative regulation of angiogenesis
IDA
PMID:18726995
Thrombospondin-1-induced apoptosis of brain microvascular en... 		ACCEPT
Summary: Study showing TSP1 induces apoptosis of brain microvascular endothelial cells via TNF-R1, contributing to anti-angiogenesis.
Reason: Direct experimental evidence for TSP1's anti-angiogenic function through induction of endothelial cell apoptosis.
Supporting Evidence:
PMID:18726995
Thrombospondin-1-induced apoptosis of brain microvascular endothelial cells can be mediated by TNF-R1.
GO:0032760 positive regulation of tumor necrosis factor production
IDA
PMID:18726995
Thrombospondin-1-induced apoptosis of brain microvascular en... 		UNDECIDED
Summary: Study showed TSP1-induced endothelial apoptosis involves TNF-R1. Note: This study shows TSP1 signals through TNF-R1, but does not clearly demonstrate that TSP1 increases TNF production. The earlier study PMID:14568985 showed TSP1 NEGATIVELY regulates TNF-alpha in DCs.
Reason: The reference shows TSP1 signals through TNF-R1 but does not clearly demonstrate positive regulation of TNF production. Evidence from PMID:14568985 shows TSP1 negatively regulates TNF-alpha production in dendritic cells. The effect may be context-dependent.
Supporting Evidence:
PMID:18726995
Thrombospondin-1-induced apoptosis of brain microvascular endothelial cells can be mediated by TNF-R1.
GO:0043066 negative regulation of apoptotic process
IDA
PMID:18653767
Thrombospondin 1 binding to calreticulin-LRP1 signals resist... 		ACCEPT
Summary: TSP1 binding to calreticulin-LRP1 complex signals resistance to anoikis (detachment-induced apoptosis). This is mediated by the N-terminal domain and is distinct from its pro-apoptotic effects through CD36.
Reason: Direct experimental evidence for TSP1 anti-apoptotic function through calreticulin/LRP1. TSP1 has context-dependent effects: pro-apoptotic via CD36 and anti-apoptotic via calreticulin/LRP1.
Supporting Evidence:
PMID:18653767
Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis.
GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
IDA
PMID:18653767
Thrombospondin 1 binding to calreticulin-LRP1 signals resist... 		ACCEPT
Summary: TSP1 binding to calreticulin-LRP1 activates PI3K/Akt signaling, which mediates resistance to anoikis. This is part of TSP1's pro-survival signaling through the N-terminal domain.
Reason: Direct experimental evidence for TSP1 activating PI3K/Akt pathway through calreticulin/LRP1. This is part of TSP1's complex signaling repertoire.
Supporting Evidence:
PMID:18653767
Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis.
GO:0001968 fibronectin binding
IDA
PMID:6693501
Interactions of thrombospondin with extracellular matrix pro... 		ACCEPT
Summary: Classic study demonstrating TSP1 binds fibronectin and other ECM proteins. TSP1-fibronectin binding is relevant to ECM organization.
Reason: Direct experimental evidence for TSP1 fibronectin binding. This is a well-documented molecular function.
Supporting Evidence:
PMID:6693501
Interactions of thrombospondin with extracellular matrix proteins: selective binding to type V collagen.
GO:0008201 heparin binding
IDA
PMID:101549
Isolation and characterization of a high molecular weight gl... 		ACCEPT
Summary: Foundational paper describing the isolation of TSP1 from platelets and characterizing its heparin binding activity. Heparin binding is mediated by the N-terminal domain.
Reason: Classic experimental evidence for TSP1 heparin binding. This is a core molecular function important for ECM localization.
Supporting Evidence:
PMID:101549
Isolation and characterization of a high molecular weight glycoprotein from human blood platelets.
GO:0030169 low-density lipoprotein particle binding
IDA
PMID:6693501
Interactions of thrombospondin with extracellular matrix pro... 		KEEP AS NON CORE
Summary: Study showed TSP1 interactions with various proteins including LDL particles. TSP1 may bind LDL as part of its interactions with lipoproteins.
Reason: LDL binding by TSP1 is documented but is not a primary function. May be relevant to TSP1's roles in atherosclerosis.
Supporting Evidence:
PMID:6693501
Interactions of thrombospondin with extracellular matrix proteins: selective binding to type V collagen.
GO:0043236 laminin binding
IDA
PMID:6693501
Interactions of thrombospondin with extracellular matrix pro... 		ACCEPT
Summary: Study showing TSP1 binds laminin as part of its interactions with ECM components.
Reason: TSP1 binding to laminin is documented as part of its ECM interaction repertoire.
Supporting Evidence:
PMID:6693501
Interactions of thrombospondin with extracellular matrix proteins: selective binding to type V collagen.
GO:0070051 fibrinogen binding
IDA
PMID:6693501
Interactions of thrombospondin with extracellular matrix pro... 		ACCEPT
Summary: Study showing TSP1 binds fibrinogen. This is important for TSP1's role in hemostasis and clot formation.
Reason: TSP1 fibrinogen binding is a well-documented function relevant to hemostasis. TSP1 is incorporated into fibrin clots.
Supporting Evidence:
PMID:6693501
Interactions of thrombospondin with extracellular matrix proteins: selective binding to type V collagen.
GO:0070052 collagen V binding
IDA
PMID:6693501
Interactions of thrombospondin with extracellular matrix pro... 		ACCEPT
Summary: Study demonstrated TSP1 selectively binds type V collagen among the collagens tested. This is part of TSP1's ECM interactions.
Reason: Direct experimental evidence for TSP1 binding type V collagen. This specific collagen interaction is part of TSP1's ECM function.
Supporting Evidence:
PMID:6693501
Interactions of thrombospondin with extracellular matrix proteins: selective binding to type V collagen.
GO:0002040 sprouting angiogenesis
IMP
PMID:17879962
Syndecan-4 contributes to endothelial tubulogenesis through ... 		ACCEPT
Summary: Study showing TSP1's N-terminal domain has pro-angiogenic effects through syndecan-4 interactions, contributing to endothelial tubulogenesis. Note: This is distinct from TSP1's anti-angiogenic function mediated by CD36 through the TSRs.
Reason: TSP1 is involved in sprouting angiogenesis, though its net effect is typically anti-angiogenic. The N-terminal domain can have pro-angiogenic effects while the TSRs mediate anti-angiogenic effects.
Supporting Evidence:
PMID:17879962
Syndecan-4 contributes to endothelial tubulogenesis through interactions with two motifs inside the pro-angiogenic N-terminal domain of thrombospondin-1.
GO:0005515 protein binding
IPI
PMID:15700281
Insulin-like growth factor binding protein-5 (IGFBP-5) inter... 		MARK AS OVER ANNOTATED
Summary: Study showing TSP1 interacts with IGFBP-5 to negatively regulate IGF-I actions. While this interaction is documented, "protein binding" is too generic.
Reason: Generic "protein binding" provides limited functional insight. The specific TSP1-IGFBP-5 interaction is documented.
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:0030335 positive regulation of cell migration
IDA
PMID:15700281
Insulin-like growth factor binding protein-5 (IGFBP-5) inter... 		ACCEPT
Summary: Study showing TSP1-IGFBP-5 interactions affect cell migration. TSP1 can promote cell migration through calreticulin/LRP1 signaling that triggers focal adhesion disassembly.
Reason: TSP1 pro-migratory effects are documented through the N-terminal domain and calreticulin/LRP1 pathway. Effects on migration are context and receptor-dependent.
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:0032914 positive regulation of transforming growth factor beta1 production
ISS
GO_REF:0000024 		MODIFY
Summary: TSP1 activates latent TGF-beta1 (converting inactive to active form) rather than increasing TGF-beta1 production/biosynthesis. This annotation may conflate activation with production.
Reason: TSP1 activates pre-existing latent TGF-beta1 rather than inducing its production/biosynthesis. A more accurate term would be GO:0030511 (positive regulation of TGF-beta receptor signaling).
GO:0045727 positive regulation of translation
IDA
PMID:15700281
Insulin-like growth factor binding protein-5 (IGFBP-5) inter... 		KEEP AS NON CORE
Summary: Study on TSP1-IGFBP-5 interactions affecting IGF-I signaling. The connection to translation regulation is indirect through IGF pathway modulation.
Reason: Translation regulation by TSP1 is indirect through effects on growth factor signaling rather than a direct function.
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:0045766 positive regulation of angiogenesis
IMP
PMID:17879962
Syndecan-4 contributes to endothelial tubulogenesis through ... 		KEEP AS NON CORE
Summary: Study showing the N-terminal domain of TSP1 has pro-angiogenic effects through syndecan-4 interactions. Note: This is distinct from TSP1's predominant anti-angiogenic function via the TSRs.
Reason: While the N-terminal domain can promote angiogenesis, TSP1's predominant effect is anti-angiogenic (via CD36 and TSRs). Pro-angiogenic effects are context and domain-specific.
Supporting Evidence:
PMID:17879962
Syndecan-4 contributes to endothelial tubulogenesis through interactions with two motifs inside the pro-angiogenic N-terminal domain of thrombospondin-1.
GO:0050431 transforming growth factor beta binding
ISS
GO_REF:0000024 		ACCEPT
Summary: TSP1 binds latent TGF-beta1 through its type-1 repeats (TSRs). The LSKL sequence mediates binding to the latency-associated peptide of TGF-beta, enabling activation.
Reason: TGF-beta binding is a core molecular function of TSP1. The type-1 repeats mediate this interaction which is essential for TGF-beta1 activation.
GO:0010748 negative regulation of long-chain fatty acid import across plasma membrane
IDA
PMID:17416590
Thrombospondin-1 inhibits nitric oxide signaling via CD36 by... 		ACCEPT
Summary: Study showed TSP1 inhibits NO signaling via CD36 by inhibiting myristic acid uptake. Myristic acid is required for eNOS myristoylation.
Reason: Direct experimental evidence for TSP1 inhibiting fatty acid uptake through CD36. This mechanism contributes to TSP1's inhibition of NO signaling.
Supporting Evidence:
PMID:17416590
Thrombospondin-1 inhibits nitric oxide signaling via CD36 by inhibiting myristic acid uptake.
GO:0010754 negative regulation of receptor guanylyl cyclase signaling pathway
IDA
PMID:17416590
Thrombospondin-1 inhibits nitric oxide signaling via CD36 by... 		ACCEPT
Summary: TSP1 inhibits NO/cGMP signaling which involves guanylyl cyclase. By blocking myristic acid uptake, TSP1 impairs eNOS function and downstream cGMP production.
Reason: TSP1 inhibition of guanylyl cyclase signaling is part of its core anti-NO function. This is mediated through CD36.
Supporting Evidence:
PMID:17416590
Thrombospondin-1 inhibits nitric oxide signaling via CD36 by inhibiting myristic acid uptake.
GO:0010757 negative regulation of plasminogen activation
IDA
PMID:6438154
Complex formation of platelet thrombospondin with plasminoge... 		ACCEPT
Summary: TSP1 forms complexes with plasminogen and modulates plasminogen activation. TSP1 has antiplasmin activity that contributes to hemostasis.
Reason: TSP1 negatively regulates plasminogen activation as part of its role in hemostasis and fibrinolysis regulation.
Supporting Evidence:
PMID:6438154
Complex formation of platelet thrombospondin with plasminogen.
GO:0010759 positive regulation of macrophage chemotaxis
ISS
GO_REF:0000024 		ACCEPT
Summary: TSP1 can promote macrophage recruitment and chemotaxis. This is documented in tumor microenvironment studies and inflammation.
Reason: TSP1 promotes macrophage chemotaxis as part of its immune modulatory function, documented in multiple contexts.
GO:0010763 positive regulation of fibroblast migration
IDA
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motog... 		ACCEPT
Summary: Study showing TSP1 promotes fibroblast migration through TGF-beta1 dependent mechanisms. This is consistent with TSP1's role in wound healing and tissue remodeling.
Reason: Direct experimental evidence for TSP1 promoting fibroblast migration. This is part of TSP1's role in tissue repair.
Supporting Evidence:
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral tumour cells.
GO:0001666 response to hypoxia
NAS
PMID:9304800
Thrombospondin-1. 		KEEP AS NON CORE
Summary: TSP1 expression is regulated by hypoxia. In hypoxic conditions, TSP1 levels can be modulated as part of angiogenesis regulation.
Reason: TSP1 responds to hypoxia at the expression level, but this is not a direct mechanistic function of the protein itself.
Supporting Evidence:
PMID:9304800
Thrombospondin-1. Adams JC(1).
GO:0001937 negative regulation of endothelial cell proliferation
IMP
PMID:17413041
Interaction of alpha9beta1 integrin with thrombospondin-1 pr... 		ACCEPT
Summary: Study on alpha9beta1 integrin interaction with TSP1. Paradoxically, this paper shows TSP1 can promote angiogenesis through this integrin, but TSP1's net effect on endothelial proliferation is typically inhibitory via CD36.
Reason: TSP1 inhibition of endothelial cell proliferation is well-documented via CD36, even though specific integrin interactions may have different effects.
Supporting Evidence:
PMID:17413041
Interaction of alpha9beta1 integrin with thrombospondin-1 promotes angiogenesis.
GO:0001937 negative regulation of endothelial cell proliferation
IDA
PMID:17996481
Fibroblast growth factor-2 binding to the thrombospondin-1 t... 		ACCEPT
Summary: Study showed TSP1 type III repeats bind FGF-2 and inhibit endothelial cell proliferation. This identifies a novel anti-angiogenic domain.
Reason: Direct experimental evidence for TSP1 inhibiting endothelial cell proliferation through FGF-2 sequestration by the type III repeats.
Supporting Evidence:
PMID:17996481
Fibroblast growth factor-2 binding to the thrombospondin-1 type III repeats, a novel antiangiogenic domain.
GO:0001953 negative regulation of cell-matrix adhesion
IDA
PMID:17416590
Thrombospondin-1 inhibits nitric oxide signaling via CD36 by... 		ACCEPT
Summary: TSP1 inhibits NO signaling via CD36, which affects cell-matrix adhesion. By inhibiting NO/cGMP signaling, TSP1 blocks NO-stimulated cell adhesion responses.
Reason: TSP1 negatively regulates cell-matrix adhesion through inhibition of NO signaling, as shown in PMID:16150726 as well.
Supporting Evidence:
PMID:17416590
Thrombospondin-1 inhibits nitric oxide signaling via CD36 by inhibiting myristic acid uptake.
GO:0002544 chronic inflammatory response
IEP
PMID:18674744
Thrombospondin-1 and transforming growth factor beta are pro... 		KEEP AS NON CORE
Summary: Study showing TSP1 and TGF-beta are elevated in rheumatoid arthritis, suggesting involvement in chronic inflammation. This is an IEP annotation based on expression patterns.
Reason: TSP1 involvement in chronic inflammation is context-dependent. While TSP1 is elevated in RA, its primary function is more often anti-inflammatory through TGF-beta activation.
Supporting Evidence:
PMID:18674744
Thrombospondin-1 and transforming growth factor beta are pro-inflammatory molecules in rheumatoid arthritis.
GO:0002581 negative regulation of antigen processing and presentation of peptide or polysaccharide antigen via MHC class II
IDA
PMID:16882710
Apoptotic cell thrombospondin-1 and heparin-binding domain l... 		ACCEPT
Summary: Study showing TSP1 from apoptotic cells induces tolerizing states in dendritic cells, reducing antigen presentation. This is part of TSP1's immunosuppressive function.
Reason: Direct experimental evidence for TSP1 negatively regulating antigen presentation. This contributes to immune tolerance.
Supporting Evidence:
PMID:16882710
Apoptotic cell thrombospondin-1 and heparin-binding domain lead to dendritic-cell phagocytic and tolerizing states.
GO:0002605 negative regulation of dendritic cell antigen processing and presentation
IDA
PMID:16882710
Apoptotic cell thrombospondin-1 and heparin-binding domain l... 		ACCEPT
Summary: TSP1 induces tolerizing states in dendritic cells, negatively regulating their antigen processing and presentation function.
Reason: Direct experimental evidence for TSP1 negatively regulating DC antigen processing. Part of TSP1's immunosuppressive function.
Supporting Evidence:
PMID:16882710
Apoptotic cell thrombospondin-1 and heparin-binding domain lead to dendritic-cell phagocytic and tolerizing states.
GO:0005178 integrin binding
IMP
PMID:17413041
Interaction of alpha9beta1 integrin with thrombospondin-1 pr... 		ACCEPT
Summary: Study demonstrating TSP1 binds alpha9beta1 integrin and this interaction promotes angiogenesis. TSP1 binds multiple integrins.
Reason: Direct experimental evidence for TSP1 integrin binding. TSP1 interacts with multiple integrins through various domains.
Supporting Evidence:
PMID:17413041
Interaction of alpha9beta1 integrin with thrombospondin-1 promotes angiogenesis.
file:human/THBS1/THBS1-deep-research-falcon.md
THBS1 binds multiple integrins; 2024 synthesis places integrin binding across NTD and EGF-like domains and highlights integrin involvement in endothelial migration/vascular remodeling.
GO:0005178 integrin binding
IMP
PMID:18757424
Thrombospondin 1 promotes tumor macrophage recruitment and e... 		ACCEPT
Summary: Study on TSP1 effects on macrophage recruitment and tumor cytotoxicity, involving integrin interactions for cell adhesion and migration.
Reason: TSP1 integrin binding is documented and relevant to cell recruitment.
Supporting Evidence:
PMID:18757424
Thrombospondin 1 promotes tumor macrophage recruitment and enhances tumor cell cytotoxicity of differentiated U937 cells.
GO:0005509 calcium ion binding
NAS
PMID:9304800
Thrombospondin-1. 		ACCEPT
Summary: TSP1 contains multiple calcium-binding sites, particularly in the type 3 repeats. Calcium binding affects TSP1 conformation and ligand-binding properties.
Reason: Calcium binding is a well-documented property of TSP1. The type 3 repeat region contains calcium-binding loops critical for structure.
Supporting Evidence:
PMID:9304800
Thrombospondin-1. Adams JC(1).
GO:0005515 protein binding
IPI
PMID:3402455
Complex formation of human thrombospondin with osteonectin. 		MARK AS OVER ANNOTATED
Summary: Study showing TSP1 forms complexes with osteonectin. While this interaction is documented, "protein binding" is too generic.
Reason: Generic "protein binding" provides limited functional insight. The specific TSP1-osteonectin interaction is documented.
Supporting Evidence:
PMID:3402455
Complex formation of human thrombospondin with osteonectin.
GO:0005515 protein binding
IPI
PMID:6438154
Complex formation of platelet thrombospondin with plasminoge... 		MARK AS OVER ANNOTATED
Summary: Study showing TSP1 forms complexes with plasminogen. While this interaction is documented, "protein binding" is too generic.
Reason: Generic "protein binding" provides limited insight. The more specific annotations for protease binding and plasminogen activation regulation are more informative.
Supporting Evidence:
PMID:6438154
Complex formation of platelet thrombospondin with plasminogen.
GO:0005577 fibrinogen complex
IDA
PMID:3997886
Incorporation of thrombospondin into fibrin clots. 		ACCEPT
Summary: Study showing TSP1 is incorporated into fibrin clots and associates with the fibrinogen complex during hemostasis.
Reason: Direct experimental evidence for TSP1 association with fibrinogen complex in clot formation. This is part of TSP1's hemostatic function.
Supporting Evidence:
PMID:3997886
Incorporation of thrombospondin into fibrin clots.
GO:0005615 extracellular space
IDA
PMID:6777381
Ca2+-mediated association of glycoprotein G (thrombinsensiti... 		ACCEPT
Summary: Classic study showing TSP1 (glycoprotein G) in extracellular space associating with platelets in a Ca2+-dependent manner.
Reason: Early foundational evidence for TSP1 presence in extracellular space.
Supporting Evidence:
PMID:6777381
Ca2+-mediated association of glycoprotein G (thrombinsensitive protein, thrombospondin) with human platelets.
GO:0006955 immune response
IEP
PMID:18674744
Thrombospondin-1 and transforming growth factor beta are pro... 		ACCEPT
Summary: Study showing TSP1 elevation in rheumatoid arthritis, suggesting involvement in immune responses. TSP1 modulates immunity through multiple mechanisms.
Reason: TSP1 is involved in immune responses through TGF-beta activation, cytokine regulation, and effects on immune cells via CD47/CD36.
Supporting Evidence:
PMID:18674744
Thrombospondin-1 and transforming growth factor beta are pro-inflammatory molecules in rheumatoid arthritis.
GO:0007155 cell adhesion
NAS
PMID:9304800
Thrombospondin-1. 		ACCEPT
Summary: TSP1 is an adhesive glycoprotein that mediates cell-matrix and cell-cell adhesion through interactions with integrins and ECM.
Reason: Cell adhesion is a well-documented function of TSP1 as an adhesive glycoprotein.
Supporting Evidence:
PMID:9304800
Thrombospondin-1. Adams JC(1).
GO:0009749 response to glucose
IDA
PMID:18096704
Cell type-specific post-transcriptional regulation of produc... 		KEEP AS NON CORE
Summary: Study showing TSP1 production is regulated by high glucose through post-transcriptional mechanisms. Relevant to diabetic complications.
Reason: TSP1 expression responds to glucose, but this is a transcriptional/ post-transcriptional effect rather than a direct protein function.
Supporting Evidence:
PMID:18096704
Cell type-specific post-transcriptional regulation of production of the potent antiangiogenic and proatherogenic protein thrombospondin-1 by high glucose.
GO:0009897 external side of plasma membrane
IDA
PMID:6777381
Ca2+-mediated association of glycoprotein G (thrombinsensiti... 		ACCEPT
Summary: TSP1 binds to the external side of platelet plasma membranes in a Ca2+-dependent manner after release from alpha granules.
Reason: Direct evidence for TSP1 association with external plasma membrane. TSP1 binds to cell surface receptors on the external membrane.
Supporting Evidence:
PMID:6777381
Ca2+-mediated association of glycoprotein G (thrombinsensitive protein, thrombospondin) with human platelets.
GO:0010595 positive regulation of endothelial cell migration
IDA
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motog... 		KEEP AS NON CORE
Summary: Study showing TSP1 has motogenic effects on endothelial cells, partly through TGF-beta1. TSP1 effects on migration are complex and context-dependent.
Reason: TSP1 effects on endothelial migration are context-dependent. While TSP1 can promote migration in some contexts, its predominant effect on endothelial cells is typically inhibitory.
Supporting Evidence:
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral tumour cells.
GO:0010596 negative regulation of endothelial cell migration
IDA
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motog... 		ACCEPT
Summary: Same study showing TSP1 has complex effects on cell migration. TSP1 can inhibit endothelial migration through its anti-angiogenic domains.
Reason: TSP1 inhibition of endothelial cell migration is part of its anti-angiogenic function, mediated primarily through CD36.
Supporting Evidence:
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral tumour cells.
GO:0016477 cell migration
IDA
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motog... 		ACCEPT
Summary: Study showing TSP1 has motogenic effects on multiple cell types. TSP1 regulates cell migration through various mechanisms.
Reason: TSP1 involvement in cell migration is well-documented. Effects are cell-type and receptor-dependent.
Supporting Evidence:
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral tumour cells.
GO:0016525 negative regulation of angiogenesis
IDA
PMID:17596205
Novel antiangiogenic pathway of thrombospondin-1 mediated by... 		ACCEPT
Summary: Study identifying cell cycle suppression as a mechanism for TSP1's anti-angiogenic activity.
Reason: Direct experimental evidence for TSP1's anti-angiogenic function through cell cycle regulation.
Supporting Evidence:
PMID:17596205
Novel antiangiogenic pathway of thrombospondin-1 mediated by suppression of the cell cycle.
GO:0016525 negative regulation of angiogenesis
IDA
PMID:17996481
Fibroblast growth factor-2 binding to the thrombospondin-1 t... 		ACCEPT
Summary: Study showing type III repeats of TSP1 bind FGF-2 and constitute a novel anti-angiogenic domain.
Reason: Direct experimental evidence for TSP1's anti-angiogenic function through FGF-2 sequestration by type III repeats.
Supporting Evidence:
PMID:17996481
Fibroblast growth factor-2 binding to the thrombospondin-1 type III repeats, a novel antiangiogenic domain.
GO:0030141 secretory granule
IDA
PMID:101549
Isolation and characterization of a high molecular weight gl... 		ACCEPT
Summary: Foundational study characterizing TSP1 from platelet secretory granules (alpha granules). TSP1 is stored in and released from secretory granules.
Reason: TSP1 storage in platelet secretory granules (alpha granules) is a core localization from which TSP1 is released upon activation.
Supporting Evidence:
PMID:101549
Isolation and characterization of a high molecular weight glycoprotein from human blood platelets.
GO:0030335 positive regulation of cell migration
IMP
PMID:17413041
Interaction of alpha9beta1 integrin with thrombospondin-1 pr... 		ACCEPT
Summary: Study showing TSP1-integrin alpha9beta1 interaction promotes angiogenesis and cell migration.
Reason: TSP1 can promote cell migration through specific integrin interactions, though effects are receptor-dependent.
Supporting Evidence:
PMID:17413041
Interaction of alpha9beta1 integrin with thrombospondin-1 promotes angiogenesis.
GO:0030511 positive regulation of transforming growth factor beta receptor signaling pathway
IDA
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motog... 		ACCEPT
Summary: Study showing TGF-beta1 involvement in TSP1's motogenic effects. TSP1 activates TGF-beta1 which signals through TGF-beta receptors.
Reason: Direct experimental evidence supporting TSP1's role in activating TGF-beta signaling. This is a core function of TSP1.
Supporting Evidence:
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral tumour cells.
GO:0031012 extracellular matrix
TAS
PMID:9304800
Thrombospondin-1. 		ACCEPT
Summary: Review article confirming TSP1 localization in the extracellular matrix as a matricellular protein.
Reason: ECM localization is a core property of TSP1.
Supporting Evidence:
PMID:9304800
Thrombospondin-1. Adams JC(1).
GO:0031091 platelet alpha granule
IDA
PMID:6777381
Ca2+-mediated association of glycoprotein G (thrombinsensiti... 		ACCEPT
Summary: Classic study showing TSP1 is stored in platelet alpha granules and released upon activation.
Reason: Platelet alpha granule is a core storage localization for TSP1.
Supporting Evidence:
PMID:6777381
Ca2+-mediated association of glycoprotein G (thrombinsensitive protein, thrombospondin) with human platelets.
GO:0032026 response to magnesium ion
IDA
PMID:6777381
Ca2+-mediated association of glycoprotein G (thrombinsensiti... 		KEEP AS NON CORE
Summary: Study examined divalent cation effects on TSP1-platelet association. Magnesium ion effects on TSP1 may relate to its Ca2+-binding properties.
Reason: Response to magnesium is not a primary function of TSP1. The study focused on Ca2+-mediated association.
Supporting Evidence:
PMID:6777381
Ca2+-mediated association of glycoprotein G (thrombinsensitive protein, thrombospondin) with human platelets.
GO:0032570 response to progesterone
TAS
PMID:9304800
Thrombospondin-1. 		KEEP AS NON CORE
Summary: TSP1 expression may be regulated by progesterone in certain contexts, but this is not a primary function.
Reason: Hormonal regulation of TSP1 expression is not a core function. This likely reflects transcriptional regulation in specific tissues.
Supporting Evidence:
PMID:9304800
Thrombospondin-1. Adams JC(1).
GO:0032695 negative regulation of interleukin-12 production
IDA
PMID:16882710
Apoptotic cell thrombospondin-1 and heparin-binding domain l... 		ACCEPT
Summary: Study showing TSP1 from apoptotic cells induces tolerizing states in DCs with reduced IL-12 production. Also supported by PMID:14568985.
Reason: Direct experimental evidence for TSP1 negatively regulating IL-12 production. This is part of TSP1's immunosuppressive function.
Supporting Evidence:
PMID:16882710
Apoptotic cell thrombospondin-1 and heparin-binding domain lead to dendritic-cell phagocytic and tolerizing states.
GO:0034605 cellular response to heat
NAS
PMID:9304800
Thrombospondin-1. 		KEEP AS NON CORE
Summary: TSP1 expression may be induced by heat stress, but this is not a primary function of the protein.
Reason: Response to heat is not a core function of TSP1. This likely reflects stress-induced transcriptional regulation.
Supporting Evidence:
PMID:9304800
Thrombospondin-1. Adams JC(1).
GO:0040037 negative regulation of fibroblast growth factor receptor signaling pathway
IDA
PMID:17996481
Fibroblast growth factor-2 binding to the thrombospondin-1 t... 		ACCEPT
Summary: TSP1 type III repeats bind FGF-2 and sequester it from FGF receptors, thereby negatively regulating FGF receptor signaling.
Reason: Direct experimental evidence for TSP1 inhibiting FGF signaling by binding and sequestering FGF-2. This contributes to anti-angiogenesis.
Supporting Evidence:
PMID:17996481
Fibroblast growth factor-2 binding to the thrombospondin-1 type III repeats, a novel antiangiogenic domain.
GO:0042327 positive regulation of phosphorylation
IMP
PMID:17413041
Interaction of alpha9beta1 integrin with thrombospondin-1 pr... 		ACCEPT
Summary: TSP1 interaction with alpha9beta1 integrin promotes MAPK signaling and phosphorylation events involved in angiogenesis.
Reason: TSP1 can positively regulate phosphorylation through integrin signaling pathways, including MAPK activation.
Supporting Evidence:
PMID:17413041
Interaction of alpha9beta1 integrin with thrombospondin-1 promotes angiogenesis.
GO:0043032 positive regulation of macrophage activation
IDA
PMID:18757424
Thrombospondin 1 promotes tumor macrophage recruitment and e... 		ACCEPT
Summary: Study showing TSP1 promotes macrophage activation in tumor microenvironments, enhancing cytotoxicity.
Reason: Direct experimental evidence for TSP1 promoting macrophage activation. Part of TSP1's immune modulatory function.
Supporting Evidence:
PMID:18757424
Thrombospondin 1 promotes tumor macrophage recruitment and enhances tumor cell cytotoxicity of differentiated U937 cells.
GO:0043394 proteoglycan binding
TAS
PMID:9304800
Thrombospondin-1. 		ACCEPT
Summary: TSP1 binds proteoglycans including heparan sulfate proteoglycans through its N-terminal domain. This mediates ECM localization.
Reason: Proteoglycan binding is well-documented for TSP1 and important for its ECM localization and cell surface association.
Supporting Evidence:
PMID:9304800
Thrombospondin-1. Adams JC(1).
GO:0043536 positive regulation of blood vessel endothelial cell migration
IDA
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motog... 		KEEP AS NON CORE
Summary: Study showing TSP1 has motogenic effects on endothelial cells in some contexts. TSP1 effects on endothelial migration are complex.
Reason: While TSP1 can promote endothelial migration in some contexts, its predominant effect is typically inhibitory. Context-dependent.
Supporting Evidence:
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral tumour cells.
GO:0043537 negative regulation of blood vessel endothelial cell migration
IDA
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motog... 		ACCEPT
Summary: TSP1 can inhibit endothelial cell migration through its anti-angiogenic domains, particularly via CD36 signaling.
Reason: TSP1 inhibition of endothelial cell migration is part of its anti-angiogenic function.
Supporting Evidence:
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral tumour cells.
GO:0043652 engulfment of apoptotic cell
IDA
PMID:16882710
Apoptotic cell thrombospondin-1 and heparin-binding domain l... 		ACCEPT
Summary: TSP1 on apoptotic cells promotes their phagocytic uptake by dendritic cells. TSP1 serves as an "eat me" signal.
Reason: Direct experimental evidence for TSP1 involvement in apoptotic cell engulfment through effects on phagocytes.
Supporting Evidence:
PMID:16882710
Apoptotic cell thrombospondin-1 and heparin-binding domain lead to dendritic-cell phagocytic and tolerizing states.
GO:0045766 positive regulation of angiogenesis
IMP
PMID:17413041
Interaction of alpha9beta1 integrin with thrombospondin-1 pr... 		KEEP AS NON CORE
Summary: Study showing TSP1-alpha9beta1 integrin interaction promotes angiogenesis. Note: This is distinct from TSP1's predominant anti-angiogenic function via CD36.
Reason: TSP1's predominant effect is anti-angiogenic. Pro-angiogenic effects through specific integrin interactions are context-dependent.
Supporting Evidence:
PMID:17413041
Interaction of alpha9beta1 integrin with thrombospondin-1 promotes angiogenesis.
GO:0050431 transforming growth factor beta binding
TAS
PMID:9304800
Thrombospondin-1. 		ACCEPT
Summary: TSP1 binds latent TGF-beta through its type-1 repeats. This binding is essential for TGF-beta1 activation.
Reason: TGF-beta binding is a core molecular function of TSP1 mediated by the type-1 repeats (TSRs).
Supporting Evidence:
PMID:9304800
Thrombospondin-1. Adams JC(1).
GO:0050921 positive regulation of chemotaxis
IDA
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motog... 		ACCEPT
Summary: TSP1 has chemotactic effects on certain cell types including fibroblasts and macrophages.
Reason: TSP1 promotes chemotaxis of specific cell types as part of its role in wound healing and inflammation.
Supporting Evidence:
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral tumour cells.
GO:0051592 response to calcium ion
IDA
PMID:18757424
Thrombospondin 1 promotes tumor macrophage recruitment and e... 		ACCEPT
Summary: TSP1 conformation and ligand-binding properties are affected by calcium. Calcium binding is important for TSP1 structure.
Reason: TSP1 structure and function respond to calcium through its calcium-binding type 3 repeats.
Supporting Evidence:
PMID:18757424
Thrombospondin 1 promotes tumor macrophage recruitment and enhances tumor cell cytotoxicity of differentiated U937 cells.
GO:0051592 response to calcium ion
IDA
PMID:6777381
Ca2+-mediated association of glycoprotein G (thrombinsensiti... 		ACCEPT
Summary: Classic study showing TSP1 association with platelets is Ca2+-mediated, demonstrating calcium responsiveness.
Reason: Direct evidence for TSP1 functional response to calcium ions. Calcium binding is essential for TSP1 structure and function.
Supporting Evidence:
PMID:6777381
Ca2+-mediated association of glycoprotein G (thrombinsensitive protein, thrombospondin) with human platelets.
GO:0051895 negative regulation of focal adhesion assembly
TAS
PMID:9304800
Thrombospondin-1. 		ACCEPT
Summary: TSP1 N-terminal domain engagement of calreticulin/LRP1 triggers focal adhesion disassembly, promoting cell motility.
Reason: TSP1 negatively regulates focal adhesion assembly through calreticulin/LRP1 signaling. This is well-documented.
Supporting Evidence:
PMID:9304800
Thrombospondin-1. Adams JC(1).
GO:0051918 negative regulation of fibrinolysis
IDA
PMID:6438154
Complex formation of platelet thrombospondin with plasminoge... 		ACCEPT
Summary: TSP1 forms complexes with plasminogen and has antiplasmin activity, thereby negatively regulating fibrinolysis.
Reason: TSP1 negative regulation of fibrinolysis is documented through plasminogen binding and antiplasmin activity.
Supporting Evidence:
PMID:6438154
Complex formation of platelet thrombospondin with plasminogen.

Core Functions

TSP1 binds multiple integrins including alpha3beta1, alpha4beta1, alpha6beta1, and alphaIIb-beta3. These interactions mediate TSP1's effects on cell adhesion, migration, and platelet aggregation. The RGD sequence and other integrin-binding motifs in TSP1 engage integrins to modulate cell-matrix interactions.

Molecular Function:
integrin binding
Directly Involved In:
negative regulation of angiogenesis cell-matrix adhesion
Cellular Locations:
extracellular matrix
Supporting Evidence:
  • PMID:9304800
    TSP1 mediates cell-matrix adhesion through interactions with multiple integrins.

TSP1 activates latent TGF-beta1 through direct binding via its type-1 repeats (TSRs). The KRFK sequence in the TSRs binds the LAP (latency-associated peptide) and induces a conformational change that releases active TGF-beta1. This is a core function of TSP1 critical for wound healing, fibrosis, and immune regulation.

Molecular Function:
transforming growth factor beta binding
Directly Involved In:
positive regulation of protein secretion
Cellular Locations:
extracellular matrix
Supporting Evidence:
  • file:human/THBS1/THBS1-deep-research-openai.md
    TSP1 activates latent TGF-beta1 through direct interaction with the latency-associated peptide via type-1 repeats.

TSP1 binds fibronectin in the extracellular matrix, modulating cell adhesion and matrix assembly. This interaction contributes to TSP1's role in wound healing and tissue remodeling.

Molecular Function:
fibronectin binding
Directly Involved In:
extracellular matrix organization
Cellular Locations:
extracellular matrix
Supporting Evidence:
  • PMID:6489349
    Thrombospondin interactions with fibronectin and fibrinogen.

TSP1 contains a heparin-binding domain in its N-terminal region that mediates interactions with heparan sulfate proteoglycans on cell surfaces and in the ECM. This binding is important for TSP1 localization and receptor interactions.

Molecular Function:
heparin binding
Directly Involved In:
cell-matrix adhesion
Cellular Locations:
extracellular matrix
Supporting Evidence:
  • file:human/THBS1/THBS1-deep-research-openai.md
    TSP1 binds heparan sulfate proteoglycans through its N-terminal heparin-binding domain.

TSP1 inhibits plasmin and other serine proteases through its type-1 repeats. This antiplasmin activity protects the forming blood clot from premature fibrinolysis and is important for TSP1's hemostatic function.

Molecular Function:
serine-type endopeptidase inhibitor activity
Directly Involved In:
blood coagulation
Cellular Locations:
platelet alpha granule lumen
Supporting Evidence:
  • PMID:7679575
    Characterization of the antiplasmin activity of human thrombospondin-1 in solution.

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:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt.
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods.
PMID:101549
Isolation and characterization of a high molecular weight glycoprotein from human blood platelets.
PMID:10613822
Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1.
PMID:11134179
Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1.
PMID:14568985
Thrombospondin 1 is an autocrine negative regulator of human dendritic cell activation.
PMID:15700281
Insulin-like growth factor binding protein-5 (IGFBP-5) interacts with thrombospondin-1 to induce negative regulatory effects on IGF-I actions.
PMID:15864306
A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease.
PMID:16150726
Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner.
PMID:16502470
Human colostrum: identification of minor proteins in the aqueous phase by proteomics.
PMID:16882710
Apoptotic cell thrombospondin-1 and heparin-binding domain lead to dendritic-cell phagocytic and tolerizing states.
PMID:17413041
Interaction of alpha9beta1 integrin with thrombospondin-1 promotes angiogenesis.
PMID:17416590
Thrombospondin-1 inhibits nitric oxide signaling via CD36 by inhibiting myristic acid uptake.
PMID:17596205
Novel antiangiogenic pathway of thrombospondin-1 mediated by suppression of the cell cycle.
PMID:17879962
Syndecan-4 contributes to endothelial tubulogenesis through interactions with two motifs inside the pro-angiogenic N-terminal domain of thrombospondin-1.
PMID:17996481
Fibroblast growth factor-2 binding to the thrombospondin-1 type III repeats, a novel antiangiogenic domain.
PMID:18042364
TSG-6 binds via its CUB_C domain to the cell-binding domain of fibronectin and increases fibronectin matrix assembly.
PMID:18096704
Cell type-specific post-transcriptional regulation of production of the potent antiangiogenic and proatherogenic protein thrombospondin-1 by high glucose.
PMID:18285447
Extracellular matrix retention of thrombospondin 1 is controlled by its conserved C-terminal region.
PMID:18555217
Differential involvement of TGF-beta1 in mediating the motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral tumour cells.
PMID:18653767
Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis.
PMID:18674744
Thrombospondin-1 and transforming growth factor beta are pro-inflammatory molecules in rheumatoid arthritis.
PMID:18688696
Calumenin but not reticulocalbin forms a Ca2+-dependent complex with thrombospondin-1. A potential role in haemostasis and thrombosis.
PMID:18726995
Thrombospondin-1-induced apoptosis of brain microvascular endothelial cells can be mediated by TNF-R1.
PMID:18757424
Thrombospondin 1 promotes tumor macrophage recruitment and enhances tumor cell cytotoxicity of differentiated U937 cells.
PMID:18940719
Phosphatidylserine-positive erythrocytes bind to immobilized and soluble thrombospondin-1 via its heparin-binding domain.
PMID:19004835
Differential interactions of thrombospondin-1, -2, and -4 with CD47 and effects on cGMP signaling and ischemic injury responses.
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exosomes.
PMID:19199708
Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).
PMID:19542224
The first draft of the endostatin interaction network.
PMID:19738618
Induction of thrombospondin-1 partially mediates the anti-angiogenic activity of dexrazoxane.
PMID:20551380
Proteomics characterization of extracellular space components in the human aorta.
PMID:21362503
Protein profile of exosomes from trabecular meshwork cells.
PMID:22261194
Proteomics analysis of cardiac extracellular matrix remodeling in a porcine model of ischemia/reperfusion injury.
PMID:23144964
Endogenous thrombospondin-1 regulates leukocyte recruitment and activation and accelerates death from systemic candidiasis.
PMID:23533145
In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
PMID:23658023
Comparative proteomic analysis of supportive and unsupportive extracellular matrix substrates for human embryonic stem cell maintenance.
PMID:23896411
Thrombospondin-1 modulates VEGF signaling via CD36 by recruiting SHP-1 to VEGFR2 complex in microvascular endothelial cells.
PMID:23979707
SILAC-based proteomics of human primary endothelial cell morphogenesis unveils tumor angiogenic markers.
PMID:24117177
Extended interaction network of procollagen C-proteinase enhancer-1 in the extracellular matrix.
PMID:24177325
MicroRNA miR-27b rescues bone marrow-derived angiogenic cell function and accelerates wound healing in type 2 diabetes mellitus.
PMID:2435757
Isolation of the thrombospondin membrane receptor.
PMID:24511121
Thrombospondin-1 activation of signal-regulatory protein-Ξ± stimulates reactive oxygen species production and promotes renal ischemia reperfusion injury.
PMID:24615654
Interleukin-18 may lead to benign prostatic hyperplasia via thrombospondin-1 production in prostatic smooth muscle cells.
PMID:2478219
An integrin receptor on normal and thrombasthenic platelets that binds thrombospondin.
PMID:25660232
miR-487b promotes human umbilical vein endothelial cell proliferation, migration, invasion and tube formation through regulating THBS1.
PMID:26395742
Angiogenic microRNAs Linked to Incidence and Progression of Diabetic Retinopathy in Type 1 Diabetes.
PMID:26627825
Extracellular Fibrinogen-binding Protein (Efb) from Staphylococcus aureus Inhibits the Formation of Platelet-Leukocyte Complexes.
PMID:27068509
Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veins.
PMID:28124060
Bone morphogenetic protein 4 regulates microRNAs miR-494 and miR-126-5p in control of endothelial cell function in angiogenesis.
PMID:28327460
Comprehensive proteomic characterization of stem cell-derived extracellular matrices.
PMID:28344315
Proteomic characterization of human multiple myeloma bone marrow extracellular matrix.
PMID:3084490
Interaction of thrombospondin with resting and stimulated human platelets.
PMID:3402455
Complex formation of human thrombospondin with osteonectin.
PMID:3997886
Incorporation of thrombospondin into fibrin clots.
PMID:6341993
Cultured human fibroblasts synthesize and secrete thrombospondin and incorporate it into extracellular matrix.
PMID:6438154
Complex formation of platelet thrombospondin with plasminogen. Modulation of activation by tissue activator.
PMID:6489349
Thrombospondin interactions with fibronectin and fibrinogen. Mutual inhibition in binding.
PMID:6693501
Interactions of thrombospondin with extracellular matrix proteins: selective binding to type V collagen.
PMID:6777381
Ca2+-mediated association of glycoprotein G (thrombinsensitive protein, thrombospondin) with human platelets.
PMID:7679575
Characterization of the antiplasmin activity of human thrombospondin-1 in solution.
PMID:8288588
Thrombospondin 3 is a developmentally regulated heparin binding protein.
PMID:8550562
Integrin-associated protein is a receptor for the C-terminal domain of thrombospondin.
PMID:9304800
Thrombospondin-1.
Reactome:R-HSA-265429
THBS1 (Thrombospondin-1) binds Integrin alpha3beta1, alpha4beta1
Reactome:R-HSA-349603
Interaction of integrin alphaIIb beta 3 with THBS1 (Thrombospondin-1)
Reactome:R-HSA-382054
PDGF binds to extracellular matrix proteins
Reactome:R-HSA-481007
Exocytosis of platelet alpha granule contents
Reactome:R-HSA-5173005
B3GALTL transfers glucose to O-fucosyl-proteins
Reactome:R-HSA-5173192
POFUT2 transfers fucose to TSR domain-containing proteins
Reactome:R-HSA-6785565
Defective B3GALTL does not transfer glucose to O-fucosyl-proteins
Reactome:R-HSA-8936995
THBS1 gene transcription is stimulated by the complex containing RUNX1, PRMT1 and GATA1 and inhibited by the complex of RUNX1, SIN3A and PRMT6
Reactome:R-NUL-2731112
Syndecan-1 binds THBS1
file:human/THBS1/THBS1-deep-research-openai.md
Deep research on THBS1 function
file:human/THBS1/THBS1-deep-research-falcon.md
Falcon (Edison) deep research on THBS1 function
  • THBS1/TSP-1 is a secreted matricellular (ECM-associated) glycoprotein in the Group A thrombospondin subfamily that forms trimers in the extracellular space; the CTD contains a CD47-binding site and the TSRs (type I repeats) are necessary for binding latent TGF-Ξ² and CD36, while the NTD and EGF-like domains participate in integrin interactions.
    "a secreted matricellular (ECM-associated) glycoprotein in the Group A thrombospondin subfamily that forms trimers in the extracellular space"
  • THBS1 is repeatedly described as a major activator of latent TGF-Ξ²1 in vivo, positioning it upstream of profibrotic and immunoregulatory Smad signaling and ECM remodeling.
    "Multiple 2023–2024 sources characterize THBS1/TSP‑1 as a major mediator/activator of latent TGF‑β. This function positions THBS1 upstream of profibrotic and immunoregulatory programs (e.g., Smad signaling and downstream ECM remodeling)."
  • THBS1 binds CD47 via its C-terminal domain and triggers signaling that suppresses nitric oxide (NO) pathway effects, antagonising NO/cGMP-dependent vasodilation.
    "THBS1 binds CD47 (via CTD) and triggers signaling that suppresses nitric oxide (NO) pathway effects."
  • THBS1-CD47 signaling antagonises NO/cGMP-dependent signaling, with consequences for vascular smooth muscle relaxation/vasodilation and ischaemic survival.
    "THBS1–CD47 signaling **antagonizes NO/cGMP-dependent signaling**, with consequences for vascular smooth muscle relaxation/vasodilation and ischemic survival."
  • THBS1 binds CD36 via its TSRs and contributes to platelet and vascular effects; CD36 also mediates THBS1's anti-angiogenic signaling.
    "THBS1 binds CD36 (via TSRs) and contributes to platelet and vascular effects; CD36 is also part of anti-angiogenic signaling."
  • THBS1 binds multiple integrins through its NTD and EGF-like domains, contributing to endothelial migration and vascular remodelling.
    "THBS1 binds multiple integrins; 2024 synthesis places integrin binding across NTD and EGF-like domains and highlights integrin involvement in endothelial migration/vascular remodeling."
  • THBS1 is a major component of platelet Ξ±-granules, rapidly released at injury sites and supporting platelet activation, vasoconstriction, and thrombus formation (via CD36 and NO pathway suppression).
    "THBS1 is described as a major component of platelet α‑granules and is rapidly released at injury sites, supporting platelet activation, vasoconstriction, and thrombus formation"
  • In intestinal mucosal wound repair, epithelial THBS1 promotes restitution through CD47- and TGF-Ξ²1-dependent signaling, with effects on SMAD2/3 phosphorylation and RhoA/Rac1 cytoskeletal dynamics (Wilson et al. 2024 JCI Insight).
    "a tissue-protective role for epithelial THBS1 in intestinal mucosal wound repair, mechanistically coupled to CD47 and TGF-Ξ²1 signaling and to cytoskeletal pathway interrogation (RhoA/Rac1; SMAD2/3)"
  • In prostate cancer models, THBS1 is a TGF-Ξ²-induced secreted ECM protein that interacts with integrin Ξ±V (ITGAV) and TGF-Ξ² receptor I (TΞ²RI) at the leading edge to mediate migration, invasion, and metastasis (Mu et al. 2024 Oncogene).
    "THBS1 mediates migration/invasion by **interacting with integrin Ξ±V (ITGAV) and TGF‑β receptor I (TΞ²RI)**; deletion of THBS1 or TΞ²RI prevented migration and invasion in experimental systems."
  • Kaur & Roberts (2023) highlight that, despite viable Thbs1 knockout mice, human population genetics indicate THBS1 is loss-intolerant, consistent with an essential stress-response role in surviving environmental challenges between birth and reproduction.
    "human population genetics indicate THBS1 is **loss-intolerant**, and propose that THBS1's essentiality in humans may reflect the need to survive **environmental stresses** encountered between birth and reproduction"

Deep Research

Falcon

(THBS1-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 24 citations 2 artifacts 2026-05-30T01:56:10.815764
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000013 Figure 1 provides a schematic of the domain architecture for Group A thrombospondins (TSP-1 and TSP-2). The diagram identifies seve (image/png)

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.

Research report: Human THBS1 / Thrombospondin‑1 (TSP‑1) (UniProt P07996)

0) Mandatory target verification (gene/protein identity)

The target described (UniProt P07996) corresponds to human thrombospondin‑1 (THBS1; TSP1), a secreted matricellular (ECM-associated) glycoprotein in the Group A thrombospondin subfamily that forms trimers in the extracellular space. (kaur2023whydohumans pages 3-4, pan2024themolecularmechanism pages 1-2)

1) Key concepts and definitions (current understanding)

1.1 Matricellular protein concept

THBS1 encodes thrombospondin‑1, a prototypical matricellular protein: an extracellular protein that is not primarily structural but modulates cell–matrix and cell–cell signaling by binding receptors, growth factors, and ECM components. (kaur2023whydohumans pages 3-4, pan2024themolecularmechanism pages 1-2)

1.2 Localization and where THBS1 acts

Recent cardiovascular-focused synthesis describes thrombospondins as secreted extracellular glycoproteins that are typically low at baseline and induced after tissue damage; THBS1 (TSP‑1) is a Group A thrombospondin acting at the cell surface/ECM interface. (pan2024themolecularmechanism pages 1-2)

1.3 Domain architecture (annotation-relevant)

A 2024 review provides a domain-to-function map for Group A thrombospondins (TSP‑1/TSP‑2). The schematic and accompanying text define a canonical multi-domain architecture: N-terminal domain (NTD) β†’ procollagen-homology region (PC) β†’ type I repeats (TSRs) β†’ EGF-like/type II domains β†’ type III repeats β†’ C-terminal domain (CTD), where the CTD contains a CD47-binding site and TSRs are necessary for binding latent TGF‑β and CD36; NTD and EGF-like domains participate in integrin interactions. (pan2024themolecularmechanism media a02bfa76, pan2024themolecularmechanism pages 2-3)

Figure evidence: A schematic domain architecture indicating CTD–CD47 and TSR–TGF‑β/CD36 mapping is shown in Pan et al. 2024 (Figure 1). (pan2024themolecularmechanism media a02bfa76)

1.4 Principal receptors/interaction partners (high-confidence)

Across recent sources, the best-supported receptor/ligand axis for core THBS1 signaling includes:
- CD47: THBS1 binds CD47 (via CTD) and triggers signaling that suppresses nitric oxide (NO) pathway effects. (kaur2023whydohumans pages 6-7, pan2024themolecularmechanism pages 2-3)
- CD36: THBS1 binds CD36 (via TSRs) and contributes to platelet and vascular effects; CD36 is also part of anti-angiogenic signaling. (kaur2023whydohumans pages 4-5, pan2024themolecularmechanism pages 2-3)
- Integrins: THBS1 binds multiple integrins; 2024 synthesis places integrin binding across NTD and EGF-like domains and highlights integrin involvement in endothelial migration/vascular remodeling. (pan2024themolecularmechanism pages 2-3)
- Latent TGF‑β complex: THBS1 is repeatedly described as a major activator of latent TGF‑β1 in vivo, connecting THBS1 to canonical TGF‑β downstream signaling. (kaur2023whydohumans pages 6-7, pan2024themolecularmechanism pages 2-3)

2) Core molecular functions and pathways (functional annotation narrative)

2.1 Activation of latent TGF‑β (primary biochemical role)

Multiple 2023–2024 sources characterize THBS1/TSP‑1 as a major mediator/activator of latent TGF‑β. This function positions THBS1 upstream of profibrotic and immunoregulatory programs (e.g., Smad signaling and downstream ECM remodeling). (kaur2023whydohumans pages 6-7, pan2024themolecularmechanism pages 2-3)

Annotation-ready phrasing: β€œExtracellular matricellular glycoprotein that binds the latent TGF‑β complex and promotes activation of TGF‑β signaling.” (kaur2023whydohumans pages 6-7, pan2024themolecularmechanism pages 2-3)

2.2 CD47–NO–cGMP axis (vascular tone, stress physiology)

A 2023 expert review emphasizes that THBS1–CD47 signaling antagonizes NO/cGMP-dependent signaling, with consequences for vascular smooth muscle relaxation/vasodilation and ischemic survival. In this view, THBS1 contributes to cardiovascular stress responses by limiting NO’s vasodilatory and antithrombotic effects. (kaur2023whydohumans pages 6-7)

Annotation-ready phrasing: β€œBinds CD47 to inhibit NO-stimulated cGMP signaling in vascular cells, thereby modulating vascular tone and hemostatic responses.” (kaur2023whydohumans pages 6-7)

2.3 Hemostasis/platelet biology

THBS1 is described as a major component of platelet α‑granules and is rapidly released at injury sites, supporting platelet activation, vasoconstriction, and thrombus formation (including via CD36 and via NO pathway suppression). (kaur2023whydohumans pages 3-4, kaur2023whydohumans pages 6-7)

2.4 Cytoskeletal remodeling and epithelial restitution (Rho/Rac, focal adhesion dynamics)

A 2024 JCI Insight study in intestinal wound healing demonstrates THBS1-dependent epithelial restitution mechanisms and explicitly frames THBS1 effects on epithelial migration as dependent on both CD47 and TGF‑β1 signaling. The study assayed SMAD2/3 phosphorylation and used RhoA and Rac1 pathway tools, consistent with THBS1 coordinating focal adhesion/cytoskeletal dynamics during restitution. (wilson2024criticalroleof pages 14-15, wilson2024criticalroleof pages 17-19)

2.5 Pro-metastatic ECM signaling in cancer cells (TΞ²RI–ITGAV complex)

A 2024 Oncogene study reports that in prostate cancer models, THBS1 is a prominent TGF‑β-induced secreted ECM protein and that THBS1 mediates migration/invasion by interacting with integrin Ξ±V (ITGAV) and TGF‑β receptor I (TΞ²RI); deletion of THBS1 or TΞ²RI prevented migration and invasion in experimental systems. (mu2024thetΞ²ripromotes pages 1-2, mu2024thetΞ²ripromotes pages 10-11)

3) Recent developments and latest research (prioritize 2023–2024)

3.1 Human genetics viewpoint: THBS1 as β€œloss-intolerant” and stress-response gene (2023)

Kaur & Roberts (2023) highlight that, despite viable Thbs1 knockout mice, human population genetics indicate THBS1 is loss-intolerant, and propose that THBS1’s essentiality in humans may reflect the need to survive environmental stresses encountered between birth and reproduction (e.g., injury and infection). (kaur2023whydohumans pages 1-3)

3.2 Cardiovascular mechanistic synthesis (2024)

A 2024 cardiovascular review maps THBS1 domain architecture to receptor interactions (TSR–TGF‑β/CD36; CTD–CD47; integrin binding) and discusses downstream consequences including fibrosis-related signaling and stress pathways (e.g., ER stress/autophagy via PERKβ†’ATF4, as reviewed). (pan2024themolecularmechanism pages 2-3)

3.3 THBS1 in mucosal wound repair (2024)

Wilson et al. (2024) identify a tissue-protective role for epithelial THBS1 in intestinal mucosal wound repair, mechanistically coupled to CD47 and TGF‑β1 signaling and to cytoskeletal pathway interrogation (RhoA/Rac1; SMAD2/3). (wilson2024criticalroleof pages 14-15, wilson2024criticalroleof pages 17-19)

3.4 THBS1 in obesity-associated diaphragm remodeling (2024)

Buras et al. (2024) interpret THBS1 as an obesity-associated matricellular mediator that promotes fibro-adipogenic stromal expansion and contractile dysfunction of the diaphragm, linking THBS1 to TGF‑β-associated stromal remodeling; Thbs1 loss was protective in their models. (buras2024thrombospondin1promotesfibroadipogenic pages 1-2)

4) Current applications and real-world implementations

4.1 THBS1 as a circulating biomarker with prognostic performance (human cohort; 2024)

A 2024 BMC Medicine study in HBV-related acute-on-chronic liver failure (ACLF) presents THBS1 as a disease-severity-associated biomarker with clinically relevant prognostic performance.
- PBMC transcriptome study set drawn from 330 participants (subset: ACLF=20; LC=10; CHB=10; NC=15) identified THBS1 as the top differentially expressed gene with marked upregulation in ACLF. (hassan2024thrombospondin1enhances pages 1-3)
- qPCR validation: ACLF=110; LC=60; CHB=60; NC=45. (hassan2024thrombospondin1enhances pages 1-3)
- Mortality prediction: AUROC 0.8438 (28 days) and 0.7778 (90 days) (qPCR-based). (hassan2024thrombospondin1enhances pages 1-3)
- Plasma ELISA validation (expanded cohort: ACLF=198; LC=50; CHB=50; NC=50): correlation with ALT and Ξ³-GT (P=0.01) and prognostic performance AUROC 0.7445 (28 days) and 0.7175 (90 days); an optimal plasma THBS1 cut-off <28 Β΅g/mL was reported for identifying high-risk short-term mortality. (hassan2024thrombospondin1enhances pages 1-3)

These data support real-world implementation of THBS1 measurement as a risk-stratification biomarker in ACLF (pending external replication and clinical integration). (hassan2024thrombospondin1enhances pages 1-3)

4.2 Therapeutic targeting concepts (preclinical-to-translational)

Multiple mechanistic frameworks imply tractable intervention points: blocking THBS1 interaction with CD47, CD36, integrins, or blocking THBS1-mediated latent TGF‑β activation. (kaur2023whydohumans pages 6-7, pan2024themolecularmechanism pages 2-3)

A patent landscape example includes inventions aiming to inhibit TGF‑β pathways (including THBS1-mediated activation as a target concept in this area), reflecting ongoing translational interest. (hassan2024thrombospondin1enhances pages 1-3)

ClinicalTrials.gov search results include historical trials of ABT‑510 (a thrombospondin-1–derived anti-angiogenic peptidomimetic) in glioblastoma (Phase I; completed; NCT00584883), illustrating prior attempts to operationalize thrombospondin biology in oncology, although this is not specific to THBS1 inhibition and is not a current 2023–2024 development. (hassan2024thrombospondin1enhances pages 1-3)

5) Expert opinions and authoritative interpretation (2023–2024)

A key theme in recent authoritative synthesis is that THBS1 is context-dependent:
- Protective/stress-response framing: Human genetic loss-intolerance plus stress-challenge models support an interpretation that THBS1 contributes to survival under cardiovascular and immune stresses. (kaur2023whydohumans pages 1-3)
- Pathogenic framing: In multiple disease contexts, THBS1 can drive fibrosis-related signaling (via latent TGF‑β activation), pro-inflammatory signaling, or promote tumor cell invasion/migration in certain settings. (pan2024themolecularmechanism pages 2-3, mu2024thetΞ²ripromotes pages 10-11)
- Tissue-specific functional framing: THBS1 promotes epithelial restitution in intestinal injury models, underscoring that therapeutic targeting may require careful tissue and disease-context selection. (wilson2024criticalroleof pages 14-15)

6) Relevant statistics and data highlights (recent studies)

The strongest quantitative clinical dataset in the retrieved 2023–2024 literature is the ACLF biomarker study:
- AUROC values for mortality prediction (28-day and 90-day) from both PBMC expression and plasma levels, plus a plasma cutoff (<28 Β΅g/mL), all with explicit cohort sizes. (hassan2024thrombospondin1enhances pages 1-3)

Additional quantitative sample-size evidence for mechanistic causality includes hepatocyte-specific Thbs1 knockout survival experiments (n=18/group) reported within the ACLF paper’s mechanistic validation. (hassan2024thrombospondin1enhances pages 11-14)

7) Practical functional-annotation summary (curated statements)

Gene product: Thrombospondin‑1 (THBS1; TSP‑1) is a secreted extracellular matricellular glycoprotein that forms trimers and contains TSR/type I repeats, EGF-like domains, and a C-terminal CD47-binding region. (pan2024themolecularmechanism pages 1-2, pan2024themolecularmechanism media a02bfa76, pan2024themolecularmechanism pages 2-3)

Primary molecular functions (high-confidence):
1. Activates latent TGF‑β (extracellular activation enabling downstream TGF‑β signaling). (kaur2023whydohumans pages 6-7, pan2024themolecularmechanism pages 2-3)
2. Binds CD47 to suppress NO/cGMP signaling and modulate vascular responses and hemostasis. (kaur2023whydohumans pages 6-7)
3. Binds CD36 and integrins to regulate cell adhesion/migration and angiogenic responses (anti-angiogenic signaling is widely discussed). (kaur2023whydohumans pages 4-5, pan2024themolecularmechanism pages 2-3)

Where it acts: extracellular matrix/pericellular space, including sites of injury and tissue remodeling. (kaur2023whydohumans pages 3-4, pan2024themolecularmechanism pages 1-2)

Evidence map (for quick review)

Topic Mechanism/claim Key quantitative/statistical detail System/disease context Source (year; DOI/URL)
Identity, structure, receptors THBS1/TSP1 is a secreted extracellular matricellular glycoprotein of the Group A thrombospondins that forms a trimer; key regions include N-terminal domain, procollagen-like region, type I/TSR repeats, EGF-like/type II domains, type III repeats, and a C-terminal domain with a CD47-binding site. TSRs bind latent TGF-Ξ² and CD36; N-terminus and EGF-like domains engage integrins. Quantitative performance data not reported in the excerpt; structural summary is qualitative. Core functional annotation / extracellular matrix signaling Pan et al., 2024, Front Cardiovasc Med, doi:10.3389/fcvm.2024.1337586, https://doi.org/10.3389/fcvm.2024.1337586 (pan2024themolecularmechanism pages 2-3, pan2024themolecularmechanism pages 1-2, pan2024themolecularmechanism media a02bfa76)
CD47–NO/cGMP axis, hemostasis, stress response THBS1 engages CD47 to inhibit nitric oxide/cGMP signaling, reducing vasodilation and supporting platelet activation/thrombus formation; CD36 also contributes to thrombus formation on collagen. Authors interpret THBS1 as important for surviving environmental stress, especially cardiovascular and immune challenges. No explicit effect size given in the evidence snippet; mechanism emphasized as central to stress physiology. Vascular homeostasis, ischemic stress, hemostasis Kaur & Roberts, 2023, J Cell Commun Signal, doi:10.1007/s12079-023-00722-5, https://doi.org/10.1007/s12079-023-00722-5 (kaur2023whydohumans pages 3-4, kaur2023whydohumans pages 4-5, kaur2023whydohumans pages 6-7, kaur2023whydohumans pages 1-3)
Latent TGF-Ξ² activation / fibrosis signaling THBS1 is a major activator of latent TGF-Ξ² in vivo; this links THBS1 to downstream Smad2/3 signaling, fibroblast activation, ECM remodeling, and fibrosis. No single pooled statistic reported in the review excerpts. Fibrosis, cardiovascular remodeling, immune regulation Pan et al., 2024, Front Cardiovasc Med, doi:10.3389/fcvm.2024.1337586, https://doi.org/10.3389/fcvm.2024.1337586; Kaur & Roberts, 2023, doi:10.1007/s12079-023-00722-5, https://doi.org/10.1007/s12079-023-00722-5 (pan2024themolecularmechanism pages 4-6, kaur2023whydohumans pages 6-7)
Epithelial wound repair pathway Exogenous THBS1 enhances intestinal epithelial migration in a CD47- and TGF-Ξ²1-dependent manner; the study assayed SMAD2/3 and RhoA/Rac1 signaling, supporting a mechanism involving focal adhesion and cytoskeletal remodeling during restitution. Quantitative effect sizes were not included in the gathered snippets, but epithelial-specific loss of THBS1 impaired wound healing in vivo. Intestinal mucosal wound repair Wilson et al., 2024, JCI Insight, doi:10.1172/jci.insight.180608, https://doi.org/10.1172/jci.insight.180608 (wilson2024criticalroleof pages 14-15, wilson2024criticalroleof pages 17-19)
TGFΞ² receptor/integrin migratory complex In prostate cancer cells, THBS1 is a major TGFΞ²-induced secreted ECM protein that interacts with ITGAV and TGFΞ² receptor I (TΞ²RI); THBS1/ITGAV/TΞ²RI colocalize at the leading edge and support migration, invasion, and metastasis. No numerical hazard ratio or AUROC reported in the gathered snippets; qualitative mechanistic evidence from CRISPR/knockdown and xenograft experiments. Prostate cancer metastasis Mu et al., 2024, Oncogene, doi:10.1038/s41388-024-03165-3, https://doi.org/10.1038/s41388-024-03165-3 (mu2024thetΞ²ripromotes pages 5-7, mu2024thetΞ²ripromotes pages 1-2, mu2024thetΞ²ripromotes pages 10-11)
Biomarker performance in ACLF THBS1 was the top significantly upregulated PBMC transcript in HBV-related ACLF and tracked disease severity, inflammation, and hepatocellular apoptosis; plasma THBS1 showed prognostic utility for short-term mortality. Transcriptome subset: ACLF=20, LC=10, CHB=10, NC=15 within 330 COSSH participants. qPCR validation: ACLF=110, LC=60, CHB=60, NC=45. AUROC 0.8438 (28 d) and 0.7778 (90 d) for qPCR; plasma ELISA cohort ACLF=198, LC=50, CHB=50, NC=50 with AUROC 0.7445 (28 d) and 0.7175 (90 d); optimal plasma cutoff <28 Β΅g/ml; correlation with ALT and Ξ³-GT, P=0.01. Acute-on-chronic liver failure (HBV-related) Hassan et al., 2024, BMC Med, doi:10.1186/s12916-024-03318-x, https://doi.org/10.1186/s12916-024-03318-x (hassan2024thrombospondin1enhances pages 11-14, hassan2024thrombospondin1enhances pages 1-3)
Functional causality in liver failure model Hepatocyte-specific THBS1 knockout improved survival and reduced inflammatory cytokines and hepatocyte apoptosis in experimental liver failure, supporting a pathogenic role for THBS1 in ACLF. Survival study n=18/group over 48 h; serum/time-point analyses n=10 per time point; reported significance included ****P<0.0001 vs WT in the excerpt. Experimental acute liver failure / ACLF mechanism Hassan et al., 2024, BMC Med, doi:10.1186/s12916-024-03318-x, https://doi.org/10.1186/s12916-024-03318-x (hassan2024thrombospondin1enhances pages 11-14)
CKD-associated cardiac remodeling THBS1 drives cardiac remodeling in CKD; murine CKD increased myocardial THBS1 with left ventricular hypertrophy, fibrosis, and dysfunction, while TSP1 knockout was protective. Quantitative cohort or AUROC values were not provided in the gathered excerpt. Chronic kidney disease–associated cardiovascular disease Julovi et al., 2024, JACC Basic Transl Sci, doi:10.1016/j.jacbts.2024.01.010, https://doi.org/10.1016/j.jacbts.2024.01.010 (julovi2024thrombospondin1drivescardiac pages 1-2)
Obesity/fibro-adipogenic remodeling THBS1 promotes fibro-adipogenic progenitor expansion and contractile dysfunction of the diaphragm in obesity through TGF-Ξ²-associated stromal remodeling; Thbs1 loss is protective. No numeric effect size in the excerpt; authors describe THBS1 as a necessary mediator and potential therapeutic target. Obesity-associated respiratory muscle dysfunction Buras et al., 2024, JCI Insight, doi:10.1172/jci.insight.175047, https://doi.org/10.1172/jci.insight.175047 (buras2024thrombospondin1promotesfibroadipogenic pages 1-2)

Table: This table summarizes verified THBS1 mechanisms, receptors, and signaling pathways alongside the main 2024 quantitative findings available in the gathered evidence. It is useful as a compact evidence map linking annotation-relevant biology to translational and disease-focused data.

Key recent sources (with dates and URLs)

  • Kaur S, Roberts DD. Why do humans need thrombospondin‑1? Jan 2023. J Cell Commun Signal. https://doi.org/10.1007/s12079-023-00722-5 (kaur2023whydohumans pages 3-4, kaur2023whydohumans pages 6-7, kaur2023whydohumans pages 1-3)
  • Pan H, et al. The molecular mechanism of thrombospondin family members in cardiovascular diseases. Mar 2024. Front Cardiovasc Med. https://doi.org/10.3389/fcvm.2024.1337586 (pan2024themolecularmechanism pages 2-3, pan2024themolecularmechanism media a02bfa76)
  • Wilson ZS, et al. Critical role of thrombospondin‑1 in promoting intestinal mucosal wound repair. Jul 2024. JCI Insight. https://doi.org/10.1172/jci.insight.180608 (wilson2024criticalroleof pages 14-15, wilson2024criticalroleof pages 17-19)
  • Mu Y, et al. The TΞ²RI promotes migration and metastasis through thrombospondin 1 and ITGAV in prostate cancer cells. Sep 2024. Oncogene. https://doi.org/10.1038/s41388-024-03165-3 (mu2024thetΞ²ripromotes pages 1-2, mu2024thetΞ²ripromotes pages 10-11)
  • Hassan HMM, et al. Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure. Mar 2024. BMC Medicine. https://doi.org/10.1186/s12916-024-03318-x (hassan2024thrombospondin1enhances pages 1-3, hassan2024thrombospondin1enhances pages 11-14)

Limitations of the present retrieval

This report focuses on evidence captured by the current tool-retrieved corpus; several potentially relevant 2024 reviews (e.g., glioblastoma-focused) were flagged as unobtainable in the current run, and thus are not cited here. (hassan2024thrombospondin1enhances pages 1-3)

References

  1. (kaur2023whydohumans pages 3-4): Sukhbir Kaur and David D. Roberts. Why do humans need thrombospondin-1? Journal of Cell Communication and Signaling, 17:485-493, Jan 2023. URL: https://doi.org/10.1007/s12079-023-00722-5, doi:10.1007/s12079-023-00722-5. This article has 21 citations and is from a peer-reviewed journal.

  2. (pan2024themolecularmechanism pages 1-2): Heng Pan, Xiyi Lu, Di Ye, Yongqi Feng, Jun Wan, and Jing Ye. The molecular mechanism of thrombospondin family members in cardiovascular diseases. Frontiers in Cardiovascular Medicine, Mar 2024. URL: https://doi.org/10.3389/fcvm.2024.1337586, doi:10.3389/fcvm.2024.1337586. This article has 8 citations and is from a peer-reviewed journal.

  3. (pan2024themolecularmechanism media a02bfa76): Heng Pan, Xiyi Lu, Di Ye, Yongqi Feng, Jun Wan, and Jing Ye. The molecular mechanism of thrombospondin family members in cardiovascular diseases. Frontiers in Cardiovascular Medicine, Mar 2024. URL: https://doi.org/10.3389/fcvm.2024.1337586, doi:10.3389/fcvm.2024.1337586. This article has 8 citations and is from a peer-reviewed journal.

  4. (pan2024themolecularmechanism pages 2-3): Heng Pan, Xiyi Lu, Di Ye, Yongqi Feng, Jun Wan, and Jing Ye. The molecular mechanism of thrombospondin family members in cardiovascular diseases. Frontiers in Cardiovascular Medicine, Mar 2024. URL: https://doi.org/10.3389/fcvm.2024.1337586, doi:10.3389/fcvm.2024.1337586. This article has 8 citations and is from a peer-reviewed journal.

  5. (kaur2023whydohumans pages 6-7): Sukhbir Kaur and David D. Roberts. Why do humans need thrombospondin-1? Journal of Cell Communication and Signaling, 17:485-493, Jan 2023. URL: https://doi.org/10.1007/s12079-023-00722-5, doi:10.1007/s12079-023-00722-5. This article has 21 citations and is from a peer-reviewed journal.

  6. (kaur2023whydohumans pages 4-5): Sukhbir Kaur and David D. Roberts. Why do humans need thrombospondin-1? Journal of Cell Communication and Signaling, 17:485-493, Jan 2023. URL: https://doi.org/10.1007/s12079-023-00722-5, doi:10.1007/s12079-023-00722-5. This article has 21 citations and is from a peer-reviewed journal.

  7. (wilson2024criticalroleof pages 14-15): Zachary S. Wilson, Arturo Raya-Sandino, Jael Miranda, Shuling Fan, Jennifer C. Brazil, Miguel Quiros, Vicky Garcia-Hernandez, Qingyang Liu, Chang H. Kim, Kurt D. Hankenson, Asma Nusrat, and Charles A. Parkos. Critical role of thrombospondin-1 in promoting intestinal mucosal wound repair. JCI Insight, Jul 2024. URL: https://doi.org/10.1172/jci.insight.180608, doi:10.1172/jci.insight.180608. This article has 19 citations and is from a domain leading peer-reviewed journal.

  8. (wilson2024criticalroleof pages 17-19): Zachary S. Wilson, Arturo Raya-Sandino, Jael Miranda, Shuling Fan, Jennifer C. Brazil, Miguel Quiros, Vicky Garcia-Hernandez, Qingyang Liu, Chang H. Kim, Kurt D. Hankenson, Asma Nusrat, and Charles A. Parkos. Critical role of thrombospondin-1 in promoting intestinal mucosal wound repair. JCI Insight, Jul 2024. URL: https://doi.org/10.1172/jci.insight.180608, doi:10.1172/jci.insight.180608. This article has 19 citations and is from a domain leading peer-reviewed journal.

  9. (mu2024thetΞ²ripromotes pages 1-2): Yabing Mu, Anders Wallenius, Guangxiang Zang, Shaochun Zhu, Stina Rudolfsson, Karthik Aripaka, Anders Bergh, AndrΓ© Mateus, and MarΓ©ne LandstrΓΆm. The tΞ²ri promotes migration and metastasis through thrombospondin 1 and itgav in prostate cancer cells. Oncogene, 43:3321-3334, Sep 2024. URL: https://doi.org/10.1038/s41388-024-03165-3, doi:10.1038/s41388-024-03165-3. This article has 13 citations and is from a domain leading peer-reviewed journal.

  10. (mu2024thetΞ²ripromotes pages 10-11): Yabing Mu, Anders Wallenius, Guangxiang Zang, Shaochun Zhu, Stina Rudolfsson, Karthik Aripaka, Anders Bergh, AndrΓ© Mateus, and MarΓ©ne LandstrΓΆm. The tΞ²ri promotes migration and metastasis through thrombospondin 1 and itgav in prostate cancer cells. Oncogene, 43:3321-3334, Sep 2024. URL: https://doi.org/10.1038/s41388-024-03165-3, doi:10.1038/s41388-024-03165-3. This article has 13 citations and is from a domain leading peer-reviewed journal.

  11. (kaur2023whydohumans pages 1-3): Sukhbir Kaur and David D. Roberts. Why do humans need thrombospondin-1? Journal of Cell Communication and Signaling, 17:485-493, Jan 2023. URL: https://doi.org/10.1007/s12079-023-00722-5, doi:10.1007/s12079-023-00722-5. This article has 21 citations and is from a peer-reviewed journal.

  12. (buras2024thrombospondin1promotesfibroadipogenic pages 1-2): Eric D. Buras, Moon-Sook Woo, Romil Kaul Verma, Sri Harshita Kondisetti, Carol S. Davis, Dennis R. Claflin, Kimber Converso-Baran, Daniel E. Michele, Susan V. Brooks, and Tae-Hwa Chun. Thrombospondin-1 promotes fibro-adipogenic stromal expansion and contractile dysfunction of the diaphragm in obesity. JCI Insight, Jul 2024. URL: https://doi.org/10.1172/jci.insight.175047, doi:10.1172/jci.insight.175047. This article has 6 citations and is from a domain leading peer-reviewed journal.

  13. (hassan2024thrombospondin1enhances pages 1-3): Hozeifa Mohamed Hassan, Xi Liang, Jiaojiao Xin, Yingyan Lu, Qun Cai, Dongyan Shi, Keke Ren, Jun Li, Qi Chen, Jiang Li, Peng Li, Beibei Guo, Hui Yang, Jinjin Luo, Heng Yao, Xingping Zhou, Wen Hu, Jing Jiang, and Jun Li. Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure. BMC Medicine, Mar 2024. URL: https://doi.org/10.1186/s12916-024-03318-x, doi:10.1186/s12916-024-03318-x. This article has 27 citations and is from a domain leading peer-reviewed journal.

  14. (hassan2024thrombospondin1enhances pages 11-14): Hozeifa Mohamed Hassan, Xi Liang, Jiaojiao Xin, Yingyan Lu, Qun Cai, Dongyan Shi, Keke Ren, Jun Li, Qi Chen, Jiang Li, Peng Li, Beibei Guo, Hui Yang, Jinjin Luo, Heng Yao, Xingping Zhou, Wen Hu, Jing Jiang, and Jun Li. Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure. BMC Medicine, Mar 2024. URL: https://doi.org/10.1186/s12916-024-03318-x, doi:10.1186/s12916-024-03318-x. This article has 27 citations and is from a domain leading peer-reviewed journal.

  15. (pan2024themolecularmechanism pages 4-6): Heng Pan, Xiyi Lu, Di Ye, Yongqi Feng, Jun Wan, and Jing Ye. The molecular mechanism of thrombospondin family members in cardiovascular diseases. Frontiers in Cardiovascular Medicine, Mar 2024. URL: https://doi.org/10.3389/fcvm.2024.1337586, doi:10.3389/fcvm.2024.1337586. This article has 8 citations and is from a peer-reviewed journal.

  16. (mu2024thetΞ²ripromotes pages 5-7): Yabing Mu, Anders Wallenius, Guangxiang Zang, Shaochun Zhu, Stina Rudolfsson, Karthik Aripaka, Anders Bergh, AndrΓ© Mateus, and MarΓ©ne LandstrΓΆm. The tΞ²ri promotes migration and metastasis through thrombospondin 1 and itgav in prostate cancer cells. Oncogene, 43:3321-3334, Sep 2024. URL: https://doi.org/10.1038/s41388-024-03165-3, doi:10.1038/s41388-024-03165-3. This article has 13 citations and is from a domain leading peer-reviewed journal.

  17. (julovi2024thrombospondin1drivescardiac pages 1-2): Sohel M. Julovi, Katie Trinh, Harry Robertson, Cuicui Xu, Nikita Minhas, Seethalakshmi Viswanathan, Ellis Patrick, John D. Horowitz, Daniel N. Meijles, and Natasha M. Rogers. Thrombospondin-1 drives cardiac remodeling in chronic kidney disease. May 2024. URL: https://doi.org/10.1016/j.jacbts.2024.01.010, doi:10.1016/j.jacbts.2024.01.010. This article has 20 citations.

Artifacts

Citations

  1. pan2024themolecularmechanism pages 1-2
  2. pan2024themolecularmechanism pages 2-3
  3. kaur2023whydohumans pages 6-7
  4. kaur2023whydohumans pages 1-3
  5. wilson2024criticalroleof pages 14-15
  6. kaur2023whydohumans pages 3-4
  7. kaur2023whydohumans pages 4-5
  8. wilson2024criticalroleof pages 17-19
  9. pan2024themolecularmechanism pages 4-6
  10. https://doi.org/10.3389/fcvm.2024.1337586
  11. https://doi.org/10.1007/s12079-023-00722-5
  12. https://doi.org/10.3389/fcvm.2024.1337586;
  13. https://doi.org/10.1172/jci.insight.180608
  14. https://doi.org/10.1038/s41388-024-03165-3
  15. https://doi.org/10.1186/s12916-024-03318-x
  16. https://doi.org/10.1016/j.jacbts.2024.01.010
  17. https://doi.org/10.1172/jci.insight.175047
  18. https://doi.org/10.1007/s12079-023-00722-5,
  19. https://doi.org/10.3389/fcvm.2024.1337586,
  20. https://doi.org/10.1172/jci.insight.180608,
  21. https://doi.org/10.1038/s41388-024-03165-3,
  22. https://doi.org/10.1172/jci.insight.175047,
  23. https://doi.org/10.1186/s12916-024-03318-x,
  24. https://doi.org/10.1016/j.jacbts.2024.01.010,

OpenAI

(THBS1-deep-research-openai.md)
Thrombospondin-1 (THBS1/P07996) – Function, Processes, and Localization OpenAI o3-deep-research-2025-06-26 107 citations 2025-11-04T01:42:12.748529

Thrombospondin-1 (THBS1/P07996) – Function, Processes, and Localization

Introduction and Gene Overview

THBS1 encodes thrombospondin-1 (TSP1), a large secreted glycoprotein that plays regulatory rather than purely structural roles in the extracellular matrix (ECM) (link.springer.com) (www.genome.jp). TSP1 was originally discovered in platelets and belongs to the matricellular protein family – secreted factors that modulate cell–matrix interactions, cytokine activity, and receptor signaling without forming major structural fibers (link.springer.com). In humans, TSP1 is highly conserved and loss-of-function mutations are very rare, indicating critical importance. Deep exome analyses found far fewer inactivating mutations in THBS1 than expected (only 7 observed vs. ~56 predicted), giving THBS1 a pLI of 1.0 (highest loss-of-function intolerance) (link.springer.com). This contrasts with mice, where Thbs1 knockout is viable, suggesting that TSP1’s functions are essential for human survival under environmental stresses (link.springer.com) (link.springer.com). THBS1 is broadly expressed (low tissue specificity) with notable protein-level expression in platelets and certain immune cells (e.g. dendritic cells) (www.genome.jp). Overall, thrombospondin-1 is an adhesive, multi-functional ECM protein that orchestrates cell–cell and cell–matrix communication in processes such as angiogenesis, inflammation, and tissue repair (www.genome.jp).

Structure and Localization of Thrombospondin-1

Human TSP1 is a homotrimeric protein ~450 kDa in size, composed of three identical ~150 kDa subunits. Each TSP1 monomer is modular, containing multiple domains that enable diverse interactions (www.genome.jp). The N-terminal domain is a globular region responsible for binding glycosaminoglycans (heparan sulfate) and certain receptors. For example, this N-terminal region can bind cell-surface calreticulin (with co-receptor LRP1) and integrins, mediating cell adhesion and uptake/clearance of TSP1 (pmc.ncbi.nlm.nih.gov). A short coiled-coil segment near the N-terminus allows the three monomers to assemble via interchain disulfide bonds. Just downstream, TSP1 contains three type 1 repeats (TSRs) – unique peptide modules (each ~60 amino acids) originally called properdin repeats. These TSRs are critical for TSP1’s interactions with other proteins: they harbor the WSXW motifs that bind the receptor CD36 and a conserved LSKL sequence that binds latent TGF-Ξ² (discussed below). Following the TSRs, TSP1 has three type 2 repeats (EGF-like repeats) and a set of type 3 repeats, which are calcium-binding loops. Notably, the type 3 region contains an RGD sequence that can be recognized by integrins (e.g. Ξ±vΞ²3), though this site’s accessibility is regulated by disulfide bonds (www.mdpi.com). At the C-terminus, TSP1 has a globular cell-binding domain that mediates interactions with cell surface receptors including CD47 (also known as integrin-associated protein) (www.genome.jp) (pmc.ncbi.nlm.nih.gov). This multi-domain architecture equips thrombospondin-1 to bind numerous ligands and receptors simultaneously, effectively serving as an ECM scaffold and signaling hub.

Subcellular localization: TSP1 is a secreted protein that predominantly functions in the extracellular space and matrix (www.genome.jp). It is synthesized with a signal peptide for the secretory pathway and is released from cells into the ECM or circulation. Within tissues, TSP1 often associates with the ECM and cell surfaces by binding to proteoglycans and integrins (pmc.ncbi.nlm.nih.gov). Platelets are a major storage site: TSP1 is loaded in platelet α-granules and is secreted upon platelet activation (e.g. by thrombin) (www.genome.jp). Once released, TSP1 can bind to other matrix components (like fibrinogen, fibronectin, and collagens) and cluster on cell surfaces in a Ca²⁺-dependent manner (www.genome.jp). This localized extracellular presence is crucial for its role as a mediator between cells and their microenvironment. There is also evidence that cell-surface receptors (like LRP1) can internalize TSP1 for turnover, but its primary site of action is outside the cell on the cell membrane or ECM.

Biological Functions and Mechanisms of TSP1

Thrombospondin-1 is a multifunctional regulator of cellular behavior. Rather than catalyzing a single biochemical reaction (it is not an enzyme), TSP1 serves as an adaptor protein and signaling modulator in the extracellular milieu. Through its various binding domains, TSP1 influences a broad spectrum of biological processes – from blood vessel growth to immune cell activation – often acting as a molecular bridge or antagonist in key signaling pathways (link.springer.com). Below we detail TSP1’s major functions, the mechanisms involved, and where these actions occur:

Angiogenesis Inhibition

One of the most prominent roles of TSP1 is as an endogenous inhibitor of angiogenesis (the formation of new blood vessels). TSP1 was first identified in 1990 as a potent angiogenesis inhibitor, sparking interest in its anti-cancer potential (www.mdpi.com). Thrombospondin-1 directly suppresses endothelial cell proliferation, migration, and survival, thereby blocking the growth of new capillaries (www.mdpi.com). It can even induce endothelial apoptosis when present at sufficient levels (www.mdpi.com). Mechanistically, this anti-angiogenic effect is mediated by specific interactions on the surface of endothelial cells. In particular, TSP1’s type-1 repeats engage the receptor CD36 on microvascular endothelium (www.mdpi.com). Binding of TSP1 to CD36 triggers a signaling cascade (involving the Fyn tyrosine kinase and p38 MAPK, as shown in earlier studies) that leads to endothelial cell apoptosis and growth arrest. Consistent with this, CD36 was the first identified TSP1 receptor required for its angiogenesis-inhibitory activity (www.mdpi.com). Small peptide mimetics derived from the TSP1 TSR sequence that binds CD36 (e.g. the 2nd TSR’s RFYVVM motif) have demonstrated anti-angiogenic effects in preclinical tumor models (www.mdpi.com). Some of these peptides (e.g. ABT-510) even advanced to clinical trials as anti-cancer agents, although they did not achieve significant efficacy in human studies (www.mdpi.com).

Beyond the CD36 pathway, TSP1 inhibits angiogenesis through sequestration and neutralization of pro-angiogenic factors. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) are key growth factors that stimulate blood vessel formation. TSP1 can bind directly to VEGF and FGF-2, preventing these factors from effectively engaging their receptors on endothelial cells (www.mdpi.com). By acting as a sink for pro-angiogenic cytokines, TSP1 further tilts the balance toward vessel growth suppression. TSP1 also interacts with platelet-derived growth factor (PDGF), and this interaction has been reported to modulate recruitment of cells like pericytes during angiogenesis (www.mdpi.com). In tissues, these combined actions make TSP1 a critical break on neovascularization. For example, tumors often downregulate THBS1 expression to evade its anti-angiogenic influence, and loss of TSP1 in the tumor stroma is associated with more robust angiogenesis and tumor progression (www.mdpi.com). Conversely, in normal physiology, TSP1 is upregulated during wound healing and other contexts where unchecked vessel growth needs to be curtailed once initial repair is done (www.mdpi.com). Notably, Thbs1-null mice confirmed TSP1’s angiogenic role: they show an exaggerated blood vessel response under certain stresses, although in simple wound models TSP1’s function was more nuanced (as it also affects inflammation and repair, see below) (www.mdpi.com). Overall, by binding endothelial receptors (CD36) and growth factors (VEGF, FGF-2), TSP1 acts extracellularly to enforce an anti-angiogenic signaling environment, restraining new blood vessel formation.

Activation of Latent TGF-Ξ²1 and Growth Factor Regulation

Thrombospondin-1 plays a pivotal role in the TGF-Ξ² (transforming growth factor beta) pathway by converting TGF-Ξ² from its latent to active form. TGF-Ξ²1 is secreted as part of a latent complex (with latency-associated peptide, LAP, and latent TGF-Ξ² binding proteins) that keeps it inactive. TSP1 can bind to the latent TGF-Ξ²1 complex via sequences in its type-1 repeats, and this interaction induces a conformational change that releases active TGF-Ξ²1 (link.springer.com). The ability of TSP1 to activate latent TGF-Ξ²1 was first demonstrated in the late 1990s: Crawford et al. (1998) showed that TSP1 is necessary to activate TGF-Ξ²1 in vivo, explaining certain phenotypes of TSP1-null mice (link.springer.com). In Thbs1βˆ’/βˆ’ knockout mice, failure to activate TGF-Ξ²1 led to an unchecked inflammatory response – for example, young Thbs1-null mice developed chronic lung inflammation that was attributable to loss of TSP1-mediated TGF-Ξ² activation (link.springer.com). In normal mice, TSP1 activates TGF-Ξ²1 in the lung, increasing active TGF-Ξ²1 levels which suppress inflammation and maintain immune homeostasis (link.springer.com). This is a critical function of TSP1 in tissues: as TGF-Ξ²1 is a potent immunosuppressive and pro-fibrotic cytokine, TSP1 serves as an upstream controller that modulates TGF-Ξ² bioavailability. Indeed, when TSP1 is absent, not only inflammation but also certain tissue repair processes are altered. For instance, studies found that administering a TSP1-derived peptide (LSKL) that blocks TSP1–TGFΞ² interaction can reduce fibrosis in injury models, underlining TSP1’s role in driving TGF-Ξ² activation in fibrosis (link.springer.com).

Beyond TGF-Ξ²1, TSP1 can bind other growth factors or cytokines. It has affinity for vascular endothelial growth factor (VEGF) as noted, and can bind fibroblast growth factor-2, which affects not just angiogenesis but also general tissue remodeling (www.mdpi.com). TSP1 may also indirectly influence connective tissue growth factor (CTGF/CCN2): in a bleomycin-induced lung injury model, TSP1 limited tissue damage and was associated with reduced CTGF expression and collagen deposition, suggesting that TSP1’s activation of TGF-Ξ² (which can induce CTGF) is context-dependent and tightly regulated (link.springer.com). In summary, thrombospondin-1’s type-1 repeat domains provide a mechanism to activate latent TGF-Ξ²1 in the ECM (link.springer.com). Through this mechanism, TSP1 influences pathways of inflammation, immune tolerance, and fibrosis, since TGF-Ξ²1 signaling affects immune cell differentiation (e.g. promoting regulatory T-cells), extracellular matrix production, and resolution of inflammatory responses. This function is extracellular – TSP1 and latent TGF-Ξ² interact in the ECM or on cell surfaces, after TSP1 is secreted. By controlling a major cytokine’s activation state, TSP1 essentially links cell injury or stress signals (that induce TSP1 expression) to the TGF-β–driven healing and immune modulation response.

Cell Adhesion and ECM Remodeling

As an adhesive glycoprotein, thrombospondin-1 also contributes to cell–matrix and cell–cell adhesion dynamics. TSP1 can bind various matrix components and cell receptors to influence how cells attach, migrate, or organize in the tissue. For example, the N-terminal domain of TSP1 binds to glycosaminoglycans (e.g. heparan sulfate proteoglycans) in the matrix, effectively anchoring TSP1 to cell surfaces or the ECM (pmc.ncbi.nlm.nih.gov). Through this anchorage, TSP1 can present other binding sites to cells. Integrins are one set of receptors that interact with TSP1: the presence of an RGD sequence in TSP1’s type 3 repeats allows binding to integrins like Ξ±vΞ²3 (though under redox control) (www.mdpi.com), and other regions of TSP1 can engage integrin Ξ±4Ξ²1】 and Ξ±IIbΞ²3 (on platelets) as shown in various studies. By binding integrins, TSP1 can mediate cell adhesion to the matrix and influence signal transduction from the ECM. Interestingly, TSP1’s N-terminal domain also binds to a complex of calreticulin (a surface-expressed chaperone) with LDL-receptor–related protein-1 (LRP1). This calreticulin/LRP1/TSP1 interaction can trigger focal adhesion disassembly and cell motility, as shown in fibroblasts – essentially, TSP1 engagement causes cells to release from substratum and migrate, an activity requiring its N-terminal/collagen-like domain and the cell’s endocytic receptors (pmc.ncbi.nlm.nih.gov). Thus, TSP1 can have pro-migratory effects by modulating adhesion sites. In the ECM remodeling context, TSP1 has been reported to bind matrix proteases and protease inhibitors – for instance, it can bind MMP2 proenzyme and tissue inhibitor TIMP-2, localizing them on the ECM and regulating proteolytic activity. In a microbial infection model, TSP1 protected tissues from proteolytic damage by inhibiting proteases: in Pseudomonas-infected lungs, TSP1 limited pathogen and host protease activity, reducing injury (link.springer.com). These findings illustrate a broader structural/adaptor role: TSP1 organizes molecular complexes in the pericellular space, affecting cell adhesion, migration, and matrix turnover. Notably, platelet aggregation is partly facilitated by TSP1’s adhesive function: TSP1 can bind fibrinogen and fibronectin, helping to crosslink platelets during clot formation (pmc.ncbi.nlm.nih.gov). This occurs when TSP1 is released from platelet granules into a forming clot, where it binds fibrin/fibrinogen matrices and platelet integrins, thereby stabilizing platelet plugs. In summary, thrombospondin-1 acts as an extracellular β€œglue” and organizer, connecting cells to the matrix and concentrating molecules (integrins, proteases, growth factors) to specific sites, which is essential for connective tissue organization and wound repair (link.springer.com).

Regulation of Nitric Oxide Signaling and Vascular Tone

Thrombospondin-1 is a significant regulator of vasoactive signaling, particularly through its receptor CD47. Work by Isenberg, Roberts, and colleagues uncovered that TSP1–CD47 signaling antagonizes nitric oxide (NO)–cGMP signaling in vascular cells (link.springer.com). NO is a key endothelium-derived relaxing factor that binds and activates soluble guanylate cyclase in smooth muscle and platelets, raising cGMP to induce vasodilation and inhibit platelet activation. TSP1 binding to CD47 effectively blocks this pathway. Specifically, when TSP1 engages CD47 on endothelial cells, smooth muscle cells, or platelets, it inhibits NO-stimulated cGMP production and downstream signaling (link.springer.com). This occurs through CD47-dependent signaling that interferes with NO receptor activation and may promote degradation of the NO signaling components. Functionally, this means TSP1 can cause vasoconstriction and make platelets and vessels less responsive to NO. Indeed, experiments showed that blood vessels or platelets from Thbs1βˆ’/βˆ’ or Cd47βˆ’/βˆ’ mice have enhanced responses to NO (greater vasodilation, less platelet aggregation), whereas adding TSP1 blunts those responses (link.springer.com) (www.mdpi.com).

The physiological consequence of TSP1’s anti-NO signaling is context-dependent. In acute injury, this function is protective: TSP1 is rapidly released by platelets at wound sites and acts as a potent vasoconstrictor, helping to limit bleeding and promote hemostasis (www.mdpi.com). By constricting damaged blood vessels and making platelets more aggregable (less inhibited by NO), TSP1 via CD47 aids in clot stabilization (www.mdpi.com). Consistently, TSP1 is considered an autocrine factor in platelets that reinforces platelet activation and clot formation upon vascular injury (www.mdpi.com). However, in ischemic conditions (e.g. after a heart attack or in ischemic tissue wounds), TSP1’s vasoconstrictive action can be detrimental – it limits blood flow and tissue perfusion when more circulation would be beneficial (www.mdpi.com). This duality was seen in experiments: Thbs1-null mice recover better from certain ischemic injuries (due to unopposed NO signaling and better blood perfusion), yet they might bleed more without TSP1’s acute hemostatic effect (www.mdpi.com) (www.mdpi.com). Thus, TSP1 is a critical regulator of vascular tone and perfusion, exerting its effects outside the cell by binding CD47 on the cell surface. Notably, CD47 shares TSP1’s loss-of-function intolerance in humans (pLI ~0.9), suggesting evolutionary pressure to maintain this NO-inhibitory pathway for survival (link.springer.com) (link.springer.com). In summary, through the TSP1–CD47 axis, thrombospondin-1 integrates with the nitric oxide signaling pathway, inhibiting vasodilatory signals and promoting vasoconstriction and thrombosis as needed in vascular homeostasis (www.mdpi.com) (www.mdpi.com).

Immune Modulation and Inflammation

Thrombospondin-1 also modulates the immune system, with effects on both innate and adaptive immunity. Some of these effects are mediated by the pathways discussed above (TGF-Ξ² activation and NO signaling), while others involve direct cell–cell interactions. Active TGF-Ξ²1 generated by TSP1 can promote immune tolerance by driving the differentiation of regulatory T cells and suppressing effector T-cell activation, as well as by inhibiting excessive inflammatory responses (link.springer.com). This is exemplified by the Thbs1βˆ’/βˆ’ mouse’s inflammatory lung phenotype, which was rescued by restoring TGF-Ξ² activity (link.springer.com). In addition, TSP1’s interaction with CD47 influences immune cell behavior. CD47 is expressed on many immune cells and often functions as a β€œdo-not-eat-me” signal by interacting with SIRPΞ± on phagocytes. Binding of TSP1 to CD47 on T cells, dendritic cells, or NK cells can transmit signals that alter their activity. Studies have found that TSP1–CD47 signaling tends to dampen T-cell and NK cell activation, thereby limiting anti-tumor and anti-microbial immunity (www.mdpi.com) (link.springer.com). For instance, in cancer models, TSP1 is known to limit antitumor immunity: it can inhibit T-cell proliferation and cytotoxicity and also affect NK cell function via CD47, creating a more immunosuppressive tumor microenvironment (www.mdpi.com). Conversely, mice lacking TSP1 or CD47 show enhanced T-cell responses in some contexts, but they may also be more susceptible to certain infections due to dysregulated inflammation (link.springer.com) (link.springer.com). The net effect of TSP1 on immunity appears context-specific: it can either protect against overzealous inflammation (as in preventing immunopathology in infection or autoimmunity) or impede effective immune clearance (as in anti-tumor immunity).

TSP1 also affects innate immune cells such as macrophages. It is reported to bind CD36 on macrophages and synergize with Toll-like receptors, potentially enhancing inflammasome activation in sterile inflammation contexts (insight.jci.org). A recent study in kidney ischemia-reperfusion injury showed TSP1 interacting with CD36 on renal tubular cells and macrophages to amplify IL-1Ξ² production and inflammation (insight.jci.org) (insight.jci.org). Additionally, TSP1 can be released by immune cells themselves: for example, dendritic cells secrete TSP1, which then can act in an autocrine or paracrine manner to influence cell maturation and T-cell priming. In summary, TSP1 is a modulator of immune responses, operating largely in the extracellular space to control cytokine activation (e.g. TGF-Ξ²), to engage inhibitory receptors (CD47, CD36) on immune cells, and to shape the inflammatory milieu. These activities contribute to its role in regulating inflammation, host defense, and tissue immune privilege (link.springer.com). For instance, during an infection or injury, TSP1 might help contain damage by activating TGF-Ξ² and reducing NO (thus limiting inflammation and oxidative stress), but during cancer or chronic disease, high TSP1 can contribute to immune evasion and persistent inflammation (see below).

Pathways and Interactions Summary

Thrombospondin-1 does not function in isolation; it sits at nexus of multiple signaling and structural pathways. To summarize key pathways involving TSP1:

  • Angiogenesis Pathway: TSP1 opposes the pro-angiogenic VEGF/FGF pathways by directly binding growth factors and by triggering apoptosis in endothelial cells via CD36 (www.mdpi.com) (www.mdpi.com). It also modulates PDGF signaling in vessel maturation (www.mdpi.com). In this way, TSP1 is part of the body’s system for negative regulation of angiogenesis.
  • TGF-Ξ² Activation: TSP1 is an activator in the TGF-Ξ² signaling pathway, binding latent TGF-Ξ²1 and releasing active cytokine (link.springer.com). This places TSP1 upstream of numerous TGF-β–mediated processes (fibrosis, immune regulation, cell growth inhibition).
  • NO–cGMP Signaling: Through CD47, TSP1 intersects with the nitric oxide signaling cascade, inhibiting NO’s effects on cGMP production in vascular cells (link.springer.com). Thus, TSP1 is a counter-regulator in pathways controlling vasodilation, blood flow, and platelet reactivity.
  • Integrin and Adhesion signaling: By binding integrins (Ξ±vΞ²3, Ξ±IIbΞ²3>, etc.), TSP1 influences FAK and Src-family kinase signaling associated with cell adhesion and migration. Its interaction with calreticulin/LRP1 on cells triggers cytoskeletal signaling leading to focal adhesion turnover. These interactions tie TSP1 to pathways of cell motility and ECM remodeling.
  • Immune signaling: TSP1 impacts immune cell receptor pathways – for example, signals through CD47 on T cells (which can modulate Ca²⁺ and cyclic nucleotide signals in those cells), and CD36/TLR in macrophages (affecting NF-ΞΊB and inflammasome pathways) (insight.jci.org). TSP1-activated TGF-Ξ² also feeds into Smad signaling in immune cells to promote regulatory phenotypes. Thus, TSP1 intersects with inflammatory signaling networks (e.g. NF-ΞΊB, NLRP3 inflammasome, TGF-Ξ²/Smad).

Importantly, these pathways do not act in isolation. For instance, in a wound-healing scenario, TSP1 is upregulated and simultaneously inhibits angiogenesis (via CD36), promotes clotting and vasoconstriction (via CD47), and activates TGF-Ξ² (via TSRs) to control scar formation and inflammation. These coordinated actions illustrate how TSP1 functions as a matricellular coordinator of complex biological responses (link.springer.com).

Current Research and Clinical Perspectives

Because of its central regulatory roles, THBS1/TSP1 has been a focus of both fundamental and translational research. Current developments (2023–2024) continue to uncover new dimensions of TSP1 function and potential clinical applications:

  • β€œInflammaging” and Aging: A 2023 study identified TSP1 as a key driver of age-related chronic inflammation (inflammaging) in blood stem cells (pubmed.ncbi.nlm.nih.gov). Old hematopoietic stem cells show elevated Thbs1, and genetic or pharmacologic suppression of TSP1 improved stem cell function and reduced inflammatory cytokines, effectively prolonging hematopoietic healthspan in mice (pubmed.ncbi.nlm.nih.gov). This positions TSP1 as a promising target to mitigate age-associated immune decline.
  • Metabolic and Fibrotic Diseases: TSP1 has been implicated in metabolic syndrome (promoting adipose tissue inflammation and insulin resistance) (www.genome.jp) and in organ fibrosis (via TGF-Ξ² activation). For example, blocking TSP1–TGFΞ² interaction is being explored to treat fibrosis in kidneys, lungs, and liver (link.springer.com). Upregulated THBS1 is observed in fibrotic or inflammatory lesions, and animal models with Thbs1 knockout are protected in some settings of obesity-related inflammation and tissue fibrosis (www.genome.jp).
  • Cancer Therapy: Given its role in suppressing angiogenesis and immune surveillance in tumors, TSP1 is being studied as both a therapeutic target and a therapeutic agent. On one hand, downregulating TSP1 or blocking its receptors (like CD47) can boost anti-tumor immunity and blood flow to tumors; indeed, anti-CD47 antibodies are in clinical trials to stimulate macrophage-mediated tumor clearance (these trials were motivated in part by the knowledge that TSP1-CD47 signaling restrains immune attack on tumors) (www.mdpi.com). On the other hand, analogs of TSP1 have been tested to inhibit tumor angiogenesis – e.g., the TSP1-mimetic peptide ABT-510 was trialed in cancer patients to cut off tumor blood supply. While safe, these TSP1-mimetics had limited efficacy as single agents (www.mdpi.com), suggesting combination approaches or more potent formulations may be needed.
  • Cardiovascular Disease: THBS1 polymorphisms in humans have been linked to cardiovascular risk. A notable example is a THBS1 allele associated with early myocardial infarction and altered calcium-binding in TSP1 (link.springer.com). Elevated TSP1 is also found in atherosclerotic plaques and may influence plaque stability by regulating proteases and calling in inflammatory cells (via its chemoattractant domains for monocytes) (pmc.ncbi.nlm.nih.gov). Therapies aimed at TSP1-CD47 are being considered for improving tissue survival after heart attack or stroke by relieving TSP1’s brake on NO-mediated blood flow (www.mdpi.com).
  • Biomarker Potential: TSP1 is emerging as a biomarker for disease severity in certain conditions. For instance, a 2024 clinical study in acute-on-chronic liver failure (ACLF) identified THBS1 as the most upregulated gene in patients’ blood cells, with TSP1 levels closely correlating with inflammation and liver injury severity (pmc.ncbi.nlm.nih.gov). High plasma TSP1 predicted short-term mortality in ACLF (28-day AUROC ~0.74) (pmc.ncbi.nlm.nih.gov), highlighting its value as a prognostic marker. This makes sense given TSP1’s role in amplifying systemic inflammation; indeed, in ACLF models, TSP1 exacerbates inflammatory injury in the liver and TSP1 knockout mice were protected from liver damage (pmc.ncbi.nlm.nih.gov). Such findings underscore TSP1’s relevance not only as a functional player but also as an indicator of disease activity.

In summary, thrombospondin-1 (THBS1) is a versatile extracellular regulator with a well-defined primary role: it mediates cell–matrix interactions and modulates key signaling pathways (angiogenic, TGF-Ξ², NO/cGMP) in the extracellular environment. Its action is largely outside the cell, where it binds to other proteins and receptors to influence processes like angiogenesis (inhibition), wound healing, immune regulation, and vascular homeostasis (link.springer.com). TSP1’s functions are supported by substantial experimental evidence, from molecular interaction studies to animal models, and even human genetic data. Authoritative reviews and studies (as of 2023) stress that while TSP1 is not required for basic development in mice, it becomes crucial under stress conditions – regulating bleeding, ischemia, and infection outcomes (link.springer.com) (www.mdpi.com). This explains why humans have evolved to strongly conserve THBS1. Its multifaceted roles in pathology also make it a target of interest for new therapies and a useful biomarker in inflammatory and vascular diseases. Continuing research is actively uncovering new mechanisms (like in aging and stem cell niches) for this protein, reaffirming thrombospondin-1 as a central extracellular β€œorchestrator” of cellular function in human biology (link.springer.com).

Sources:

  • Bornstein P. & Sage E. (2014). Matricellular proteins in cell-matrix communication. Matrix Biol. (Review) (link.springer.com) (link.springer.com).
  • Adams J.C. & Lawler J. (2004). The thrombospondin family: multifunctional regulators of cell interactions. J. Cell Sci. (Review) (www.genome.jp) (pmc.ncbi.nlm.nih.gov).
  • Lawler J. et al. (1998). Thrombospondin-1–null mice: inflammation and tissue homeostasis findings. J. Clin. Invest. (link.springer.com).
  • Crawford S.E. et al. (1998). Thrombospondin-1 enables latent TGF-Ξ² activation in vivo. J. Clin. Invest. (link.springer.com).
  • Isenberg J.S. et al. (2008). Thrombospondin-1/CD47 blocking of nitric oxide signaling modulates vascular responses. Proc. Natl. Acad. Sci. USA (link.springer.com).
  • Kaur S. et al. (2021). Functions of Thrombospondin-1 in the Tumor Microenvironment. Int. J. Mol. Sci. 22(9):4570 (www.mdpi.com) (www.mdpi.com).
  • Gao A.G. et al. (1996). TSP1 binds CD47 to regulate integrin-associated signaling. J. Biol. Chem. (www.genome.jp).
  • JimΓ©nez B. et al. (2000). Signals through CD36 mediate TSP1’s anti-angiogenic effects. Nature Med. (www.genome.jp).
  • β€œWhy do humans need thrombospondin-1?” – Roberts D.D. (2023). J. Cell Commun. Signal. 17:485–493 (Review) (link.springer.com) (link.springer.com).
  • BMC Medicine (2024). THBS1 as biomarker in acute-on-chronic liver failure. BMC Med. 22:95 (pmc.ncbi.nlm.nih.gov). (Plus additional references within text)

Citations

  1. AnnotationURLCitation(end_index=444, start_index=280, title='Why do humans need thrombospondin-1? | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00722-5#:~:text=Several%20families%20of%20secreted%20proteins,2014%20%3B%20Leask%20%2010')
  2. AnnotationURLCitation(end_index=605, start_index=445, title='UniProt: P07996', type='url_citation', url='https://www.genome.jp/dbget-bin/www_bget?uniprot%3AP07996=#:~:text=CC%20%20%20,PubMed%3A15014436%2C%20PubMed%3A18285447%2C%20PubMed%3A2430973')
  3. AnnotationURLCitation(end_index=1004, start_index=840, title='Why do humans need thrombospondin-1? | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00722-5#:~:text=Several%20families%20of%20secreted%20proteins,2014%20%3B%20Leask%20%2010')
  4. AnnotationURLCitation(end_index=1463, start_index=1308, title='Why do humans need thrombospondin-1? | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00722-5#:~:text=In%20contrast%20to%20the%20Thbs1,this%20gene%20to%20be%20highly')
  5. AnnotationURLCitation(end_index=1741, start_index=1622, title='Why do humans need thrombospondin-1? | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00722-5#:~:text=Thbs1,92%29%20%28Kaur%20and')
  6. AnnotationURLCitation(end_index=1848, start_index=1742, title='Why do humans need thrombospondin-1? | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00722-5#:~:text=Thbs1,Isenberg')
  7. AnnotationURLCitation(end_index=2173, start_index=2005, title='UniProt: P07996', type='url_citation', url='https://www.genome.jp/dbget-bin/www_bget?uniprot%3AP07996=#:~:text=CC%20%20%20,ECO%3A0000269%7CPubMed%3A101549%2C%20ECO%3A0000269%7CPubMed%3A14568985')
  8. AnnotationURLCitation(end_index=2535, start_index=2375, title='UniProt: P07996', type='url_citation', url='https://www.genome.jp/dbget-bin/www_bget?uniprot%3AP07996=#:~:text=CC%20%20%20,PubMed%3A15014436%2C%20PubMed%3A18285447%2C%20PubMed%3A2430973')
  9. AnnotationURLCitation(end_index=2952, start_index=2792, title='UniProt: P07996', type='url_citation', url='https://www.genome.jp/dbget-bin/www_bget?uniprot%3AP07996=#:~:text=CC%20%20%20,PubMed%3A15014436%2C%20PubMed%3A18285447%2C%20PubMed%3A2430973')
  10. AnnotationURLCitation(end_index=3391, start_index=3252, title='The Structures of the Thrombospondin-1 N-Terminal Domain and Its Complex with a Synthetic Pentameric Heparin - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2896259/#:~:text=interaction%20with%20,a%20%CE%B2%20sandwich%20with%2013')
  11. AnnotationURLCitation(end_index=4293, start_index=4204, title='Functions of Thrombospondin-1 in the Tumor Microenvironment', type='url_citation', url='https://www.mdpi.com/1088670#:~:text=integrins%20mediate%20the%20pro,30')
  12. AnnotationURLCitation(end_index=4640, start_index=4480, title='UniProt: P07996', type='url_citation', url='https://www.genome.jp/dbget-bin/www_bget?uniprot%3AP07996=#:~:text=CC%20%20%20,PubMed%3A15014436%2C%20PubMed%3A18285447%2C%20PubMed%3A2430973')
  13. AnnotationURLCitation(end_index=4780, start_index=4641, title='The Structures of the Thrombospondin-1 N-Terminal Domain and Its Complex with a Synthetic Pentameric Heparin - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2896259/#:~:text=interaction%20with%20,a%20%CE%B2%20sandwich%20with%2013')
  14. AnnotationURLCitation(end_index=5186, start_index=5079, title='UniProt: P07996', type='url_citation', url='https://www.genome.jp/dbget-bin/www_bget?uniprot%3AP07996=#:~:text=CC%20%20%20,activated')
  15. AnnotationURLCitation(end_index=5588, start_index=5425, title='The Structures of the Thrombospondin-1 N-Terminal Domain and Its Complex with a Synthetic Pentameric Heparin - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2896259/#:~:text=In%20many%20cases%2C%20the%20TSPN,might%20direct%20the%20cell%20differentiation')
  16. AnnotationURLCitation(end_index=5841, start_index=5728, title='UniProt: P07996', type='url_citation', url='https://www.genome.jp/dbget-bin/www_bget?uniprot%3AP07996=#:~:text=CC%20%20%20%20,Incorporated')
  17. AnnotationURLCitation(end_index=6115, start_index=6005, title='UniProt: P07996', type='url_citation', url='https://www.genome.jp/dbget-bin/www_bget?uniprot%3AP07996=#:~:text=CC%20%20%20,Incorporated')
  18. AnnotationURLCitation(end_index=7102, start_index=6933, title='Why do humans need thrombospondin-1? | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00722-5#:~:text=The%20diverse%20biological%20functions%20of,knockout%20mice%20can%20also%20be')
  19. AnnotationURLCitation(end_index=7632, start_index=7480, title='Functions of Thrombospondin-1 in the Tumor Microenvironment', type='url_citation', url='https://www.mdpi.com/1088670#:~:text=independent%20reports%20in%201990%20identifying,results%2C%20TSP1%20inhibited%20angiogenesis%20in')
  20. AnnotationURLCitation(end_index=7931, start_index=7779, title='Functions of Thrombospondin-1 in the Tumor Microenvironment', type='url_citation', url='https://www.mdpi.com/1088670#:~:text=independent%20reports%20in%201990%20identifying,results%2C%20TSP1%20inhibited%20angiogenesis%20in')
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  27. AnnotationURLCitation(end_index=10305, start_index=10250, title='Functions of Thrombospondin-1 in the Tumor Microenvironment', type='url_citation', url='https://www.mdpi.com/1088670#:~:text=')
  28. AnnotationURLCitation(end_index=10690, start_index=10595, title='Functions of Thrombospondin-1 in the Tumor Microenvironment', type='url_citation', url='https://www.mdpi.com/1088670#:~:text=cancers,the%20tumor%20and%20its%20stroma')
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  97. AnnotationURLCitation(end_index=39940, start_index=39801, title='The Structures of the Thrombospondin-1 N-Terminal Domain and Its Complex with a Synthetic Pentameric Heparin - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2896259/#:~:text=interaction%20with%20,a%20%CE%B2%20sandwich%20with%2013')
  98. AnnotationURLCitation(end_index=40240, start_index=40068, title='Why do humans need thrombospondin-1? | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00722-5#:~:text=Studies%20have%20identified%20several%20mechanisms,However%2C%20the%20originally')
  99. AnnotationURLCitation(end_index=40528, start_index=40356, title='Why do humans need thrombospondin-1? | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00722-5#:~:text=Studies%20have%20identified%20several%20mechanisms,However%2C%20the%20originally')
  100. AnnotationURLCitation(end_index=40789, start_index=40683, title='Why do humans need thrombospondin-1? | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00722-5#:~:text=Thbs1,Isenberg')
  101. AnnotationURLCitation(end_index=41066, start_index=40914, title='Functions of Thrombospondin-1 in the Tumor Microenvironment', type='url_citation', url='https://www.mdpi.com/1088670#:~:text=independent%20reports%20in%201990%20identifying,results%2C%20TSP1%20inhibited%20angiogenesis%20in')
  102. AnnotationURLCitation(end_index=41176, start_index=41067, title='Functions of Thrombospondin-1 in the Tumor Microenvironment', type='url_citation', url='https://www.mdpi.com/1088670#:~:text=match%20at%20L310%20CD36%20was,have%20been%20developed')
  103. AnnotationURLCitation(end_index=41402, start_index=41286, title='UniProt: P07996', type='url_citation', url='https://www.genome.jp/dbget-bin/www_bget?uniprot%3AP07996=#:~:text=RP%20%20%20FUNCTION%2C%20AND,A')
  104. AnnotationURLCitation(end_index=41648, start_index=41513, title='UniProt: P07996', type='url_citation', url='https://www.genome.jp/dbget-bin/www_bget?uniprot%3AP07996=#:~:text=RP%20%20%20FUNCTION%2C%20AND,RA%20%20%20Bouck%20N')
  105. AnnotationURLCitation(end_index=41870, start_index=41764, title='Why do humans need thrombospondin-1? | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00722-5#:~:text=Thbs1,Isenberg')
  106. AnnotationURLCitation(end_index=42043, start_index=41871, title='Why do humans need thrombospondin-1? | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00722-5#:~:text=Studies%20have%20identified%20several%20mechanisms,However%2C%20the%20originally')
  107. AnnotationURLCitation(end_index=42329, start_index=42145, title='Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10913480/#:~:text=THBS1%20was%20the%20top%20significantly,ACLF%E2%80%89%3D%E2%80%89198%3B%20LC%E2%80%89%3D%E2%80%8950')

πŸ“„ View Raw YAML

 
id: P07996
gene_symbol: THBS1
product_type: PROTEIN
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >
  Thrombospondin-1 is a secreted matricellular glycoprotein that mediates cell-matrix
  interactions and modulates key signaling pathways (angiogenic, TGF-beta, NO/cGMP)
  in
  the extracellular environment. It functions as a negative regulator of angiogenesis
  via CD36 receptor engagement, an activator of latent TGF-beta1, and an inhibitor
  of
  nitric oxide signaling via CD47. TSP1 is stored in platelet alpha granules and
  released upon activation, where it promotes hemostasis and vasoconstriction.
existing_annotations:
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >
      TSP1 is a well-established component of the extracellular matrix. The deep research
      confirms that TSP1 is "secreted into the ECM or circulation" and "associates
      with
      the ECM and cell surfaces by binding to proteoglycans and integrins" [PMID:6341993].
      This is a core localization for TSP1.
    action: ACCEPT
    reason: >
      Strong phylogenetic and experimental evidence supports TSP1 localization to
      the
      extracellular matrix. TSP1 is a matricellular protein that functions in the
      ECM
      to regulate cell-matrix interactions.
    supported_by:
    - reference_id: file:human/THBS1/THBS1-deep-research-openai.md
      supporting_text: >
        TSP1 is a secreted protein that predominantly functions in the extracellular
        space
        and matrix. Within tissues, TSP1 often associates with the ECM and cell surfaces
        by binding to proteoglycans and integrins.
    - reference_id: file:human/THBS1/THBS1-deep-research-falcon.md
      supporting_text: >-
        a secreted matricellular (ECM-associated) glycoprotein in the Group A
        thrombospondin subfamily that forms trimers in the extracellular space
- term:
    id: GO:0016525
    label: negative regulation of angiogenesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >
      Negative regulation of angiogenesis is one of the best-documented core functions
      of TSP1. The protein was first identified as a potent angiogenesis inhibitor
      in 1990.
      TSP1 suppresses endothelial cell proliferation, migration, survival, and can
      induce
      endothelial apoptosis via CD36 receptor engagement [PMID:10613822].
    action: ACCEPT
    reason: >
      This represents a core function of TSP1. The IBA annotation is well-supported
      by
      extensive experimental evidence showing TSP1 inhibits angiogenesis through CD36-mediated
      signaling and sequestration of pro-angiogenic factors like VEGF and FGF-2.
    supported_by:
    - reference_id: file:human/THBS1/THBS1-deep-research-openai.md
      supporting_text: >
        TSP1 directly suppresses endothelial cell proliferation, migration, and survival,
        thereby blocking the growth of new capillaries. It can even induce endothelial
        apoptosis when present at sufficient levels.
    - reference_id: file:human/THBS1/THBS1-deep-research-falcon.md
      supporting_text: >-
        THBS1 binds CD36 (via TSRs) and contributes to platelet and vascular
        effects; CD36 is also part of anti-angiogenic signaling.
- term:
    id: GO:0001525
    label: angiogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >
      TSP1 is involved in angiogenesis, though primarily as a negative regulator.
      The
      broader term "angiogenesis" is appropriate as TSP1 modulates this process. However,
      a more specific term (negative regulation of angiogenesis) better captures its
      function.
    action: ACCEPT
    reason: >
      While the more specific term "negative regulation of angiogenesis" is more accurate,
      this broader term is not incorrect. TSP1 is indeed involved in angiogenesis
      as a
      key regulator. The IEA annotation from keyword mapping is acceptable.
- term:
    id: GO:0001937
    label: negative regulation of endothelial cell proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >
      TSP1 inhibits endothelial cell proliferation as part of its anti-angiogenic
      function.
      This is well-documented through multiple mechanisms including CD36-mediated
      signaling
      and inhibition of growth factor signaling [PMID:10613822, PMID:17596205].
    action: ACCEPT
    reason: >
      This is a well-supported aspect of TSP1's anti-angiogenic function. Multiple
      studies
      demonstrate TSP1 suppresses endothelial cell proliferation through CD36 engagement
      and growth factor sequestration.
- term:
    id: GO:0002684
    label: positive regulation of immune system process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >
      TSP1 has complex effects on the immune system. Evidence suggests TSP1 primarily
      has immunosuppressive effects - negatively regulating cytokine production through
      CD47 and CD36 interactions [PMID:14568985]. However, it can also amplify certain
      inflammatory responses in specific contexts.
    action: MARK_AS_OVER_ANNOTATED
    reason: >
      This annotation is too broad and somewhat misleading. TSP1's predominant role
      is
      immunosuppressive - it negatively regulates IL-12, TNF-alpha, and IL-10 production
      through CD47/CD36 signaling and limits T-cell/NK cell activation. While TSP1
      can
      enhance certain immune responses in specific contexts, this broad positive
      regulation term does not accurately capture TSP1's function.
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >
      TSP1 contains multiple calcium-binding sites, particularly within its type 3
      repeats. Calcium binding is essential for TSP1 structure and function, affecting
      its conformation and ligand-binding properties. The UniProt record documents
      calcium-binding sites throughout the protein.
    action: ACCEPT
    reason: >
      Calcium binding is a well-documented property of TSP1. The type 3 repeat region
      contains multiple calcium-binding loops that are critical for protein structure
      and function. This is supported by structural studies and InterPro domain analysis.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >
      TSP1 is a secreted protein that functions in the extracellular region. It is
      synthesized with a signal peptide and released from cells into the ECM or circulation.
    action: ACCEPT
    reason: >
      This is a core localization for TSP1 as a secreted matricellular protein.
      The protein is synthesized with a signal peptide and released into the
      extracellular space.
    supported_by:
    - reference_id: file:human/THBS1/THBS1-deep-research-falcon.md
      supporting_text: >-
        thrombospondins as secreted extracellular glycoproteins that are
        typically low at baseline and induced after tissue damage; THBS1
        (TSP-1) is a Group A thrombospondin acting at the cell surface/ECM
        interface.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >
      TSP1 transits through the ER as part of its secretory pathway. The ER lumen
      is
      where TSP1 undergoes post-translational modifications including glycosylation
      and disulfide bond formation prior to secretion.
    action: ACCEPT
    reason: >
      As a secreted protein, TSP1 transits through the ER during biosynthesis. This
      is a transit compartment rather than a site of function, but the annotation
      is
      accurate for localization purposes.
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >
      TSP1 is involved in apoptosis, particularly in inducing apoptosis of endothelial
      cells via CD36 signaling as part of its anti-angiogenic function [PMID:10613822].
      TSP1 can also promote or protect against apoptosis depending on context and
      receptor.
    action: ACCEPT
    reason: >
      TSP1 is clearly involved in apoptotic processes. It induces endothelial cell
      apoptosis through CD36-mediated signaling (key to anti-angiogenic function)
      but
      can also signal survival through calreticulin/LRP1. The broad term is appropriate.
- term:
    id: GO:0006954
    label: inflammatory response
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >
      TSP1 is involved in modulating the inflammatory response. TSP1 null mice show
      persistent multi-organ inflammation, indicating TSP1 normally helps resolve
      inflammation. TSP1 activates TGF-beta1 (immunosuppressive) and negatively
      regulates cytokine production through CD47/CD36 [PMID:14568985].
    action: ACCEPT
    reason: >
      TSP1 plays important roles in inflammatory responses, primarily as an
      immunosuppressive/anti-inflammatory mediator. The annotation is appropriate
      though it does not capture the directional effect.
- term:
    id: GO:0006986
    label: response to unfolded protein
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >
      This annotation appears to derive from UniProt keyword mapping. TSP1 expression
      may be induced under ER stress conditions, but there is limited direct evidence
      that TSP1 is a primary component of the unfolded protein response.
    action: KEEP_AS_NON_CORE
    reason: >
      While TSP1 may be induced during ER stress, this is not a core function. The
      annotation is likely based on induction rather than direct mechanistic
      involvement in the UPR pathway.
- term:
    id: GO:0007155
    label: cell adhesion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >
      TSP1 is an adhesive glycoprotein that mediates cell-matrix and cell-cell adhesion.
      It binds integrins, proteoglycans, and other ECM components to influence cell
      attachment and migration. The N-terminal domain binds calreticulin/LRP1 to
      modulate focal adhesion dynamics [deep research].
    action: ACCEPT
    reason: >
      Cell adhesion is a well-documented function of TSP1 as an adhesive glycoprotein.
      TSP1 binds multiple integrins and ECM components to mediate cell-matrix interactions.
- term:
    id: GO:0008201
    label: heparin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >
      TSP1 binds heparin and heparan sulfate proteoglycans through its N-terminal
      domain. This binding is important for TSP1 localization in the ECM and for
      some of its biological activities [PMID:101549].
    action: ACCEPT
    reason: >
      Heparin binding is a well-documented property of TSP1. The N-terminal domain
      contains a heparin-binding region that mediates interactions with glycosaminoglycans.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >
      TSP1 can associate with the cell surface through binding to membrane receptors
      (CD36, CD47, integrins) and proteoglycans. Upon release from platelets, TSP1
      binds to platelet surfaces in a Ca2+-dependent manner [PMID:6777381].
    action: ACCEPT
    reason: >
      Cell surface association is well-documented for TSP1. The secreted protein
      binds to various cell surface receptors and can accumulate on cell membranes.
- term:
    id: GO:0010810
    label: regulation of cell-substrate adhesion
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >
      TSP1 modulates cell-substrate adhesion through its interactions with integrins
      and the calreticulin/LRP1 complex. The N-terminal domain can trigger focal
      adhesion disassembly and promote cell motility [deep research].
    action: ACCEPT
    reason: >
      TSP1 regulates cell-substrate adhesion as part of its matricellular function.
      It can both promote and inhibit adhesion depending on context and receptor
      engagement.
- term:
    id: GO:0016529
    label: sarcoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >
      This annotation may derive from UniProt subcellular location mapping. TSP1 is
      primarily known as an extracellular/secreted protein. Localization to SR may
      relate to expression in muscle cells during biosynthesis.
    action: KEEP_AS_NON_CORE
    reason: >
      Sarcoplasmic reticulum localization is not a well-established or primary site
      for TSP1 function. The protein primarily functions in the extracellular space.
- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >
      TSP1 can promote cell migration in certain contexts. Through calreticulin/LRP1
      engagement, TSP1 triggers focal adhesion disassembly and promotes cell motility.
      It can also stimulate migration of fibroblasts and some tumor cells [PMID:18555217].
    action: ACCEPT
    reason: >
      TSP1 has documented pro-migratory effects in specific cellular contexts,
      particularly through calreticulin/LRP1 signaling that promotes focal adhesion
      turnover. However, effects on migration are cell-type dependent.
- term:
    id: GO:0030511
    label: positive regulation of transforming growth factor beta receptor
      signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >
      TSP1 activates latent TGF-beta1 through direct binding via sequences in its
      type-1 repeats. This releases active TGF-beta1 which can then signal through
      TGF-beta receptors. This is a core function of TSP1 [deep research].
    action: ACCEPT
    reason: >
      This is a well-established core function of TSP1. TSP1 is necessary to activate
      TGF-beta1 in vivo, and TSP1-null mice phenocopy aspects of TGF-beta1 null mice
      with multi-organ inflammation.
    supported_by:
    - reference_id: file:human/THBS1/THBS1-deep-research-falcon.md
      supporting_text: >-
        Multiple 2023–2024 sources characterize THBS1/TSP‑1 as a major
        mediator/activator of latent TGF‑β. This function positions THBS1
        upstream of profibrotic and immunoregulatory programs (e.g., Smad
        signaling and downstream ECM remodeling).
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >
      Duplicate of the IBA annotation. TSP1 is a well-established ECM component.
    action: ACCEPT
    reason: >
      Same term as IBA annotation - TSP1 localization to ECM is well supported.
- term:
    id: GO:0031091
    label: platelet alpha granule
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >
      TSP1 was originally discovered in platelets where it is stored in alpha granules
      and released upon platelet activation (e.g., by thrombin) [PMID:101549, deep
      research].
      This is a primary storage site for TSP1.
    action: ACCEPT
    reason: >
      Platelet alpha granule is a core localization for TSP1. The protein was first
      characterized from platelets and alpha granule storage is well-documented.
- term:
    id: GO:0048514
    label: blood vessel morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >
      TSP1 is involved in blood vessel morphogenesis, primarily as a negative regulator
      that limits vessel growth. It affects vessel density in normal tissues and
      curtails tumor neovascularization [PMID:10613822].
    action: ACCEPT
    reason: >
      TSP1 clearly participates in blood vessel morphogenesis through its anti-angiogenic
      activities. The annotation is appropriate for this core function.
- term:
    id: GO:0050840
    label: extracellular matrix binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >
      TSP1 binds to multiple ECM components including fibronectin, fibrinogen, collagen
      (especially type V), laminin, and proteoglycans [PMID:6489349, PMID:6693501].
    action: ACCEPT
    reason: >
      ECM binding is well-documented for TSP1. The protein interacts with numerous
      matrix components as part of its matricellular function.
- term:
    id: GO:0050921
    label: positive regulation of chemotaxis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >
      TSP1 can promote chemotaxis of certain cell types, including macrophages and
      some endothelial cells, depending on context and receptor engagement [PMID:18555217].
    action: ACCEPT
    reason: >
      TSP1 has documented chemotactic effects, particularly for monocytes/macrophages.
      The annotation is supported by experimental evidence.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15864306
  review:
    summary: >
      This IPI annotation indicates TSP1 binds to CILP (cartilage intermediate layer
      protein). TSP1 interacts with numerous proteins, so binding to CILP is plausible
      but "protein binding" is too generic.
    action: MARK_AS_OVER_ANNOTATED
    reason: >
      Generic "protein binding" annotations provide limited functional insight. While
      TSP1 does bind many proteins, more specific molecular function terms are preferred.
      The paper focuses on CILP SNP effects on disc disease susceptibility.
    supported_by:
    - reference_id: PMID:15864306
      supporting_text: A functional SNP in CILP, encoding cartilage intermediate
        layer protein, is associated with susceptibility to lumbar disc disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18042364
  review:
    summary: >
      This annotation relates to TSG-6 binding to fibronectin - the relevance to
      TSP1 is unclear from the title. TSP1 does bind fibronectin but this reference
      appears to be about TSG-6.
    action: MARK_AS_OVER_ANNOTATED
    reason: >
      Generic "protein binding" provides limited information. The reference title
      mentions TSG-6, not TSP1 directly. TSP1-fibronectin binding is documented
      elsewhere (PMID:6489349).
    supported_by:
    - reference_id: PMID:18042364
      supporting_text: TSG-6 binds via its CUB_C domain to the cell-binding
        domain of fibronectin and increases fibronectin matrix assembly.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19542224
  review:
    summary: >
      This annotation comes from an endostatin interaction network study. TSP1 may
      interact with endostatin or related proteins, but "protein binding" is too
      generic to be informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >
      Generic protein binding annotation from an interactome study. While TSP1
      interacts with many proteins, this annotation adds limited functional insight.
    supported_by:
    - reference_id: PMID:19542224
      supporting_text: The first draft of the endostatin interaction network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24117177
  review:
    summary: >
      This annotation derives from a study of procollagen C-proteinase enhancer-1
      interactions in the ECM, indicating TSP1 participates in this interaction network.
    action: MARK_AS_OVER_ANNOTATED
    reason: >
      Generic protein binding from an interaction network study. TSP1 is known to
      interact with many ECM proteins, but "protein binding" provides limited
      functional insight.
    supported_by:
    - reference_id: PMID:24117177
      supporting_text: Extended interaction network of procollagen C-proteinase
        enhancer-1 in the extracellular matrix.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >
      TSP1 is secreted into the extracellular space where it functions. This is
      a core localization for this matricellular protein.
    action: ACCEPT
    reason: >
      Extracellular space is a core localization for TSP1 as a secreted protein
      that functions outside the cell.
- term:
    id: GO:0009612
    label: response to mechanical stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >
      TSP1 expression may be induced by mechanical stimuli in certain tissues.
      This is plausible given TSP1's roles in wound healing and tissue remodeling.
    action: KEEP_AS_NON_CORE
    reason: >
      While TSP1 may respond to mechanical stimuli, this is not a primary or
      well-characterized function. The annotation is likely based on expression
      data rather than direct functional involvement.
- term:
    id: GO:0016525
    label: negative regulation of angiogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >
      Duplicate of IBA annotation - negative regulation of angiogenesis is a core
      function of TSP1.
    action: ACCEPT
    reason: >
      Same term as IBA annotation. This is a well-established core function of TSP1.
- term:
    id: GO:0033574
    label: response to testosterone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >
      TSP1 expression may be regulated by testosterone in certain tissues. This is
      not a core function but may be relevant in specific physiological contexts.
    action: KEEP_AS_NON_CORE
    reason: >
      Hormonal regulation of TSP1 expression is not a primary function. This likely
      reflects expression data from specific tissue contexts.
- term:
    id: GO:0050431
    label: transforming growth factor beta binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >
      TSP1 binds latent TGF-beta1 through its type-1 repeats (TSRs), which is
      essential for activating latent TGF-beta. The LSKL sequence in TSP1 binds
      the latency-associated peptide of TGF-beta [deep research].
    action: ACCEPT
    reason: >
      TGF-beta binding is a core molecular function of TSP1. The type-1 repeats
      mediate binding to latent TGF-beta1 and its subsequent activation.
    supported_by:
    - reference_id: file:human/THBS1/THBS1-deep-research-falcon.md
      supporting_text: >-
        TSRs are necessary for binding latent TGF‑β and CD36
- term:
    id: GO:0071356
    label: cellular response to tumor necrosis factor
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >
      TSP1 expression may be induced by TNF-alpha, and TSP1 in turn can regulate
      TNF-alpha production by dendritic cells [PMID:14568985].
    action: KEEP_AS_NON_CORE
    reason: >
      While TSP1 may respond to TNF signaling, this is not a core function. The
      more relevant annotation is TSP1's effect on regulating TNF production.
- term:
    id: GO:0071363
    label: cellular response to growth factor stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >
      TSP1 expression is regulated by various growth factors and TSP1 modulates
      growth factor signaling (VEGF, FGF-2, TGF-beta). This broad term captures
      TSP1's involvement in growth factor responses.
    action: KEEP_AS_NON_CORE
    reason: >
      While accurate, this is a very broad term. TSP1's specific roles in
      sequestering VEGF/FGF-2 and activating TGF-beta are more informative.
- term:
    id: GO:0071636
    label: positive regulation of transforming growth factor beta production
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >
      TSP1 activates latent TGF-beta1 (converting inactive to active form) rather
      than increasing TGF-beta production per se. This annotation may conflate
      activation with production.
    action: MODIFY
    reason: >
      TSP1 activates pre-existing latent TGF-beta1 rather than inducing its production.
      A more accurate term would be related to TGF-beta activation or signaling
      pathway regulation.
    proposed_replacement_terms:
    - id: GO:0030511
      label: positive regulation of transforming growth factor beta receptor
        signaling pathway
- term:
    id: GO:0141151
    label: negative regulation of nitric oxide-cGMP mediated signal transduction
  evidence_type: IDA
  original_reference_id: PMID:19004835
  review:
    summary: >
      TSP1 binding to CD47 inhibits NO-stimulated cGMP production in vascular cells.
      This is a well-established core function of TSP1 that affects vascular tone
      and platelet reactivity [PMID:19004835, deep research].
    action: ACCEPT
    reason: >
      This is a core function of TSP1. TSP1-CD47 signaling antagonizes NO-cGMP
      signaling, leading to vasoconstriction and enhanced platelet activation.
      This mechanism is critical for hemostasis.
    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.
    - reference_id: file:human/THBS1/THBS1-deep-research-falcon.md
      supporting_text: >-
        THBS1 binds CD47 (via CTD) and triggers signaling that suppresses
        nitric oxide (NO) pathway effects.
- term:
    id: GO:0072378
    label: blood coagulation, fibrin clot formation
  evidence_type: IDA
  original_reference_id: PMID:3997886
  review:
    summary: >
      TSP1 is incorporated into fibrin clots and contributes to hemostasis. Released
      from activated platelets, TSP1 helps stabilize clots by binding fibrinogen
      and fibrin [PMID:3997886].
    action: ACCEPT
    reason: >
      TSP1 participation in fibrin clot formation is well-documented. The protein
      binds fibrinogen/fibrin and is incorporated into clots, contributing to
      hemostasis.
    supported_by:
    - reference_id: PMID:3997886
      supporting_text: Incorporation of thrombospondin into fibrin clots.
    - reference_id: file:human/THBS1/THBS1-deep-research-falcon.md
      supporting_text: >-
        THBS1 is described as a major component of platelet α‑granules and is
        rapidly released at injury sites, supporting platelet activation,
        vasoconstriction, and thrombus formation
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:23658023
  review:
    summary: >
      Proteomic identification of TSP1 in ECM preparations. Consistent with its
      known localization as a matricellular protein.
    action: ACCEPT
    reason: >
      High-throughput proteomic evidence supporting TSP1 localization in ECM.
      Consistent with extensive prior evidence.
    supported_by:
    - reference_id: PMID:23658023
      supporting_text: Comparative proteomic analysis of supportive and
        unsupportive extracellular matrix substrates for human embryonic stem
        cell maintenance.
- term:
    id: GO:0043410
    label: positive regulation of MAPK cascade
  evidence_type: IMP
  original_reference_id: PMID:17413041
  review:
    summary: >
      TSP1 interaction with alpha9beta1 integrin can activate MAPK signaling. This
      is context-dependent - through different receptors TSP1 can have opposing
      effects on MAPK signaling [PMID:17413041].
    action: ACCEPT
    reason: >
      TSP1 can positively regulate MAPK cascade through integrin engagement. This
      is part of its complex signaling effects that are receptor-dependent.
    supported_by:
    - reference_id: PMID:17413041
      supporting_text: Interaction of alpha9beta1 integrin with thrombospondin-1
        promotes angiogenesis.
- term:
    id: GO:0016525
    label: negative regulation of angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:10613822
  review:
    summary: >
      Direct experimental evidence from a landmark paper showing TSP1 inhibits
      angiogenesis through CD36-mediated endothelial cell apoptosis. TSP1 induced
      apoptosis at tumor margins in vivo [PMID:10613822].
    action: ACCEPT
    reason: >
      High-quality experimental evidence supporting TSP1's anti-angiogenic function.
      The study demonstrated the CD36-p59fyn-caspase-3-p38 MAPK signaling cascade
      leading to endothelial apoptosis.
    supported_by:
    - reference_id: PMID:10613822
      supporting_text: >
        Thrombospondin-1 (TSP-1) is a naturally occurring inhibitor of angiogenesis
        that
        limits vessel density in normal tissues and curtails tumor growth.
- term:
    id: GO:0032693
    label: negative regulation of interleukin-10 production
  evidence_type: IDA
  original_reference_id: PMID:14568985
  review:
    summary: >
      PMID:14568985 demonstrated that endogenous TSP produced by dendritic cells
      negatively regulates IL-10 production through CD47 and CD36 interactions.
      Anti-TSP antibodies enhanced IL-10 synthesis.
    action: ACCEPT
    reason: >
      Direct experimental evidence showing TSP1 negatively regulates IL-10 production
      by dendritic cells. This is part of TSP1's immunomodulatory function.
    supported_by:
    - reference_id: PMID:14568985
      supporting_text: >
        The endogenous TSP produced during early DC activation negatively regulates
        IL-12, TNF-alpha, and IL-10 release through its interactions with CD47 and
        CD36.
- term:
    id: GO:0032695
    label: negative regulation of interleukin-12 production
  evidence_type: IDA
  original_reference_id: PMID:14568985
  review:
    summary: >
      PMID:14568985 showed that endogenous TSP negatively regulates IL-12 production
      by dendritic cells. Blocking TSP-CD47/CD36 interactions enhanced IL-12 synthesis.
    action: ACCEPT
    reason: >
      Direct experimental evidence demonstrating TSP1 negatively regulates IL-12
      production. This contributes to TSP1's immunosuppressive function.
    supported_by:
    - reference_id: PMID:14568985
      supporting_text: >
        The endogenous TSP produced during early DC activation negatively regulates
        IL-12, TNF-alpha, and IL-10 release through its interactions with CD47 and
        CD36.
- term:
    id: GO:0032720
    label: negative regulation of tumor necrosis factor production
  evidence_type: IDA
  original_reference_id: PMID:14568985
  review:
    summary: >
      PMID:14568985 demonstrated that endogenous TSP negatively regulates TNF-alpha
      production by dendritic cells through CD47 and CD36 receptor engagement.
    action: ACCEPT
    reason: >
      Direct experimental evidence showing TSP1 negatively regulates TNF-alpha
      production. Part of TSP1's anti-inflammatory/immunosuppressive function.
    supported_by:
    - reference_id: PMID:14568985
      supporting_text: >
        The endogenous TSP produced during early DC activation negatively regulates
        IL-12, TNF-alpha, and IL-10 release through its interactions with CD47 and
        CD36.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19004835
  review:
    summary: >
      This IPI documents TSP1 interaction with CD47. The specific binding to CD47
      is
      well-characterized but "protein binding" is too generic.
    action: MARK_AS_OVER_ANNOTATED
    reason: >
      TSP1-CD47 binding is real and functionally important, but "protein binding"
      is uninformative. More specific receptor binding terms would be preferable.
    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:24511121
  review:
    summary: >
      IPI documents TSP1 interaction with SIRPalpha. This represents a specific
      receptor interaction but "protein binding" is too generic.
    action: MARK_AS_OVER_ANNOTATED
    reason: >
      TSP1-SIRPalpha binding is documented but "protein binding" is uninformative.
    supported_by:
    - reference_id: PMID:24511121
      supporting_text: Thrombospondin-1 activation of signal-regulatory
        protein-Ξ± stimulates reactive oxygen species production and promotes
        renal ischemia reperfusion injury.
- term:
    id: GO:2000379
    label: positive regulation of reactive oxygen species metabolic process
  evidence_type: IDA
  original_reference_id: PMID:24511121
  review:
    summary: >
      TSP1 activation of SIRPalpha stimulates ROS production. This is documented
      in the context of renal ischemia-reperfusion injury [PMID:24511121].
    action: KEEP_AS_NON_CORE
    reason: >
      While TSP1 can stimulate ROS production through SIRPalpha signaling, this
      is a context-dependent effect rather than a core function of the protein.
    supported_by:
    - reference_id: PMID:24511121
      supporting_text: Thrombospondin-1 activation of signal-regulatory
        protein-Ξ± stimulates reactive oxygen species production and promotes
        renal ischemia reperfusion injury.
- term:
    id: GO:0001968
    label: fibronectin binding
  evidence_type: IDA
  original_reference_id: PMID:6489349
  review:
    summary: >
      TSP1 directly binds fibronectin. This interaction is well-characterized
      and relevant to TSP1's ECM functions [PMID:6489349].
    action: ACCEPT
    reason: >
      Fibronectin binding is a well-documented molecular function of TSP1,
      contributing to its role in ECM organization and cell adhesion.
    supported_by:
    - reference_id: PMID:6489349
      supporting_text: Thrombospondin interactions with fibronectin and
        fibrinogen.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:2478219
  review:
    summary: >
      IPI documenting TSP1 binding to integrin receptors on platelets. The
      specific integrin binding is more informative than generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: >
      This documents integrin binding which is real but "protein binding" is
      too generic. The integrin binding annotation is more informative.
    supported_by:
    - reference_id: PMID:2478219
      supporting_text: An integrin receptor on normal and thrombasthenic
        platelets that binds thrombospondin.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8550562
  review:
    summary: >
      IPI documenting TSP1 binding to CD47 (integrin-associated protein). This
      is a critical receptor interaction for TSP1's vascular signaling functions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >
      TSP1-CD47 binding is critically important for TSP1 function but "protein
      binding" is uninformative. A CD47 receptor binding term would be more specific.
    supported_by:
    - reference_id: PMID:8550562
      supporting_text: Integrin-associated protein is a receptor for the
        C-terminal domain of thrombospondin.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: IDA
  original_reference_id: PMID:18285447
  review:
    summary: >
      Direct evidence for TSP1 localization in the ECM. The study characterized
      how TSP1's C-terminal region controls its retention in the ECM.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 ECM localization, consistent with
      its established role as a matricellular protein.
    supported_by:
    - reference_id: PMID:18285447
      supporting_text: Extracellular matrix retention of thrombospondin 1 is
        controlled by its conserved C-terminal region.
- term:
    id: GO:0070051
    label: fibrinogen binding
  evidence_type: IDA
  original_reference_id: PMID:6489349
  review:
    summary: >
      TSP1 directly binds fibrinogen. This interaction is important for TSP1's
      role in hemostasis and clot formation [PMID:6489349].
    action: ACCEPT
    reason: >
      Fibrinogen binding is a well-documented molecular function of TSP1,
      relevant to its role in hemostasis and clot stabilization.
    supported_by:
    - reference_id: PMID:6489349
      supporting_text: Thrombospondin interactions with fibronectin and
        fibrinogen.
- term:
    id: GO:0005201
    label: extracellular matrix structural constituent
  evidence_type: RCA
  original_reference_id: PMID:23979707
  review:
    summary: >
      TSP1 was identified in ECM proteomics. However, TSP1 is a matricellular
      protein (regulatory) rather than a structural constituent of ECM.
    action: MODIFY
    reason: >
      TSP1 is a matricellular protein that modulates cell-matrix interactions
      rather than forming structural fibers. "ECM structural constituent" implies
      a structural role that is not accurate for TSP1.
    proposed_replacement_terms:
    - id: GO:0031012
      label: extracellular matrix
    supported_by:
    - reference_id: PMID:23979707
      supporting_text: SILAC-based proteomics of human primary endothelial cell
        morphogenesis unveils tumor angiogenic markers.
- term:
    id: GO:0016525
    label: negative regulation of angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:23896411
  review:
    summary: >
      TSP1 inhibits angiogenesis by modulating VEGF signaling through CD36. The
      study showed TSP1 recruits SHP-1 phosphatase to VEGFR2, attenuating VEGF
      signaling [PMID:23896411].
    action: ACCEPT
    reason: >
      Strong experimental evidence for TSP1's anti-angiogenic mechanism involving
      CD36-mediated attenuation of VEGF receptor signaling.
    supported_by:
    - reference_id: PMID:23896411
      supporting_text: Thrombospondin-1 modulates VEGF signaling via CD36 by
        recruiting SHP-1 to VEGFR2 complex in microvascular endothelial cells.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: IDA
  original_reference_id: PMID:6341993
  review:
    summary: >
      Classic study demonstrating fibroblasts synthesize TSP1 and incorporate
      it into the ECM [PMID:6341993]. Foundational evidence for TSP1 ECM localization.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 secretion and incorporation into ECM
      by fibroblasts.
    supported_by:
    - reference_id: PMID:6341993
      supporting_text: Cultured human fibroblasts synthesize and secrete
        thrombospondin and incorporate it into extracellular matrix.
- term:
    id: GO:0038060
    label: nitric oxide-cGMP-mediated signaling
  evidence_type: IDA
  original_reference_id: PMID:17416590
  review:
    summary: >
      TSP1 is involved in NO-cGMP signaling, specifically as an inhibitor of this
      pathway. TSP1 inhibits NO signaling via CD36 by inhibiting myristic acid
      uptake required for eNOS myristoylation [PMID:17416590].
    action: ACCEPT
    reason: >
      TSP1 participates in NO-cGMP signaling as a negative regulator. The annotation
      captures TSP1's involvement in this pathway.
    supported_by:
    - reference_id: PMID:17416590
      supporting_text: Thrombospondin-1 inhibits nitric oxide signaling via CD36
        by inhibiting myristic acid uptake.
- term:
    id: GO:0002020
    label: protease binding
  evidence_type: IPI
  original_reference_id: PMID:7679575
  review:
    summary: >
      TSP1 binds plasmin and has antiplasmin activity. This contributes to
      regulation of fibrinolysis [PMID:7679575].
    action: ACCEPT
    reason: >
      TSP1 binding to plasmin is well-documented and functionally relevant
      to its role in regulating fibrinolysis.
    supported_by:
    - reference_id: PMID:7679575
      supporting_text: Characterization of the antiplasmin activity of human
        thrombospondin-1 in solution.
- term:
    id: GO:0004866
    label: endopeptidase inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:7679575
  review:
    summary: >
      TSP1 has antiplasmin activity, inhibiting the serine protease plasmin.
      This contributes to regulation of fibrinolysis [PMID:7679575].
    action: ACCEPT
    reason: >
      TSP1's endopeptidase inhibitor activity against plasmin is documented
      and functionally relevant.
    supported_by:
    - reference_id: PMID:7679575
      supporting_text: Characterization of the antiplasmin activity of human
        thrombospondin-1 in solution.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:7679575
  review:
    summary: >
      TSP1 forms homotrimers (not homodimers). The term "homodimerization" may be
      inaccurate - TSP1 is a homotrimeric protein.
    action: MODIFY
    reason: >
      TSP1 forms homotrimers via disulfide bonds in the coiled-coil region, not
      homodimers. A more accurate term would reflect homo-oligomerization.
    proposed_replacement_terms:
    - id: GO:0051260
      label: protein homooligomerization
    supported_by:
    - reference_id: PMID:7679575
      supporting_text: Characterization of the antiplasmin activity of human
        thrombospondin-1 in solution.
- term:
    id: GO:0001968
    label: fibronectin binding
  evidence_type: IDA
  original_reference_id: PMID:18042364
  review:
    summary: >
      The reference title mentions TSG-6, not TSP1 directly. TSP1 fibronectin
      binding is well-documented elsewhere (PMID:6489349). This annotation may
      be misattributed.
    action: ACCEPT
    reason: >
      TSP1 fibronectin binding is well-established from other studies even if
      this specific reference may be misattributed.
    supported_by:
    - reference_id: PMID:18042364
      supporting_text: TSG-6 binds via its CUB_C domain to the cell-binding
        domain of fibronectin and increases fibronectin matrix assembly.
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: IDA
  original_reference_id: PMID:17596205
  review:
    summary: >
      TSP1 inhibits cell proliferation, particularly of endothelial cells, as part
      of its anti-angiogenic mechanism. The study revealed cell cycle suppression
      as a mechanism [PMID:17596205].
    action: ACCEPT
    reason: >
      TSP1's anti-proliferative effect on endothelial cells is well-documented
      and contributes to its anti-angiogenic function.
    supported_by:
    - reference_id: PMID:17596205
      supporting_text: Novel antiangiogenic pathway of thrombospondin-1 mediated
        by suppression of the cell cycle.
- term:
    id: GO:0005201
    label: extracellular matrix structural constituent
  evidence_type: HDA
  original_reference_id: PMID:28344315
  review:
    summary: >
      TSP1 identified in ECM proteomics. However, TSP1 is matricellular (regulatory)
      rather than a structural ECM constituent.
    action: MODIFY
    reason: >
      TSP1 is not a structural ECM component. It modulates cell-matrix interactions
      but does not form structural fibers. Localization term is more appropriate.
    proposed_replacement_terms:
    - id: GO:0031012
      label: extracellular matrix
    supported_by:
    - reference_id: PMID:28344315
      supporting_text: Proteomic characterization of human multiple myeloma bone
        marrow extracellular matrix.
- term:
    id: GO:0005201
    label: extracellular matrix structural constituent
  evidence_type: RCA
  original_reference_id: PMID:28327460
  review:
    summary: >
      TSP1 identified in ECM proteomics. TSP1 is matricellular rather than structural.
    action: MODIFY
    reason: >
      TSP1 is not a structural ECM component.
    proposed_replacement_terms:
    - id: GO:0031012
      label: extracellular matrix
    supported_by:
    - reference_id: PMID:28327460
      supporting_text: Comprehensive proteomic characterization of stem
        cell-derived extracellular matrices.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:28327460
  review:
    summary: >
      Proteomic evidence for TSP1 in ECM. Consistent with its established localization.
    action: ACCEPT
    reason: >
      HDA evidence supporting TSP1 ECM localization.
    supported_by:
    - reference_id: PMID:28327460
      supporting_text: Comprehensive proteomic characterization of stem
        cell-derived extracellular matrices.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:28344315
  review:
    summary: >
      Proteomic evidence for TSP1 in ECM from bone marrow samples.
    action: ACCEPT
    reason: >
      HDA evidence supporting TSP1 ECM localization.
    supported_by:
    - reference_id: PMID:28344315
      supporting_text: Proteomic characterization of human multiple myeloma bone
        marrow extracellular matrix.
- term:
    id: GO:0005201
    label: extracellular matrix structural constituent
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >
      TSP1 is a matricellular protein (regulatory) rather than a structural ECM
      component. This term is inaccurate for TSP1.
    action: MODIFY
    reason: >
      TSP1 modulates cell-matrix interactions but does not form structural fibers
      like collagens or elastin. ECM localization is accurate; structural role is
      not.
    proposed_replacement_terms:
    - id: GO:0031012
      label: extracellular matrix
- term:
    id: GO:0005201
    label: extracellular matrix structural constituent
  evidence_type: RCA
  original_reference_id: PMID:20551380
  review:
    summary: >
      TSP1 identified in aorta ECM proteomics. TSP1 is matricellular, not structural.
    action: MODIFY
    reason: >
      TSP1 is not a structural ECM component.
    proposed_replacement_terms:
    - id: GO:0031012
      label: extracellular matrix
    supported_by:
    - reference_id: PMID:20551380
      supporting_text: Proteomics characterization of extracellular space
        components in the human aorta.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: HDA
  original_reference_id: PMID:27068509
  review:
    summary: >
      Proteomic evidence for TSP1 in extracellular region from varicose vein samples.
    action: ACCEPT
    reason: >
      HDA evidence supporting TSP1 extracellular localization.
    supported_by:
    - reference_id: PMID:27068509
      supporting_text: Extracellular matrix remodelling in response to venous
        hypertension
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: HDA
  original_reference_id: PMID:20551380
  review:
    summary: >
      Proteomic evidence for TSP1 in extracellular space from aorta samples.
    action: ACCEPT
    reason: >
      HDA evidence supporting TSP1 extracellular localization.
    supported_by:
    - reference_id: PMID:20551380
      supporting_text: Proteomics characterization of extracellular space
        components in the human aorta.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:20551380
  review:
    summary: >
      Proteomic evidence for TSP1 in ECM from aorta samples.
    action: ACCEPT
    reason: >
      HDA evidence supporting TSP1 ECM localization.
    supported_by:
    - reference_id: PMID:20551380
      supporting_text: Proteomics characterization of extracellular space
        components in the human aorta.
- term:
    id: GO:1903671
    label: negative regulation of sprouting angiogenesis
  evidence_type: IGI
  original_reference_id: PMID:28124060
  review:
    summary: >
      TSP1 inhibits sprouting angiogenesis. This study examined BMP4 regulation
      of miRNAs that affect endothelial function, with TSP1 involvement.
    action: ACCEPT
    reason: >
      TSP1 inhibition of sprouting angiogenesis is consistent with its well-established
      anti-angiogenic function.
    supported_by:
    - reference_id: PMID:28124060
      supporting_text: Bone morphogenetic protein 4 regulates microRNAs miR-494
        and miR-126-5p in control of endothelial cell function in angiogenesis.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: ISS
  original_reference_id: PMID:22261194
  review:
    summary: >
      Proteomic identification of TSP1 in cardiac ECM.
    action: ACCEPT
    reason: >
      Evidence supporting TSP1 ECM localization from cardiac tissue.
    supported_by:
    - reference_id: PMID:22261194
      supporting_text: Proteomics analysis of cardiac extracellular matrix
        remodeling in a porcine model of ischemia/reperfusion injury.
- term:
    id: GO:0016525
    label: negative regulation of angiogenesis
  evidence_type: IMP
  original_reference_id: PMID:24177325
  review:
    summary: >
      Study examining miR-27b effects on angiogenesis and wound healing, with
      TSP1 as a target. Consistent with TSP1's anti-angiogenic role.
    action: ACCEPT
    reason: >
      Supports TSP1's role in negative regulation of angiogenesis.
    supported_by:
    - reference_id: PMID:24177325
      supporting_text: MicroRNA miR-27b rescues bone marrow-derived angiogenic
        cell function and accelerates wound healing in type 2 diabetes mellitus.
- term:
    id: GO:0090051
    label: negative regulation of cell migration involved in sprouting
      angiogenesis
  evidence_type: IMP
  original_reference_id: PMID:25660232
  review:
    summary: >
      Study showing miR-487b targets THBS1 to promote endothelial cell migration,
      implying THBS1 normally inhibits this migration.
    action: ACCEPT
    reason: >
      Consistent with TSP1's role in inhibiting endothelial cell migration as
      part of its anti-angiogenic function.
    supported_by:
    - reference_id: PMID:25660232
      supporting_text: miR-487b promotes human umbilical vein endothelial cell
        proliferation, migration, invasion and tube formation through regulating
        THBS1.
- term:
    id: GO:1903588
    label: negative regulation of blood vessel endothelial cell proliferation
      involved in sprouting angiogenesis
  evidence_type: IMP
  original_reference_id: PMID:25660232
  review:
    summary: >
      Study showing miR-487b targets THBS1 to promote endothelial proliferation,
      implying THBS1 normally inhibits proliferation.
    action: ACCEPT
    reason: >
      Consistent with TSP1's role in inhibiting endothelial cell proliferation.
    supported_by:
    - reference_id: PMID:25660232
      supporting_text: miR-487b promotes human umbilical vein endothelial cell
        proliferation, migration, invasion and tube formation through regulating
        THBS1.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:23979707
  review:
    summary: >
      Proteomic evidence for TSP1 in ECM from endothelial cell studies.
    action: ACCEPT
    reason: >
      HDA evidence supporting TSP1 ECM localization.
    supported_by:
    - reference_id: PMID:23979707
      supporting_text: SILAC-based proteomics of human primary endothelial cell
        morphogenesis unveils tumor angiogenic markers.
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IDA
  original_reference_id: PMID:24615654
  review:
    summary: >
      Study suggesting TSP1 may promote proliferation of prostatic smooth muscle
      cells. This is context-dependent - TSP1 can have opposing effects on
      proliferation depending on cell type.
    action: KEEP_AS_NON_CORE
    reason: >
      TSP1's effect on proliferation is cell-type dependent. In endothelial cells
      it inhibits proliferation; in smooth muscle it may promote. Not a core function.
    supported_by:
    - reference_id: PMID:24615654
      supporting_text: Interleukin-18 may lead to benign prostatic hyperplasia
        via thrombospondin-1 production in prostatic smooth muscle cells.
- term:
    id: GO:0048661
    label: positive regulation of smooth muscle cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:24615654
  review:
    summary: >
      Study suggesting TSP1 may promote smooth muscle cell proliferation in
      prostate tissue. Cell-type specific effect.
    action: KEEP_AS_NON_CORE
    reason: >
      Context-dependent effect on smooth muscle cells. Not a core function of TSP1.
    supported_by:
    - reference_id: PMID:24615654
      supporting_text: Interleukin-18 may lead to benign prostatic hyperplasia
        via thrombospondin-1 production in prostatic smooth muscle cells.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:26395742
  review:
    summary: >
      TSP1 is a secreted protein that localizes to the extracellular space.
      This study examined angiogenic miRNAs in diabetic retinopathy, where
      TSP1 would be present in the extracellular milieu.
    action: ACCEPT
    reason: >
      Extracellular space is a core localization for TSP1 as a secreted
      matricellular protein.
    supported_by:
    - reference_id: PMID:26395742
      supporting_text: Angiogenic microRNAs Linked to Incidence and Progression
        of Diabetic Retinopathy in Type 1 Diabetes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26627825
  review:
    summary: >
      This IPI documents TSP1 interaction with Staphylococcus aureus
      extracellular fibrinogen-binding protein (Efb). While TSP1 does
      bind fibrinogen and participate in platelet-leukocyte complexes,
      "protein binding" is too generic.
    action: MARK_AS_OVER_ANNOTATED
    reason: >
      Generic "protein binding" provides limited functional insight. The
      study examines bacterial protein interactions in platelet biology.
    supported_by:
    - reference_id: PMID:26627825
      supporting_text: Extracellular Fibrinogen-binding Protein (Efb) from
        Staphylococcus aureus Inhibits the Formation of Platelet-Leukocyte
        Complexes.
- term:
    id: GO:0001937
    label: negative regulation of endothelial cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:16150726
  review:
    summary: >
      PMID:16150726 demonstrated that TSP1 inhibits NO-stimulated endothelial
      cell proliferation at picomolar concentrations. The study showed that
      "proliferation stimulated by 10 ΞΌM DETA/NO was inhibited by 50% at
      <22 pM TSP1" in multiple endothelial cell types.
    action: ACCEPT
    reason: >
      Strong direct experimental evidence showing TSP1 inhibits endothelial
      cell proliferation via antagonism of NO/cGMP signaling. This is a
      core anti-angiogenic function of TSP1.
    supported_by:
    - reference_id: PMID:16150726
      supporting_text: >
        proliferation stimulated by 10 ΞΌM DETA/NO was inhibited by 50%
        at <22 pM TSP1
- term:
    id: GO:0001953
    label: negative regulation of cell-matrix adhesion
  evidence_type: IDA
  original_reference_id: PMID:16150726
  review:
    summary: >
      PMID:16150726 showed that TSP1 potently inhibits NO-stimulated
      endothelial cell adhesion to collagen substrates. Exogenous TSP1
      at <2.2 pM abrogated NO-stimulated cell adhesion and reversed
      effects on cell spreading.
    action: ACCEPT
    reason: >
      Direct experimental evidence showing TSP1 inhibits cell-matrix
      adhesion through antagonism of NO/cGMP signaling. This is mediated
      by the type-1 repeats (TSRs) via CD36.
    supported_by:
    - reference_id: PMID:16150726
      supporting_text: >
        Exogenous TSP1 at <2.2 pM abrogated the stimulation by NO of
        cell adhesion to collagen
- term:
    id: GO:0010751
    label: negative regulation of nitric oxide mediated signal transduction
  evidence_type: IDA
  original_reference_id: PMID:16150726
  review:
    summary: >
      PMID:16150726 demonstrated that TSP1 is a potent inhibitor of NO signaling.
      TSP1 inhibits NO-stimulated cGMP accumulation and downstream signaling.
      The study showed "Addition of 100 pM TSP1 prevented the NO-stimulated
      increase in cGMP."
    action: ACCEPT
    reason: >
      This is a core function of TSP1. The study provided strong evidence
      that TSP1 inhibits NO signaling both upstream (cGMP synthesis) and
      downstream of cGMP. This is mediated via CD36 and the type-1 repeats.
    supported_by:
    - reference_id: PMID:16150726
      supporting_text: >
        Addition of 100 pM TSP1 prevented the NO-stimulated increase in cGMP
    - reference_id: file:human/THBS1/THBS1-deep-research-falcon.md
      supporting_text: >-
        THBS1-CD47 signaling antagonizes NO/cGMP-dependent signaling, with
        consequences for vascular smooth muscle relaxation/vasodilation and
        ischemic survival.
- term:
    id: GO:0016525
    label: negative regulation of angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:16150726
  review:
    summary: >
      PMID:16150726 demonstrated TSP1 inhibits angiogenesis by antagonizing
      NO/cGMP signaling. TSP1-null muscle explants showed exaggerated
      angiogenic responses to NO that were reversed by adding exogenous TSP1.
    action: ACCEPT
    reason: >
      Strong experimental evidence for TSP1's anti-angiogenic function
      through inhibition of NO-cGMP signaling in endothelial cells.
    supported_by:
    - reference_id: PMID:16150726
      supporting_text: >
        explants from mice lacking the angiogenesis inhibitor
        thrombospondin-1 (TSP1) exhibit exaggerated angiogenic responses
        to an exogenous NO donor, which could be reversed by providing
        exogenous TSP1
- term:
    id: GO:2001027
    label: negative regulation of endothelial cell chemotaxis
  evidence_type: IDA
  original_reference_id: PMID:16150726
  review:
    summary: >
      PMID:16150726 showed TSP1 potently inhibits NO-stimulated endothelial
      cell chemotaxis. "TSP1 inhibited HUVEC chemotaxis stimulated by 10 ΞΌM
      DETA/NO with an IC50 of 7 pM."
    action: ACCEPT
    reason: >
      Strong direct experimental evidence showing TSP1 inhibits endothelial
      cell chemotaxis through antagonism of NO signaling via the type-1
      repeats. This is a core anti-angiogenic function.
    supported_by:
    - reference_id: PMID:16150726
      supporting_text: >
        TSP1 inhibited HUVEC chemotaxis stimulated by 10 ΞΌM DETA/NO with
        an IC 50 of 7 pM
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  review:
    summary: >
      Proteomic identification of TSP1 in exosomes from prostatic secretions.
      As a secreted protein, TSP1 can be incorporated into exosomes.
    action: ACCEPT
    reason: >
      HDA evidence supporting TSP1 presence in extracellular exosomes.
      This is consistent with TSP1 being a secreted protein that can
      associate with various extracellular vesicles.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: In-depth proteomic analyses of exosomes isolated from
        expressed prostatic secretions in urine.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: HDA
  original_reference_id: PMID:16502470
  review:
    summary: >
      Proteomic identification of TSP1 in human colostrum, consistent with
      its presence in extracellular fluids as a secreted protein.
    action: ACCEPT
    reason: >
      HDA evidence supporting TSP1 presence in extracellular space.
      Consistent with its known localization as a secreted protein.
    supported_by:
    - reference_id: PMID:16502470
      supporting_text: 'Human colostrum: identification of minor proteins in the aqueous
        phase by proteomics.'
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5173005
  review:
    summary: >
      TSP1 transits through the ER lumen during biosynthesis as a secreted
      protein. It undergoes post-translational modifications including
      glycosylation and disulfide bond formation in the ER.
    action: ACCEPT
    reason: >
      As a secreted protein, TSP1 passes through the ER lumen during
      synthesis. Reactome evidence for secretory pathway transit.
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5173192
  review:
    summary: >
      Duplicate Reactome evidence for TSP1 transit through ER lumen during
      biosynthesis.
    action: ACCEPT
    reason: >
      TSP1 passes through the ER lumen as part of the secretory pathway.
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785565
  review:
    summary: >
      Reactome evidence for TSP1 presence in ER lumen during protein
      maturation and secretion.
    action: ACCEPT
    reason: >
      TSP1 transits through the ER lumen as a secreted protein.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  review:
    summary: >
      Proteomic identification of TSP1 in parotid gland exosomes.
    action: ACCEPT
    reason: >
      HDA evidence supporting TSP1 presence in extracellular exosomes.
      Consistent with TSP1 being a secreted protein.
    supported_by:
    - reference_id: PMID:19199708
      supporting_text: Proteomic analysis of human parotid gland exosomes by
        multidimensional protein identification technology (MudPIT).
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  review:
    summary: >
      Proteomic identification of TSP1 in urinary exosomes.
    action: ACCEPT
    reason: >
      HDA evidence supporting TSP1 presence in extracellular exosomes.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: Large-scale proteomics and phosphoproteomics of urinary
        exosomes.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >
      TSP1 transits through the ER during biosynthesis as a secreted
      protein. It is synthesized with a signal peptide and processed
      in the ER before secretion.
    action: ACCEPT
    reason: >
      As a secreted protein, TSP1 passes through the ER during synthesis.
      This is a transit compartment, not a site of function.
- term:
    id: GO:0016529
    label: sarcoplasmic reticulum
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >
      Sarcoplasmic reticulum localization is not a primary site for TSP1.
      This annotation may relate to ER localization in muscle cells during
      biosynthesis. TSP1 primarily functions extracellularly.
    action: KEEP_AS_NON_CORE
    reason: >
      Not a primary site of TSP1 function. The protein is secreted and
      functions in the extracellular space.
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >
      TSP1 expression may be induced during ER stress, but this is not
      a well-characterized core function of TSP1.
    action: KEEP_AS_NON_CORE
    reason: >
      While TSP1 may be upregulated during ER stress, response to ER
      stress is not a primary function. This is likely a secondary
      transcriptional effect rather than a direct mechanistic role.
- term:
    id: GO:0048266
    label: behavioral response to pain
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >
      TSP1 may have indirect effects on pain responses through its
      effects on inflammation and vascular function, but this is not
      a primary function of the protein.
    action: KEEP_AS_NON_CORE
    reason: >
      Behavioral response to pain is not a well-characterized direct
      function of TSP1. Any effect would be indirect through its
      roles in inflammation or vascular regulation.
- term:
    id: GO:1902043
    label: positive regulation of extrinsic apoptotic signaling pathway via
      death domain receptors
  evidence_type: IDA
  original_reference_id: PMID:18726995
  review:
    summary: >
      PMID:18726995 showed TSP1 induces apoptosis of brain microvascular
      endothelial cells through TNF-R1 (a death domain receptor). This
      is part of TSP1's anti-angiogenic mechanism.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 promoting extrinsic apoptosis
      via TNF-R1. This is consistent with TSP1's known pro-apoptotic
      effects on endothelial cells.
    supported_by:
    - reference_id: PMID:18726995
      supporting_text: Thrombospondin-1-induced apoptosis of brain microvascular
        endothelial cells can be mediated by TNF-R1.
- term:
    id: GO:2001237
    label: negative regulation of extrinsic apoptotic signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:17879962
  review:
    summary: >
      The N-terminal domain of TSP1 can promote cell survival through
      interactions with calreticulin/LRP1, which signals resistance to
      anoikis. This study shows syndecan-4 interactions with TSP1's
      N-terminal pro-angiogenic domain.
    action: KEEP_AS_NON_CORE
    reason: >
      TSP1 can have both pro-apoptotic (via CD36) and anti-apoptotic
      (via calreticulin/LRP1) effects depending on the receptor engaged.
      The anti-apoptotic effect through the N-terminal domain is a
      context-dependent function.
    supported_by:
    - reference_id: PMID:17879962
      supporting_text: Syndecan-4 contributes to endothelial tubulogenesis
        through interactions with two motifs inside the pro-angiogenic
        N-terminal domain of thrombospondin-1.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:2435757
  review:
    summary: >
      TSP1 binds to cell surface receptors and can accumulate on cell
      membranes. This classic study isolated the thrombospondin membrane
      receptor, demonstrating TSP1 cell surface association.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 association with cell surface
      through receptor binding. This is a core localization for TSP1
      as it interacts with membrane receptors (CD36, CD47, integrins).
    supported_by:
    - reference_id: PMID:2435757
      supporting_text: Isolation of the thrombospondin membrane receptor.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:3084490
  review:
    summary: >
      Classic study showing TSP1 binds to platelet surfaces. Upon
      platelet activation, TSP1 is released from alpha granules and
      binds to the platelet cell surface.
    action: ACCEPT
    reason: >
      Direct evidence for TSP1 association with platelet cell surface.
      This is a well-established localization for TSP1.
    supported_by:
    - reference_id: PMID:3084490
      supporting_text: Interaction of thrombospondin with resting and stimulated
        human platelets.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:6777381
  review:
    summary: >
      Classic study showing TSP1 (called glycoprotein G at the time)
      binds to platelet surfaces in a Ca2+-dependent manner.
    action: ACCEPT
    reason: >
      Early foundational evidence for TSP1 association with platelet
      cell surface through calcium-dependent binding.
    supported_by:
    - reference_id: PMID:6777381
      supporting_text: Ca2+-mediated association of glycoprotein G
        (thrombinsensitive protein, thrombospondin) with human platelets.
- term:
    id: GO:2000353
    label: positive regulation of endothelial cell apoptotic process
  evidence_type: IDA
  original_reference_id: PMID:18726995
  review:
    summary: >
      PMID:18726995 showed TSP1 induces apoptosis of brain microvascular
      endothelial cells via TNF-R1 signaling. This is a key mechanism
      of TSP1's anti-angiogenic function.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 promoting endothelial cell
      apoptosis. This is a core anti-angiogenic function of TSP1, also
      demonstrated via CD36 in other studies [PMID:10613822].
    supported_by:
    - reference_id: PMID:18726995
      supporting_text: Thrombospondin-1-induced apoptosis of brain microvascular
        endothelial cells can be mediated by TNF-R1.
- term:
    id: GO:0031093
    label: platelet alpha granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-481007
  review:
    summary: >
      TSP1 is stored in platelet alpha granule lumen and released upon
      platelet activation. This is a well-established storage site.
    action: ACCEPT
    reason: >
      Platelet alpha granule lumen is a core storage localization for
      TSP1. The protein was first characterized from platelets and
      this localization is well-documented.
    supported_by:
    - reference_id: file:human/THBS1/THBS1-deep-research-falcon.md
      supporting_text: >-
        THBS1 is described as a major component of platelet Ξ±-granules and is
        rapidly released at injury sites
- term:
    id: GO:0031093
    label: platelet alpha granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8936995
  review:
    summary: >
      Duplicate Reactome evidence for TSP1 storage in platelet alpha
      granule lumen.
    action: ACCEPT
    reason: >
      TSP1 storage in platelet alpha granules is well-established.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-265429
  review:
    summary: >
      Reactome evidence for TSP1 localization in the extracellular region.
    action: ACCEPT
    reason: >
      Extracellular region is a core localization for TSP1 as a secreted
      matricellular protein.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-349603
  review:
    summary: >
      Reactome evidence for TSP1 in extracellular region.
    action: ACCEPT
    reason: >
      Core localization for TSP1 as a secreted protein.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-382054
  review:
    summary: >
      Reactome evidence for TSP1 in extracellular region.
    action: ACCEPT
    reason: >
      Core localization for TSP1 as a secreted protein.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-481007
  review:
    summary: >
      Reactome evidence for TSP1 in extracellular region.
    action: ACCEPT
    reason: >
      Core localization for TSP1 as a secreted protein.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-2731112
  review:
    summary: >
      Reactome evidence for TSP1 in extracellular region.
    action: ACCEPT
    reason: >
      Core localization for TSP1 as a secreted protein.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:21362503
  review:
    summary: >
      Proteomic identification of TSP1 in exosomes from trabecular
      meshwork cells.
    action: ACCEPT
    reason: >
      HDA evidence supporting TSP1 presence in extracellular exosomes.
    supported_by:
    - reference_id: PMID:21362503
      supporting_text: Protein profile of exosomes from trabecular meshwork
        cells.
- term:
    id: GO:0006954
    label: inflammatory response
  evidence_type: IDA
  original_reference_id: PMID:23144964
  review:
    summary: >
      Study showing TSP1 regulates leukocyte recruitment and activation
      during systemic candidiasis, indicating TSP1 is involved in
      inflammatory responses. TSP1 accelerated death from infection.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 involvement in inflammatory
      response. TSP1 modulates inflammation through multiple mechanisms
      including TGF-beta activation and cytokine regulation.
    supported_by:
    - reference_id: PMID:23144964
      supporting_text: Endogenous thrombospondin-1 regulates leukocyte
        recruitment and activation and accelerates death from systemic
        candidiasis.
- term:
    id: GO:0017134
    label: fibroblast growth factor binding
  evidence_type: IDA
  original_reference_id: PMID:17996481
  review:
    summary: >
      PMID:17996481 demonstrated that FGF-2 binds to the type III repeats
      of TSP1. This binding sequesters FGF-2 and contributes to TSP1's
      anti-angiogenic function.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 binding FGF-2. This is a
      core molecular function that contributes to TSP1's anti-angiogenic
      activity by sequestering pro-angiogenic growth factors.
    supported_by:
    - reference_id: PMID:17996481
      supporting_text: Fibroblast growth factor-2 binding to the
        thrombospondin-1 type III repeats, a novel antiangiogenic domain.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11134179
  review:
    summary: >
      Study showing histidine-rich glycoprotein (HRG) binds TSP1 and
      inhibits its anti-angiogenic effect. While the interaction is
      documented, "protein binding" is too generic.
    action: MARK_AS_OVER_ANNOTATED
    reason: >
      Generic "protein binding" provides limited functional insight.
      The specific TSP1-HRG interaction is documented but a more
      specific term would be more informative.
    supported_by:
    - reference_id: PMID:11134179
      supporting_text: Histidine-rich glycoprotein inhibits the antiangiogenic
        effect of thrombospondin-1.
- term:
    id: GO:2000379
    label: positive regulation of reactive oxygen species metabolic process
  evidence_type: IDA
  original_reference_id: PMID:18757424
  review:
    summary: >
      TSP1 enhances tumor cell cytotoxicity through macrophage activation,
      which involves ROS production. This is a context-dependent effect
      in tumor microenvironments.
    action: KEEP_AS_NON_CORE
    reason: >
      ROS regulation by TSP1 is context-dependent and secondary to its
      effects on macrophage activation, not a core function of the protein.
    supported_by:
    - reference_id: PMID:18757424
      supporting_text: Thrombospondin 1 promotes tumor macrophage recruitment
        and enhances tumor cell cytotoxicity of differentiated U937 cells.
- term:
    id: GO:0008201
    label: heparin binding
  evidence_type: IDA
  original_reference_id: PMID:8288588
  review:
    summary: >
      Note: This reference is about thrombospondin-3 (THBS3), not THBS1.
      However, TSP1 does have heparin binding activity through its
      N-terminal domain, well-documented in other studies.
    action: ACCEPT
    reason: >
      Heparin binding is a well-documented property of TSP1. The N-terminal
      domain contains a heparin-binding region. This annotation is valid
      for TSP1 even though the specific reference is about TSP3.
    supported_by:
    - reference_id: PMID:8288588
      supporting_text: Thrombospondin 3 is a developmentally regulated heparin
        binding protein.
- term:
    id: GO:0001786
    label: phosphatidylserine binding
  evidence_type: IDA
  original_reference_id: PMID:18940719
  review:
    summary: >
      Study showing that phosphatidylserine-exposing erythrocytes bind
      to TSP1 via its heparin-binding domain. This mediates clearance
      of damaged/apoptotic cells.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 binding phosphatidylserine.
      This function is relevant to TSP1's roles in hemostasis and
      clearance of apoptotic cells.
    supported_by:
    - reference_id: PMID:18940719
      supporting_text: Phosphatidylserine-positive erythrocytes bind to
        immobilized and soluble thrombospondin-1 via its heparin-binding domain.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18688696
  review:
    summary: >
      Study showing calumenin forms a Ca2+-dependent complex with TSP1.
      While this interaction is documented, "protein binding" is too generic.
    action: MARK_AS_OVER_ANNOTATED
    reason: >
      Generic "protein binding" provides limited functional insight.
      The specific TSP1-calumenin interaction is documented.
    supported_by:
    - reference_id: PMID:18688696
      supporting_text: Calumenin but not reticulocalbin forms a Ca2+-dependent
        complex with thrombospondin-1.
- term:
    id: GO:0009410
    label: response to xenobiotic stimulus
  evidence_type: IEP
  original_reference_id: PMID:19738618
  review:
    summary: >
      TSP1 expression is induced by dexrazoxane (a xenobiotic drug),
      which contributes to the drug's anti-angiogenic activity.
    action: KEEP_AS_NON_CORE
    reason: >
      TSP1 expression may be induced by xenobiotics, but this is not
      a core function. This is an IEP (expression pattern) annotation
      reflecting transcriptional regulation rather than direct function.
    supported_by:
    - reference_id: PMID:19738618
      supporting_text: Induction of thrombospondin-1 partially mediates the
        anti-angiogenic activity of dexrazoxane.
- term:
    id: GO:0016525
    label: negative regulation of angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:18726995
  review:
    summary: >
      Study showing TSP1 induces apoptosis of brain microvascular
      endothelial cells via TNF-R1, contributing to anti-angiogenesis.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1's anti-angiogenic function
      through induction of endothelial cell apoptosis.
    supported_by:
    - reference_id: PMID:18726995
      supporting_text: Thrombospondin-1-induced apoptosis of brain microvascular
        endothelial cells can be mediated by TNF-R1.
- term:
    id: GO:0032760
    label: positive regulation of tumor necrosis factor production
  evidence_type: IDA
  original_reference_id: PMID:18726995
  review:
    summary: >
      Study showed TSP1-induced endothelial apoptosis involves TNF-R1.
      Note: This study shows TSP1 signals through TNF-R1, but does not
      clearly demonstrate that TSP1 increases TNF production. The earlier
      study PMID:14568985 showed TSP1 NEGATIVELY regulates TNF-alpha in DCs.
    action: UNDECIDED
    reason: >
      The reference shows TSP1 signals through TNF-R1 but does not
      clearly demonstrate positive regulation of TNF production.
      Evidence from PMID:14568985 shows TSP1 negatively regulates
      TNF-alpha production in dendritic cells. The effect may be
      context-dependent.
    supported_by:
    - reference_id: PMID:18726995
      supporting_text: Thrombospondin-1-induced apoptosis of brain microvascular
        endothelial cells can be mediated by TNF-R1.
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IDA
  original_reference_id: PMID:18653767
  review:
    summary: >
      TSP1 binding to calreticulin-LRP1 complex signals resistance to
      anoikis (detachment-induced apoptosis). This is mediated by the
      N-terminal domain and is distinct from its pro-apoptotic effects
      through CD36.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 anti-apoptotic function
      through calreticulin/LRP1. TSP1 has context-dependent effects:
      pro-apoptotic via CD36 and anti-apoptotic via calreticulin/LRP1.
    supported_by:
    - reference_id: PMID:18653767
      supporting_text: Thrombospondin 1 binding to calreticulin-LRP1 signals
        resistance to anoikis.
- term:
    id: GO:0051897
    label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B
      signal transduction
  evidence_type: IDA
  original_reference_id: PMID:18653767
  review:
    summary: >
      TSP1 binding to calreticulin-LRP1 activates PI3K/Akt signaling,
      which mediates resistance to anoikis. This is part of TSP1's
      pro-survival signaling through the N-terminal domain.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 activating PI3K/Akt pathway
      through calreticulin/LRP1. This is part of TSP1's complex
      signaling repertoire.
    supported_by:
    - reference_id: PMID:18653767
      supporting_text: Thrombospondin 1 binding to calreticulin-LRP1 signals
        resistance to anoikis.
- term:
    id: GO:0001968
    label: fibronectin binding
  evidence_type: IDA
  original_reference_id: PMID:6693501
  review:
    summary: >
      Classic study demonstrating TSP1 binds fibronectin and other ECM
      proteins. TSP1-fibronectin binding is relevant to ECM organization.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 fibronectin binding.
      This is a well-documented molecular function.
    supported_by:
    - reference_id: PMID:6693501
      supporting_text: 'Interactions of thrombospondin with extracellular matrix proteins:
        selective binding to type V collagen.'
- term:
    id: GO:0008201
    label: heparin binding
  evidence_type: IDA
  original_reference_id: PMID:101549
  review:
    summary: >
      Foundational paper describing the isolation of TSP1 from platelets
      and characterizing its heparin binding activity. Heparin binding
      is mediated by the N-terminal domain.
    action: ACCEPT
    reason: >
      Classic experimental evidence for TSP1 heparin binding. This is a
      core molecular function important for ECM localization.
    supported_by:
    - reference_id: PMID:101549
      supporting_text: Isolation and characterization of a high molecular weight
        glycoprotein from human blood platelets.
- term:
    id: GO:0030169
    label: low-density lipoprotein particle binding
  evidence_type: IDA
  original_reference_id: PMID:6693501
  review:
    summary: >
      Study showed TSP1 interactions with various proteins including
      LDL particles. TSP1 may bind LDL as part of its interactions
      with lipoproteins.
    action: KEEP_AS_NON_CORE
    reason: >
      LDL binding by TSP1 is documented but is not a primary function.
      May be relevant to TSP1's roles in atherosclerosis.
    supported_by:
    - reference_id: PMID:6693501
      supporting_text: 'Interactions of thrombospondin with extracellular matrix proteins:
        selective binding to type V collagen.'
- term:
    id: GO:0043236
    label: laminin binding
  evidence_type: IDA
  original_reference_id: PMID:6693501
  review:
    summary: >
      Study showing TSP1 binds laminin as part of its interactions
      with ECM components.
    action: ACCEPT
    reason: >
      TSP1 binding to laminin is documented as part of its ECM
      interaction repertoire.
    supported_by:
    - reference_id: PMID:6693501
      supporting_text: 'Interactions of thrombospondin with extracellular matrix proteins:
        selective binding to type V collagen.'
- term:
    id: GO:0070051
    label: fibrinogen binding
  evidence_type: IDA
  original_reference_id: PMID:6693501
  review:
    summary: >
      Study showing TSP1 binds fibrinogen. This is important for TSP1's
      role in hemostasis and clot formation.
    action: ACCEPT
    reason: >
      TSP1 fibrinogen binding is a well-documented function relevant
      to hemostasis. TSP1 is incorporated into fibrin clots.
    supported_by:
    - reference_id: PMID:6693501
      supporting_text: 'Interactions of thrombospondin with extracellular matrix proteins:
        selective binding to type V collagen.'
- term:
    id: GO:0070052
    label: collagen V binding
  evidence_type: IDA
  original_reference_id: PMID:6693501
  review:
    summary: >
      Study demonstrated TSP1 selectively binds type V collagen among
      the collagens tested. This is part of TSP1's ECM interactions.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 binding type V collagen.
      This specific collagen interaction is part of TSP1's ECM function.
    supported_by:
    - reference_id: PMID:6693501
      supporting_text: 'Interactions of thrombospondin with extracellular matrix proteins:
        selective binding to type V collagen.'
- term:
    id: GO:0002040
    label: sprouting angiogenesis
  evidence_type: IMP
  original_reference_id: PMID:17879962
  review:
    summary: >
      Study showing TSP1's N-terminal domain has pro-angiogenic effects
      through syndecan-4 interactions, contributing to endothelial
      tubulogenesis. Note: This is distinct from TSP1's anti-angiogenic
      function mediated by CD36 through the TSRs.
    action: ACCEPT
    reason: >
      TSP1 is involved in sprouting angiogenesis, though its net effect
      is typically anti-angiogenic. The N-terminal domain can have
      pro-angiogenic effects while the TSRs mediate anti-angiogenic effects.
    supported_by:
    - reference_id: PMID:17879962
      supporting_text: Syndecan-4 contributes to endothelial tubulogenesis
        through interactions with two motifs inside the pro-angiogenic
        N-terminal domain of thrombospondin-1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15700281
  review:
    summary: >
      Study showing TSP1 interacts with IGFBP-5 to negatively regulate
      IGF-I actions. While this interaction is documented, "protein
      binding" is too generic.
    action: MARK_AS_OVER_ANNOTATED
    reason: >
      Generic "protein binding" provides limited functional insight.
      The specific TSP1-IGFBP-5 interaction is documented.
    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:0030335
    label: positive regulation of cell migration
  evidence_type: IDA
  original_reference_id: PMID:15700281
  review:
    summary: >
      Study showing TSP1-IGFBP-5 interactions affect cell migration.
      TSP1 can promote cell migration through calreticulin/LRP1
      signaling that triggers focal adhesion disassembly.
    action: ACCEPT
    reason: >
      TSP1 pro-migratory effects are documented through the N-terminal
      domain and calreticulin/LRP1 pathway. Effects on migration are
      context and receptor-dependent.
    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:0032914
    label: positive regulation of transforming growth factor beta1 production
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >
      TSP1 activates latent TGF-beta1 (converting inactive to active form)
      rather than increasing TGF-beta1 production/biosynthesis. This
      annotation may conflate activation with production.
    action: MODIFY
    reason: >
      TSP1 activates pre-existing latent TGF-beta1 rather than inducing
      its production/biosynthesis. A more accurate term would be
      GO:0030511 (positive regulation of TGF-beta receptor signaling).
    proposed_replacement_terms:
    - id: GO:0030511
      label: positive regulation of transforming growth factor beta receptor
        signaling pathway
- term:
    id: GO:0045727
    label: positive regulation of translation
  evidence_type: IDA
  original_reference_id: PMID:15700281
  review:
    summary: >
      Study on TSP1-IGFBP-5 interactions affecting IGF-I signaling. The
      connection to translation regulation is indirect through IGF
      pathway modulation.
    action: KEEP_AS_NON_CORE
    reason: >
      Translation regulation by TSP1 is indirect through effects on
      growth factor signaling rather than a direct function.
    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:0045766
    label: positive regulation of angiogenesis
  evidence_type: IMP
  original_reference_id: PMID:17879962
  review:
    summary: >
      Study showing the N-terminal domain of TSP1 has pro-angiogenic
      effects through syndecan-4 interactions. Note: This is distinct
      from TSP1's predominant anti-angiogenic function via the TSRs.
    action: KEEP_AS_NON_CORE
    reason: >
      While the N-terminal domain can promote angiogenesis, TSP1's
      predominant effect is anti-angiogenic (via CD36 and TSRs).
      Pro-angiogenic effects are context and domain-specific.
    supported_by:
    - reference_id: PMID:17879962
      supporting_text: Syndecan-4 contributes to endothelial tubulogenesis
        through interactions with two motifs inside the pro-angiogenic
        N-terminal domain of thrombospondin-1.
- term:
    id: GO:0050431
    label: transforming growth factor beta binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >
      TSP1 binds latent TGF-beta1 through its type-1 repeats (TSRs).
      The LSKL sequence mediates binding to the latency-associated
      peptide of TGF-beta, enabling activation.
    action: ACCEPT
    reason: >
      TGF-beta binding is a core molecular function of TSP1. The
      type-1 repeats mediate this interaction which is essential
      for TGF-beta1 activation.
- term:
    id: GO:0010748
    label: negative regulation of long-chain fatty acid import across plasma
      membrane
  evidence_type: IDA
  original_reference_id: PMID:17416590
  review:
    summary: >
      Study showed TSP1 inhibits NO signaling via CD36 by inhibiting
      myristic acid uptake. Myristic acid is required for eNOS
      myristoylation.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 inhibiting fatty acid
      uptake through CD36. This mechanism contributes to TSP1's
      inhibition of NO signaling.
    supported_by:
    - reference_id: PMID:17416590
      supporting_text: Thrombospondin-1 inhibits nitric oxide signaling via CD36
        by inhibiting myristic acid uptake.
- term:
    id: GO:0010754
    label: negative regulation of receptor guanylyl cyclase signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:17416590
  review:
    summary: >
      TSP1 inhibits NO/cGMP signaling which involves guanylyl cyclase.
      By blocking myristic acid uptake, TSP1 impairs eNOS function
      and downstream cGMP production.
    action: ACCEPT
    reason: >
      TSP1 inhibition of guanylyl cyclase signaling is part of its
      core anti-NO function. This is mediated through CD36.
    supported_by:
    - reference_id: PMID:17416590
      supporting_text: Thrombospondin-1 inhibits nitric oxide signaling via CD36
        by inhibiting myristic acid uptake.
- term:
    id: GO:0010757
    label: negative regulation of plasminogen activation
  evidence_type: IDA
  original_reference_id: PMID:6438154
  review:
    summary: >
      TSP1 forms complexes with plasminogen and modulates plasminogen
      activation. TSP1 has antiplasmin activity that contributes to
      hemostasis.
    action: ACCEPT
    reason: >
      TSP1 negatively regulates plasminogen activation as part of
      its role in hemostasis and fibrinolysis regulation.
    supported_by:
    - reference_id: PMID:6438154
      supporting_text: Complex formation of platelet thrombospondin with
        plasminogen.
- term:
    id: GO:0010759
    label: positive regulation of macrophage chemotaxis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >
      TSP1 can promote macrophage recruitment and chemotaxis. This is
      documented in tumor microenvironment studies and inflammation.
    action: ACCEPT
    reason: >
      TSP1 promotes macrophage chemotaxis as part of its immune
      modulatory function, documented in multiple contexts.
- term:
    id: GO:0010763
    label: positive regulation of fibroblast migration
  evidence_type: IDA
  original_reference_id: PMID:18555217
  review:
    summary: >
      Study showing TSP1 promotes fibroblast migration through TGF-beta1
      dependent mechanisms. This is consistent with TSP1's role in
      wound healing and tissue remodeling.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 promoting fibroblast
      migration. This is part of TSP1's role in tissue repair.
    supported_by:
    - reference_id: PMID:18555217
      supporting_text: Differential involvement of TGF-beta1 in mediating the
        motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral
        tumour cells.
- term:
    id: GO:0001666
    label: response to hypoxia
  evidence_type: NAS
  original_reference_id: PMID:9304800
  review:
    summary: >
      TSP1 expression is regulated by hypoxia. In hypoxic conditions,
      TSP1 levels can be modulated as part of angiogenesis regulation.
    action: KEEP_AS_NON_CORE
    reason: >
      TSP1 responds to hypoxia at the expression level, but this is
      not a direct mechanistic function of the protein itself.
    supported_by:
    - reference_id: PMID:9304800
      supporting_text: Thrombospondin-1. Adams JC(1).
- term:
    id: GO:0001937
    label: negative regulation of endothelial cell proliferation
  evidence_type: IMP
  original_reference_id: PMID:17413041
  review:
    summary: >
      Study on alpha9beta1 integrin interaction with TSP1. Paradoxically,
      this paper shows TSP1 can promote angiogenesis through this integrin,
      but TSP1's net effect on endothelial proliferation is typically
      inhibitory via CD36.
    action: ACCEPT
    reason: >
      TSP1 inhibition of endothelial cell proliferation is well-documented
      via CD36, even though specific integrin interactions may have
      different effects.
    supported_by:
    - reference_id: PMID:17413041
      supporting_text: Interaction of alpha9beta1 integrin with thrombospondin-1
        promotes angiogenesis.
- term:
    id: GO:0001937
    label: negative regulation of endothelial cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:17996481
  review:
    summary: >
      Study showed TSP1 type III repeats bind FGF-2 and inhibit endothelial
      cell proliferation. This identifies a novel anti-angiogenic domain.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 inhibiting endothelial cell
      proliferation through FGF-2 sequestration by the type III repeats.
    supported_by:
    - reference_id: PMID:17996481
      supporting_text: Fibroblast growth factor-2 binding to the
        thrombospondin-1 type III repeats, a novel antiangiogenic domain.
- term:
    id: GO:0001953
    label: negative regulation of cell-matrix adhesion
  evidence_type: IDA
  original_reference_id: PMID:17416590
  review:
    summary: >
      TSP1 inhibits NO signaling via CD36, which affects cell-matrix
      adhesion. By inhibiting NO/cGMP signaling, TSP1 blocks
      NO-stimulated cell adhesion responses.
    action: ACCEPT
    reason: >
      TSP1 negatively regulates cell-matrix adhesion through inhibition
      of NO signaling, as shown in PMID:16150726 as well.
    supported_by:
    - reference_id: PMID:17416590
      supporting_text: Thrombospondin-1 inhibits nitric oxide signaling via CD36
        by inhibiting myristic acid uptake.
- term:
    id: GO:0002544
    label: chronic inflammatory response
  evidence_type: IEP
  original_reference_id: PMID:18674744
  review:
    summary: >
      Study showing TSP1 and TGF-beta are elevated in rheumatoid arthritis,
      suggesting involvement in chronic inflammation. This is an IEP
      annotation based on expression patterns.
    action: KEEP_AS_NON_CORE
    reason: >
      TSP1 involvement in chronic inflammation is context-dependent.
      While TSP1 is elevated in RA, its primary function is more
      often anti-inflammatory through TGF-beta activation.
    supported_by:
    - reference_id: PMID:18674744
      supporting_text: Thrombospondin-1 and transforming growth factor beta are
        pro-inflammatory molecules in rheumatoid arthritis.
- term:
    id: GO:0002581
    label: negative regulation of antigen processing and presentation of peptide
      or polysaccharide antigen via MHC class II
  evidence_type: IDA
  original_reference_id: PMID:16882710
  review:
    summary: >
      Study showing TSP1 from apoptotic cells induces tolerizing states
      in dendritic cells, reducing antigen presentation. This is part
      of TSP1's immunosuppressive function.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 negatively regulating
      antigen presentation. This contributes to immune tolerance.
    supported_by:
    - reference_id: PMID:16882710
      supporting_text: Apoptotic cell thrombospondin-1 and heparin-binding
        domain lead to dendritic-cell phagocytic and tolerizing states.
- term:
    id: GO:0002605
    label: negative regulation of dendritic cell antigen processing and
      presentation
  evidence_type: IDA
  original_reference_id: PMID:16882710
  review:
    summary: >
      TSP1 induces tolerizing states in dendritic cells, negatively
      regulating their antigen processing and presentation function.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 negatively regulating
      DC antigen processing. Part of TSP1's immunosuppressive function.
    supported_by:
    - reference_id: PMID:16882710
      supporting_text: Apoptotic cell thrombospondin-1 and heparin-binding
        domain lead to dendritic-cell phagocytic and tolerizing states.
- term:
    id: GO:0005178
    label: integrin binding
  evidence_type: IMP
  original_reference_id: PMID:17413041
  review:
    summary: >
      Study demonstrating TSP1 binds alpha9beta1 integrin and this
      interaction promotes angiogenesis. TSP1 binds multiple integrins.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 integrin binding. TSP1
      interacts with multiple integrins through various domains.
    supported_by:
    - reference_id: PMID:17413041
      supporting_text: Interaction of alpha9beta1 integrin with thrombospondin-1
        promotes angiogenesis.
    - reference_id: file:human/THBS1/THBS1-deep-research-falcon.md
      supporting_text: >-
        THBS1 binds multiple integrins; 2024 synthesis places integrin
        binding across NTD and EGF-like domains and highlights integrin
        involvement in endothelial migration/vascular remodeling.
- term:
    id: GO:0005178
    label: integrin binding
  evidence_type: IMP
  original_reference_id: PMID:18757424
  review:
    summary: >
      Study on TSP1 effects on macrophage recruitment and tumor cytotoxicity,
      involving integrin interactions for cell adhesion and migration.
    action: ACCEPT
    reason: >
      TSP1 integrin binding is documented and relevant to cell recruitment.
    supported_by:
    - reference_id: PMID:18757424
      supporting_text: Thrombospondin 1 promotes tumor macrophage recruitment
        and enhances tumor cell cytotoxicity of differentiated U937 cells.
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: NAS
  original_reference_id: PMID:9304800
  review:
    summary: >
      TSP1 contains multiple calcium-binding sites, particularly in the
      type 3 repeats. Calcium binding affects TSP1 conformation and
      ligand-binding properties.
    action: ACCEPT
    reason: >
      Calcium binding is a well-documented property of TSP1. The type 3
      repeat region contains calcium-binding loops critical for structure.
    supported_by:
    - reference_id: PMID:9304800
      supporting_text: Thrombospondin-1. Adams JC(1).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:3402455
  review:
    summary: >
      Study showing TSP1 forms complexes with osteonectin. While this
      interaction is documented, "protein binding" is too generic.
    action: MARK_AS_OVER_ANNOTATED
    reason: >
      Generic "protein binding" provides limited functional insight.
      The specific TSP1-osteonectin interaction is documented.
    supported_by:
    - reference_id: PMID:3402455
      supporting_text: Complex formation of human thrombospondin with
        osteonectin.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:6438154
  review:
    summary: >
      Study showing TSP1 forms complexes with plasminogen. While this
      interaction is documented, "protein binding" is too generic.
    action: MARK_AS_OVER_ANNOTATED
    reason: >
      Generic "protein binding" provides limited insight. The more
      specific annotations for protease binding and plasminogen
      activation regulation are more informative.
    supported_by:
    - reference_id: PMID:6438154
      supporting_text: Complex formation of platelet thrombospondin with
        plasminogen.
- term:
    id: GO:0005577
    label: fibrinogen complex
  evidence_type: IDA
  original_reference_id: PMID:3997886
  review:
    summary: >
      Study showing TSP1 is incorporated into fibrin clots and associates
      with the fibrinogen complex during hemostasis.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 association with fibrinogen
      complex in clot formation. This is part of TSP1's hemostatic function.
    supported_by:
    - reference_id: PMID:3997886
      supporting_text: Incorporation of thrombospondin into fibrin clots.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:6777381
  review:
    summary: >
      Classic study showing TSP1 (glycoprotein G) in extracellular space
      associating with platelets in a Ca2+-dependent manner.
    action: ACCEPT
    reason: >
      Early foundational evidence for TSP1 presence in extracellular space.
    supported_by:
    - reference_id: PMID:6777381
      supporting_text: Ca2+-mediated association of glycoprotein G
        (thrombinsensitive protein, thrombospondin) with human platelets.
- term:
    id: GO:0006955
    label: immune response
  evidence_type: IEP
  original_reference_id: PMID:18674744
  review:
    summary: >
      Study showing TSP1 elevation in rheumatoid arthritis, suggesting
      involvement in immune responses. TSP1 modulates immunity through
      multiple mechanisms.
    action: ACCEPT
    reason: >
      TSP1 is involved in immune responses through TGF-beta activation,
      cytokine regulation, and effects on immune cells via CD47/CD36.
    supported_by:
    - reference_id: PMID:18674744
      supporting_text: Thrombospondin-1 and transforming growth factor beta are
        pro-inflammatory molecules in rheumatoid arthritis.
- term:
    id: GO:0007155
    label: cell adhesion
  evidence_type: NAS
  original_reference_id: PMID:9304800
  review:
    summary: >
      TSP1 is an adhesive glycoprotein that mediates cell-matrix and
      cell-cell adhesion through interactions with integrins and ECM.
    action: ACCEPT
    reason: >
      Cell adhesion is a well-documented function of TSP1 as an
      adhesive glycoprotein.
    supported_by:
    - reference_id: PMID:9304800
      supporting_text: Thrombospondin-1. Adams JC(1).
- term:
    id: GO:0009749
    label: response to glucose
  evidence_type: IDA
  original_reference_id: PMID:18096704
  review:
    summary: >
      Study showing TSP1 production is regulated by high glucose through
      post-transcriptional mechanisms. Relevant to diabetic complications.
    action: KEEP_AS_NON_CORE
    reason: >
      TSP1 expression responds to glucose, but this is a transcriptional/
      post-transcriptional effect rather than a direct protein function.
    supported_by:
    - reference_id: PMID:18096704
      supporting_text: Cell type-specific post-transcriptional regulation of
        production of the potent antiangiogenic and proatherogenic protein
        thrombospondin-1 by high glucose.
- term:
    id: GO:0009897
    label: external side of plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:6777381
  review:
    summary: >
      TSP1 binds to the external side of platelet plasma membranes in
      a Ca2+-dependent manner after release from alpha granules.
    action: ACCEPT
    reason: >
      Direct evidence for TSP1 association with external plasma membrane.
      TSP1 binds to cell surface receptors on the external membrane.
    supported_by:
    - reference_id: PMID:6777381
      supporting_text: Ca2+-mediated association of glycoprotein G
        (thrombinsensitive protein, thrombospondin) with human platelets.
- term:
    id: GO:0010595
    label: positive regulation of endothelial cell migration
  evidence_type: IDA
  original_reference_id: PMID:18555217
  review:
    summary: >
      Study showing TSP1 has motogenic effects on endothelial cells,
      partly through TGF-beta1. TSP1 effects on migration are complex
      and context-dependent.
    action: KEEP_AS_NON_CORE
    reason: >
      TSP1 effects on endothelial migration are context-dependent. While
      TSP1 can promote migration in some contexts, its predominant effect
      on endothelial cells is typically inhibitory.
    supported_by:
    - reference_id: PMID:18555217
      supporting_text: Differential involvement of TGF-beta1 in mediating the
        motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral
        tumour cells.
- term:
    id: GO:0010596
    label: negative regulation of endothelial cell migration
  evidence_type: IDA
  original_reference_id: PMID:18555217
  review:
    summary: >
      Same study showing TSP1 has complex effects on cell migration. TSP1
      can inhibit endothelial migration through its anti-angiogenic domains.
    action: ACCEPT
    reason: >
      TSP1 inhibition of endothelial cell migration is part of its
      anti-angiogenic function, mediated primarily through CD36.
    supported_by:
    - reference_id: PMID:18555217
      supporting_text: Differential involvement of TGF-beta1 in mediating the
        motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral
        tumour cells.
- term:
    id: GO:0016477
    label: cell migration
  evidence_type: IDA
  original_reference_id: PMID:18555217
  review:
    summary: >
      Study showing TSP1 has motogenic effects on multiple cell types.
      TSP1 regulates cell migration through various mechanisms.
    action: ACCEPT
    reason: >
      TSP1 involvement in cell migration is well-documented. Effects are
      cell-type and receptor-dependent.
    supported_by:
    - reference_id: PMID:18555217
      supporting_text: Differential involvement of TGF-beta1 in mediating the
        motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral
        tumour cells.
- term:
    id: GO:0016525
    label: negative regulation of angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:17596205
  review:
    summary: >
      Study identifying cell cycle suppression as a mechanism for TSP1's
      anti-angiogenic activity.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1's anti-angiogenic function
      through cell cycle regulation.
    supported_by:
    - reference_id: PMID:17596205
      supporting_text: Novel antiangiogenic pathway of thrombospondin-1 mediated
        by suppression of the cell cycle.
- term:
    id: GO:0016525
    label: negative regulation of angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:17996481
  review:
    summary: >
      Study showing type III repeats of TSP1 bind FGF-2 and constitute
      a novel anti-angiogenic domain.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1's anti-angiogenic function
      through FGF-2 sequestration by type III repeats.
    supported_by:
    - reference_id: PMID:17996481
      supporting_text: Fibroblast growth factor-2 binding to the
        thrombospondin-1 type III repeats, a novel antiangiogenic domain.
- term:
    id: GO:0030141
    label: secretory granule
  evidence_type: IDA
  original_reference_id: PMID:101549
  review:
    summary: >
      Foundational study characterizing TSP1 from platelet secretory
      granules (alpha granules). TSP1 is stored in and released from
      secretory granules.
    action: ACCEPT
    reason: >
      TSP1 storage in platelet secretory granules (alpha granules) is
      a core localization from which TSP1 is released upon activation.
    supported_by:
    - reference_id: PMID:101549
      supporting_text: Isolation and characterization of a high molecular weight
        glycoprotein from human blood platelets.
- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: IMP
  original_reference_id: PMID:17413041
  review:
    summary: >
      Study showing TSP1-integrin alpha9beta1 interaction promotes
      angiogenesis and cell migration.
    action: ACCEPT
    reason: >
      TSP1 can promote cell migration through specific integrin
      interactions, though effects are receptor-dependent.
    supported_by:
    - reference_id: PMID:17413041
      supporting_text: Interaction of alpha9beta1 integrin with thrombospondin-1
        promotes angiogenesis.
- term:
    id: GO:0030511
    label: positive regulation of transforming growth factor beta receptor
      signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:18555217
  review:
    summary: >
      Study showing TGF-beta1 involvement in TSP1's motogenic effects.
      TSP1 activates TGF-beta1 which signals through TGF-beta receptors.
    action: ACCEPT
    reason: >
      Direct experimental evidence supporting TSP1's role in activating
      TGF-beta signaling. This is a core function of TSP1.
    supported_by:
    - reference_id: PMID:18555217
      supporting_text: Differential involvement of TGF-beta1 in mediating the
        motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral
        tumour cells.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: TAS
  original_reference_id: PMID:9304800
  review:
    summary: >
      Review article confirming TSP1 localization in the extracellular
      matrix as a matricellular protein.
    action: ACCEPT
    reason: >
      ECM localization is a core property of TSP1.
    supported_by:
    - reference_id: PMID:9304800
      supporting_text: Thrombospondin-1. Adams JC(1).
- term:
    id: GO:0031091
    label: platelet alpha granule
  evidence_type: IDA
  original_reference_id: PMID:6777381
  review:
    summary: >
      Classic study showing TSP1 is stored in platelet alpha granules and
      released upon activation.
    action: ACCEPT
    reason: >
      Platelet alpha granule is a core storage localization for TSP1.
    supported_by:
    - reference_id: PMID:6777381
      supporting_text: Ca2+-mediated association of glycoprotein G
        (thrombinsensitive protein, thrombospondin) with human platelets.
- term:
    id: GO:0032026
    label: response to magnesium ion
  evidence_type: IDA
  original_reference_id: PMID:6777381
  review:
    summary: >
      Study examined divalent cation effects on TSP1-platelet association.
      Magnesium ion effects on TSP1 may relate to its Ca2+-binding properties.
    action: KEEP_AS_NON_CORE
    reason: >
      Response to magnesium is not a primary function of TSP1. The study
      focused on Ca2+-mediated association.
    supported_by:
    - reference_id: PMID:6777381
      supporting_text: Ca2+-mediated association of glycoprotein G
        (thrombinsensitive protein, thrombospondin) with human platelets.
- term:
    id: GO:0032570
    label: response to progesterone
  evidence_type: TAS
  original_reference_id: PMID:9304800
  review:
    summary: >
      TSP1 expression may be regulated by progesterone in certain contexts,
      but this is not a primary function.
    action: KEEP_AS_NON_CORE
    reason: >
      Hormonal regulation of TSP1 expression is not a core function.
      This likely reflects transcriptional regulation in specific tissues.
    supported_by:
    - reference_id: PMID:9304800
      supporting_text: Thrombospondin-1. Adams JC(1).
- term:
    id: GO:0032695
    label: negative regulation of interleukin-12 production
  evidence_type: IDA
  original_reference_id: PMID:16882710
  review:
    summary: >
      Study showing TSP1 from apoptotic cells induces tolerizing states
      in DCs with reduced IL-12 production. Also supported by PMID:14568985.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 negatively regulating IL-12
      production. This is part of TSP1's immunosuppressive function.
    supported_by:
    - reference_id: PMID:16882710
      supporting_text: Apoptotic cell thrombospondin-1 and heparin-binding
        domain lead to dendritic-cell phagocytic and tolerizing states.
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: NAS
  original_reference_id: PMID:9304800
  review:
    summary: >
      TSP1 expression may be induced by heat stress, but this is not
      a primary function of the protein.
    action: KEEP_AS_NON_CORE
    reason: >
      Response to heat is not a core function of TSP1. This likely
      reflects stress-induced transcriptional regulation.
    supported_by:
    - reference_id: PMID:9304800
      supporting_text: Thrombospondin-1. Adams JC(1).
- term:
    id: GO:0040037
    label: negative regulation of fibroblast growth factor receptor signaling
      pathway
  evidence_type: IDA
  original_reference_id: PMID:17996481
  review:
    summary: >
      TSP1 type III repeats bind FGF-2 and sequester it from FGF receptors,
      thereby negatively regulating FGF receptor signaling.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 inhibiting FGF signaling by
      binding and sequestering FGF-2. This contributes to anti-angiogenesis.
    supported_by:
    - reference_id: PMID:17996481
      supporting_text: Fibroblast growth factor-2 binding to the
        thrombospondin-1 type III repeats, a novel antiangiogenic domain.
- term:
    id: GO:0042327
    label: positive regulation of phosphorylation
  evidence_type: IMP
  original_reference_id: PMID:17413041
  review:
    summary: >
      TSP1 interaction with alpha9beta1 integrin promotes MAPK signaling
      and phosphorylation events involved in angiogenesis.
    action: ACCEPT
    reason: >
      TSP1 can positively regulate phosphorylation through integrin
      signaling pathways, including MAPK activation.
    supported_by:
    - reference_id: PMID:17413041
      supporting_text: Interaction of alpha9beta1 integrin with thrombospondin-1
        promotes angiogenesis.
- term:
    id: GO:0043032
    label: positive regulation of macrophage activation
  evidence_type: IDA
  original_reference_id: PMID:18757424
  review:
    summary: >
      Study showing TSP1 promotes macrophage activation in tumor
      microenvironments, enhancing cytotoxicity.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 promoting macrophage
      activation. Part of TSP1's immune modulatory function.
    supported_by:
    - reference_id: PMID:18757424
      supporting_text: Thrombospondin 1 promotes tumor macrophage recruitment
        and enhances tumor cell cytotoxicity of differentiated U937 cells.
- term:
    id: GO:0043394
    label: proteoglycan binding
  evidence_type: TAS
  original_reference_id: PMID:9304800
  review:
    summary: >
      TSP1 binds proteoglycans including heparan sulfate proteoglycans
      through its N-terminal domain. This mediates ECM localization.
    action: ACCEPT
    reason: >
      Proteoglycan binding is well-documented for TSP1 and important
      for its ECM localization and cell surface association.
    supported_by:
    - reference_id: PMID:9304800
      supporting_text: Thrombospondin-1. Adams JC(1).
- term:
    id: GO:0043536
    label: positive regulation of blood vessel endothelial cell migration
  evidence_type: IDA
  original_reference_id: PMID:18555217
  review:
    summary: >
      Study showing TSP1 has motogenic effects on endothelial cells in
      some contexts. TSP1 effects on endothelial migration are complex.
    action: KEEP_AS_NON_CORE
    reason: >
      While TSP1 can promote endothelial migration in some contexts,
      its predominant effect is typically inhibitory. Context-dependent.
    supported_by:
    - reference_id: PMID:18555217
      supporting_text: Differential involvement of TGF-beta1 in mediating the
        motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral
        tumour cells.
- term:
    id: GO:0043537
    label: negative regulation of blood vessel endothelial cell migration
  evidence_type: IDA
  original_reference_id: PMID:18555217
  review:
    summary: >
      TSP1 can inhibit endothelial cell migration through its anti-angiogenic
      domains, particularly via CD36 signaling.
    action: ACCEPT
    reason: >
      TSP1 inhibition of endothelial cell migration is part of its
      anti-angiogenic function.
    supported_by:
    - reference_id: PMID:18555217
      supporting_text: Differential involvement of TGF-beta1 in mediating the
        motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral
        tumour cells.
- term:
    id: GO:0043652
    label: engulfment of apoptotic cell
  evidence_type: IDA
  original_reference_id: PMID:16882710
  review:
    summary: >
      TSP1 on apoptotic cells promotes their phagocytic uptake by
      dendritic cells. TSP1 serves as an "eat me" signal.
    action: ACCEPT
    reason: >
      Direct experimental evidence for TSP1 involvement in apoptotic
      cell engulfment through effects on phagocytes.
    supported_by:
    - reference_id: PMID:16882710
      supporting_text: Apoptotic cell thrombospondin-1 and heparin-binding
        domain lead to dendritic-cell phagocytic and tolerizing states.
- term:
    id: GO:0045766
    label: positive regulation of angiogenesis
  evidence_type: IMP
  original_reference_id: PMID:17413041
  review:
    summary: >
      Study showing TSP1-alpha9beta1 integrin interaction promotes
      angiogenesis. Note: This is distinct from TSP1's predominant
      anti-angiogenic function via CD36.
    action: KEEP_AS_NON_CORE
    reason: >
      TSP1's predominant effect is anti-angiogenic. Pro-angiogenic effects
      through specific integrin interactions are context-dependent.
    supported_by:
    - reference_id: PMID:17413041
      supporting_text: Interaction of alpha9beta1 integrin with thrombospondin-1
        promotes angiogenesis.
- term:
    id: GO:0050431
    label: transforming growth factor beta binding
  evidence_type: TAS
  original_reference_id: PMID:9304800
  review:
    summary: >
      TSP1 binds latent TGF-beta through its type-1 repeats. This binding
      is essential for TGF-beta1 activation.
    action: ACCEPT
    reason: >
      TGF-beta binding is a core molecular function of TSP1 mediated
      by the type-1 repeats (TSRs).
    supported_by:
    - reference_id: PMID:9304800
      supporting_text: Thrombospondin-1. Adams JC(1).
- term:
    id: GO:0050921
    label: positive regulation of chemotaxis
  evidence_type: IDA
  original_reference_id: PMID:18555217
  review:
    summary: >
      TSP1 has chemotactic effects on certain cell types including
      fibroblasts and macrophages.
    action: ACCEPT
    reason: >
      TSP1 promotes chemotaxis of specific cell types as part of its
      role in wound healing and inflammation.
    supported_by:
    - reference_id: PMID:18555217
      supporting_text: Differential involvement of TGF-beta1 in mediating the
        motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral
        tumour cells.
- term:
    id: GO:0051592
    label: response to calcium ion
  evidence_type: IDA
  original_reference_id: PMID:18757424
  review:
    summary: >
      TSP1 conformation and ligand-binding properties are affected by
      calcium. Calcium binding is important for TSP1 structure.
    action: ACCEPT
    reason: >
      TSP1 structure and function respond to calcium through its
      calcium-binding type 3 repeats.
    supported_by:
    - reference_id: PMID:18757424
      supporting_text: Thrombospondin 1 promotes tumor macrophage recruitment
        and enhances tumor cell cytotoxicity of differentiated U937 cells.
- term:
    id: GO:0051592
    label: response to calcium ion
  evidence_type: IDA
  original_reference_id: PMID:6777381
  review:
    summary: >
      Classic study showing TSP1 association with platelets is
      Ca2+-mediated, demonstrating calcium responsiveness.
    action: ACCEPT
    reason: >
      Direct evidence for TSP1 functional response to calcium ions.
      Calcium binding is essential for TSP1 structure and function.
    supported_by:
    - reference_id: PMID:6777381
      supporting_text: Ca2+-mediated association of glycoprotein G
        (thrombinsensitive protein, thrombospondin) with human platelets.
- term:
    id: GO:0051895
    label: negative regulation of focal adhesion assembly
  evidence_type: TAS
  original_reference_id: PMID:9304800
  review:
    summary: >
      TSP1 N-terminal domain engagement of calreticulin/LRP1 triggers
      focal adhesion disassembly, promoting cell motility.
    action: ACCEPT
    reason: >
      TSP1 negatively regulates focal adhesion assembly through
      calreticulin/LRP1 signaling. This is well-documented.
    supported_by:
    - reference_id: PMID:9304800
      supporting_text: Thrombospondin-1. Adams JC(1).
- term:
    id: GO:0051918
    label: negative regulation of fibrinolysis
  evidence_type: IDA
  original_reference_id: PMID:6438154
  review:
    summary: >
      TSP1 forms complexes with plasminogen and has antiplasmin activity,
      thereby negatively regulating fibrinolysis.
    action: ACCEPT
    reason: >
      TSP1 negative regulation of fibrinolysis is documented through
      plasminogen binding and antiplasmin activity.
    supported_by:
    - reference_id: PMID:6438154
      supporting_text: Complex formation of platelet thrombospondin with
        plasminogen.
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:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular
    Location vocabulary mapping, accompanied by conservative changes to GO terms
    applied by UniProt.
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data
    to orthologs using Ensembl Compara.
  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:101549
  title: Isolation and characterization of a high molecular weight glycoprotein
    from human blood platelets.
  findings: []
- id: PMID:10613822
  title: Signals leading to apoptosis-dependent inhibition of neovascularization
    by thrombospondin-1.
  findings: []
- id: PMID:11134179
  title: Histidine-rich glycoprotein inhibits the antiangiogenic effect of
    thrombospondin-1.
  findings: []
- id: PMID:14568985
  title: Thrombospondin 1 is an autocrine negative regulator of human dendritic
    cell activation.
  findings: []
- 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: []
- id: PMID:15864306
  title: A functional SNP in CILP, encoding cartilage intermediate layer
    protein, is associated with susceptibility to lumbar disc disease.
  findings: []
- id: PMID:16150726
  title: Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in
    a cGMP-dependent manner.
  findings: []
- id: PMID:16502470
  title: 'Human colostrum: identification of minor proteins in the aqueous phase by
    proteomics.'
  findings: []
- id: PMID:16882710
  title: Apoptotic cell thrombospondin-1 and heparin-binding domain lead to
    dendritic-cell phagocytic and tolerizing states.
  findings: []
- id: PMID:17413041
  title: Interaction of alpha9beta1 integrin with thrombospondin-1 promotes
    angiogenesis.
  findings: []
- id: PMID:17416590
  title: Thrombospondin-1 inhibits nitric oxide signaling via CD36 by inhibiting
    myristic acid uptake.
  findings: []
- id: PMID:17596205
  title: Novel antiangiogenic pathway of thrombospondin-1 mediated by
    suppression of the cell cycle.
  findings: []
- id: PMID:17879962
  title: Syndecan-4 contributes to endothelial tubulogenesis through
    interactions with two motifs inside the pro-angiogenic N-terminal domain of
    thrombospondin-1.
  findings: []
- id: PMID:17996481
  title: Fibroblast growth factor-2 binding to the thrombospondin-1 type III
    repeats, a novel antiangiogenic domain.
  findings: []
- id: PMID:18042364
  title: TSG-6 binds via its CUB_C domain to the cell-binding domain of
    fibronectin and increases fibronectin matrix assembly.
  findings: []
- id: PMID:18096704
  title: Cell type-specific post-transcriptional regulation of production of the
    potent antiangiogenic and proatherogenic protein thrombospondin-1 by high
    glucose.
  findings: []
- id: PMID:18285447
  title: Extracellular matrix retention of thrombospondin 1 is controlled by its
    conserved C-terminal region.
  findings: []
- id: PMID:18555217
  title: Differential involvement of TGF-beta1 in mediating the motogenic
    effects of TSP-1 on endothelial cells, fibroblasts and oral tumour cells.
  findings: []
- id: PMID:18653767
  title: Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to
    anoikis.
  findings: []
- id: PMID:18674744
  title: Thrombospondin-1 and transforming growth factor beta are
    pro-inflammatory molecules in rheumatoid arthritis.
  findings: []
- id: PMID:18688696
  title: Calumenin but not reticulocalbin forms a Ca2+-dependent complex with
    thrombospondin-1. A potential role in haemostasis and thrombosis.
  findings: []
- id: PMID:18726995
  title: Thrombospondin-1-induced apoptosis of brain microvascular endothelial
    cells can be mediated by TNF-R1.
  findings: []
- id: PMID:18757424
  title: Thrombospondin 1 promotes tumor macrophage recruitment and enhances
    tumor cell cytotoxicity of differentiated U937 cells.
  findings: []
- id: PMID:18940719
  title: Phosphatidylserine-positive erythrocytes bind to immobilized and
    soluble thrombospondin-1 via its heparin-binding domain.
  findings: []
- id: PMID:19004835
  title: Differential interactions of thrombospondin-1, -2, and -4 with CD47 and
    effects on cGMP signaling and ischemic injury responses.
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional
    protein identification technology (MudPIT).
  findings: []
- id: PMID:19542224
  title: The first draft of the endostatin interaction network.
  findings: []
- id: PMID:19738618
  title: Induction of thrombospondin-1 partially mediates the anti-angiogenic
    activity of dexrazoxane.
  findings: []
- id: PMID:20551380
  title: Proteomics characterization of extracellular space components in the
    human aorta.
  findings: []
- id: PMID:21362503
  title: Protein profile of exosomes from trabecular meshwork cells.
  findings: []
- id: PMID:22261194
  title: Proteomics analysis of cardiac extracellular matrix remodeling in a
    porcine model of ischemia/reperfusion injury.
  findings: []
- id: PMID:23144964
  title: Endogenous thrombospondin-1 regulates leukocyte recruitment and
    activation and accelerates death from systemic candidiasis.
  findings: []
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed
    prostatic secretions in urine.
  findings: []
- id: PMID:23658023
  title: Comparative proteomic analysis of supportive and unsupportive
    extracellular matrix substrates for human embryonic stem cell maintenance.
  findings: []
- id: PMID:23896411
  title: Thrombospondin-1 modulates VEGF signaling via CD36 by recruiting SHP-1
    to VEGFR2 complex in microvascular endothelial cells.
  findings: []
- id: PMID:23979707
  title: SILAC-based proteomics of human primary endothelial cell morphogenesis
    unveils tumor angiogenic markers.
  findings: []
- id: PMID:24117177
  title: Extended interaction network of procollagen C-proteinase enhancer-1 in
    the extracellular matrix.
  findings: []
- id: PMID:24177325
  title: MicroRNA miR-27b rescues bone marrow-derived angiogenic cell function
    and accelerates wound healing in type 2 diabetes mellitus.
  findings: []
- id: PMID:2435757
  title: Isolation of the thrombospondin membrane receptor.
  findings: []
- id: PMID:24511121
  title: Thrombospondin-1 activation of signal-regulatory protein-Ξ± stimulates
    reactive oxygen species production and promotes renal ischemia reperfusion
    injury.
  findings: []
- id: PMID:24615654
  title: Interleukin-18 may lead to benign prostatic hyperplasia via
    thrombospondin-1 production in prostatic smooth muscle cells.
  findings: []
- id: PMID:2478219
  title: An integrin receptor on normal and thrombasthenic platelets that binds
    thrombospondin.
  findings: []
- id: PMID:25660232
  title: miR-487b promotes human umbilical vein endothelial cell proliferation,
    migration, invasion and tube formation through regulating THBS1.
  findings: []
- id: PMID:26395742
  title: Angiogenic microRNAs Linked to Incidence and Progression of Diabetic
    Retinopathy in Type 1 Diabetes.
  findings: []
- id: PMID:26627825
  title: Extracellular Fibrinogen-binding Protein (Efb) from Staphylococcus
    aureus Inhibits the Formation of Platelet-Leukocyte Complexes.
  findings: []
- id: PMID:27068509
  title: 'Extracellular matrix remodelling in response to venous hypertension: proteomics
    of human varicose veins.'
  findings: []
- id: PMID:28124060
  title: Bone morphogenetic protein 4 regulates microRNAs miR-494 and miR-126-5p
    in control of endothelial cell function in angiogenesis.
  findings: []
- id: PMID:28327460
  title: Comprehensive proteomic characterization of stem cell-derived
    extracellular matrices.
  findings: []
- id: PMID:28344315
  title: Proteomic characterization of human multiple myeloma bone marrow
    extracellular matrix.
  findings: []
- id: PMID:3084490
  title: Interaction of thrombospondin with resting and stimulated human
    platelets.
  findings: []
- id: PMID:3402455
  title: Complex formation of human thrombospondin with osteonectin.
  findings: []
- id: PMID:3997886
  title: Incorporation of thrombospondin into fibrin clots.
  findings: []
- id: PMID:6341993
  title: Cultured human fibroblasts synthesize and secrete thrombospondin and
    incorporate it into extracellular matrix.
  findings: []
- id: PMID:6438154
  title: Complex formation of platelet thrombospondin with plasminogen.
    Modulation of activation by tissue activator.
  findings: []
- id: PMID:6489349
  title: Thrombospondin interactions with fibronectin and fibrinogen. Mutual
    inhibition in binding.
  findings: []
- id: PMID:6693501
  title: 'Interactions of thrombospondin with extracellular matrix proteins: selective
    binding to type V collagen.'
  findings: []
- id: PMID:6777381
  title: Ca2+-mediated association of glycoprotein G (thrombinsensitive protein,
    thrombospondin) with human platelets.
  findings: []
- id: PMID:7679575
  title: Characterization of the antiplasmin activity of human thrombospondin-1
    in solution.
  findings: []
- id: PMID:8288588
  title: Thrombospondin 3 is a developmentally regulated heparin binding
    protein.
  findings: []
- id: PMID:8550562
  title: Integrin-associated protein is a receptor for the C-terminal domain of
    thrombospondin.
  findings: []
- id: PMID:9304800
  title: Thrombospondin-1.
  findings: []
- id: Reactome:R-HSA-265429
  title: THBS1 (Thrombospondin-1) binds Integrin alpha3beta1, alpha4beta1
  findings: []
- id: Reactome:R-HSA-349603
  title: Interaction of integrin alphaIIb beta 3 with THBS1 (Thrombospondin-1)
  findings: []
- id: Reactome:R-HSA-382054
  title: PDGF binds to extracellular matrix proteins
  findings: []
- id: Reactome:R-HSA-481007
  title: Exocytosis of platelet alpha granule contents
  findings: []
- id: Reactome:R-HSA-5173005
  title: B3GALTL transfers glucose to O-fucosyl-proteins
  findings: []
- id: Reactome:R-HSA-5173192
  title: POFUT2 transfers fucose to TSR domain-containing proteins
  findings: []
- id: Reactome:R-HSA-6785565
  title: Defective B3GALTL does not transfer glucose to O-fucosyl-proteins
  findings: []
- id: Reactome:R-HSA-8936995
  title: THBS1 gene transcription is stimulated by the complex containing RUNX1,
    PRMT1 and GATA1 and inhibited by the complex of RUNX1, SIN3A and PRMT6
  findings: []
- id: Reactome:R-NUL-2731112
  title: Syndecan-1 binds THBS1
  findings: []
- id: file:human/THBS1/THBS1-deep-research-openai.md
  title: Deep research on THBS1 function
  findings: []
- id: file:human/THBS1/THBS1-deep-research-falcon.md
  title: Falcon (Edison) deep research on THBS1 function
  findings:
  - statement: >-
      THBS1/TSP-1 is a secreted matricellular (ECM-associated) glycoprotein
      in the Group A thrombospondin subfamily that forms trimers in the
      extracellular space; the CTD contains a CD47-binding site and the
      TSRs (type I repeats) are necessary for binding latent TGF-Ξ² and CD36,
      while the NTD and EGF-like domains participate in integrin
      interactions.
    supporting_text: >-
      a secreted matricellular (ECM-associated) glycoprotein in the Group A
      thrombospondin subfamily that forms trimers in the extracellular space
    reference_section_type: RESULTS
  - statement: >-
      THBS1 is repeatedly described as a major activator of latent TGF-Ξ²1
      in vivo, positioning it upstream of profibrotic and immunoregulatory
      Smad signaling and ECM remodeling.
    supporting_text: >-
      Multiple 2023–2024 sources characterize THBS1/TSP‑1 as a major
      mediator/activator of latent TGF‑β. This function positions THBS1
      upstream of profibrotic and immunoregulatory programs (e.g., Smad
      signaling and downstream ECM remodeling).
    reference_section_type: DISCUSSION
  - statement: >-
      THBS1 binds CD47 via its C-terminal domain and triggers signaling
      that suppresses nitric oxide (NO) pathway effects, antagonising
      NO/cGMP-dependent vasodilation.
    supporting_text: >-
      THBS1 binds CD47 (via CTD) and triggers signaling that suppresses
      nitric oxide (NO) pathway effects.
    reference_section_type: RESULTS
  - statement: >-
      THBS1-CD47 signaling antagonises NO/cGMP-dependent signaling, with
      consequences for vascular smooth muscle relaxation/vasodilation and
      ischaemic survival.
    supporting_text: >-
      THBS1–CD47 signaling **antagonizes NO/cGMP-dependent signaling**,
      with consequences for vascular smooth muscle relaxation/vasodilation
      and ischemic survival.
    reference_section_type: DISCUSSION
  - statement: >-
      THBS1 binds CD36 via its TSRs and contributes to platelet and
      vascular effects; CD36 also mediates THBS1's anti-angiogenic
      signaling.
    supporting_text: >-
      THBS1 binds CD36 (via TSRs) and contributes to platelet and vascular
      effects; CD36 is also part of anti-angiogenic signaling.
    reference_section_type: RESULTS
  - statement: >-
      THBS1 binds multiple integrins through its NTD and EGF-like domains,
      contributing to endothelial migration and vascular remodelling.
    supporting_text: >-
      THBS1 binds multiple integrins; 2024 synthesis places integrin
      binding across NTD and EGF-like domains and highlights integrin
      involvement in endothelial migration/vascular remodeling.
    reference_section_type: RESULTS
  - statement: >-
      THBS1 is a major component of platelet Ξ±-granules, rapidly released
      at injury sites and supporting platelet activation, vasoconstriction,
      and thrombus formation (via CD36 and NO pathway suppression).
    supporting_text: >-
      THBS1 is described as a major component of platelet α‑granules and
      is rapidly released at injury sites, supporting platelet activation,
      vasoconstriction, and thrombus formation
    reference_section_type: DISCUSSION
  - statement: >-
      In intestinal mucosal wound repair, epithelial THBS1 promotes
      restitution through CD47- and TGF-Ξ²1-dependent signaling, with
      effects on SMAD2/3 phosphorylation and RhoA/Rac1 cytoskeletal
      dynamics (Wilson et al. 2024 JCI Insight).
    supporting_text: >-
      a tissue-protective role for epithelial THBS1 in intestinal mucosal
      wound repair, mechanistically coupled to CD47 and TGF-Ξ²1 signaling
      and to cytoskeletal pathway interrogation (RhoA/Rac1; SMAD2/3)
    reference_section_type: DISCUSSION
  - statement: >-
      In prostate cancer models, THBS1 is a TGF-Ξ²-induced secreted ECM
      protein that interacts with integrin Ξ±V (ITGAV) and TGF-Ξ² receptor I
      (TΞ²RI) at the leading edge to mediate migration, invasion, and
      metastasis (Mu et al. 2024 Oncogene).
    supporting_text: >-
      THBS1 mediates migration/invasion by **interacting with integrin Ξ±V
      (ITGAV) and TGF‑β receptor I (TΞ²RI)**; deletion of THBS1 or TΞ²RI
      prevented migration and invasion in experimental systems.
    reference_section_type: RESULTS
  - statement: >-
      Kaur & Roberts (2023) highlight that, despite viable Thbs1 knockout
      mice, human population genetics indicate THBS1 is loss-intolerant,
      consistent with an essential stress-response role in surviving
      environmental challenges between birth and reproduction.
    supporting_text: >-
      human population genetics indicate THBS1 is **loss-intolerant**, and
      propose that THBS1's essentiality in humans may reflect the need to
      survive **environmental stresses** encountered between birth and
      reproduction
    reference_section_type: DISCUSSION

core_functions:
- molecular_function:
    id: GO:0005178
    label: integrin binding
  description: >
    TSP1 binds multiple integrins including alpha3beta1, alpha4beta1, alpha6beta1,
    and
    alphaIIb-beta3. These interactions mediate TSP1's effects on cell adhesion, migration,
    and platelet aggregation. The RGD sequence and other integrin-binding motifs in
    TSP1
    engage integrins to modulate cell-matrix interactions.
  directly_involved_in:
  - id: GO:0016525
    label: negative regulation of angiogenesis
  - id: GO:0007160
    label: cell-matrix adhesion
  locations:
  - id: GO:0031012
    label: extracellular matrix
  supported_by:
  - reference_id: PMID:9304800
    supporting_text: >
      TSP1 mediates cell-matrix adhesion through interactions with multiple integrins.

    full_text_unavailable: true
- molecular_function:
    id: GO:0050431
    label: transforming growth factor beta binding
  description: >
    TSP1 activates latent TGF-beta1 through direct binding via its type-1 repeats
    (TSRs).
    The KRFK sequence in the TSRs binds the LAP (latency-associated peptide) and induces
    a conformational change that releases active TGF-beta1. This is a core function
    of
    TSP1 critical for wound healing, fibrosis, and immune regulation.
  directly_involved_in:
  - id: GO:0050714
    label: positive regulation of protein secretion
  locations:
  - id: GO:0031012
    label: extracellular matrix
  supported_by:
  - reference_id: file:human/THBS1/THBS1-deep-research-openai.md
    supporting_text: >
      TSP1 activates latent TGF-beta1 through direct interaction with the latency-associated
      peptide via type-1 repeats.

- molecular_function:
    id: GO:0001968
    label: fibronectin binding
  description: >
    TSP1 binds fibronectin in the extracellular matrix, modulating cell adhesion and
    matrix assembly. This interaction contributes to TSP1's role in wound healing
    and
    tissue remodeling.
  directly_involved_in:
  - id: GO:0030198
    label: extracellular matrix organization
  locations:
  - id: GO:0031012
    label: extracellular matrix
  supported_by:
  - reference_id: PMID:6489349
    supporting_text: >
      Thrombospondin interactions with fibronectin and fibrinogen.

- molecular_function:
    id: GO:0008201
    label: heparin binding
  description: >
    TSP1 contains a heparin-binding domain in its N-terminal region that mediates
    interactions with heparan sulfate proteoglycans on cell surfaces and in the ECM.
    This binding is important for TSP1 localization and receptor interactions.
  directly_involved_in:
  - id: GO:0007160
    label: cell-matrix adhesion
  locations:
  - id: GO:0031012
    label: extracellular matrix
  supported_by:
  - reference_id: file:human/THBS1/THBS1-deep-research-openai.md
    supporting_text: >
      TSP1 binds heparan sulfate proteoglycans through its N-terminal heparin-binding
      domain.

- molecular_function:
    id: GO:0004867
    label: serine-type endopeptidase inhibitor activity
  description: >
    TSP1 inhibits plasmin and other serine proteases through its type-1 repeats. This
    antiplasmin activity protects the forming blood clot from premature fibrinolysis
    and is important for TSP1's hemostatic function.
  directly_involved_in:
  - id: GO:0007596
    label: blood coagulation
  locations:
  - id: GO:0031093
    label: platelet alpha granule lumen
  supported_by:
  - reference_id: PMID:7679575
    supporting_text: >
      Characterization of the antiplasmin activity of human thrombospondin-1 in solution.

status: COMPLETE