THBS1

Existing Annotations Review

Gene Description

Existing Annotations Review

Core Functions

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.

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.

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.

References

Deep Research

Falcon

OpenAI

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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. Proposed replacements: positive regulation of transforming growth factor beta receptor signaling pathway
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.