Thrombospondin-4 (TSP-4) is a secreted extracellular matrix (ECM) glycoprotein that forms homopentamers. It belongs to the thrombospondin family (subgroup B, which lacks TSR type 1 repeats) and contains calcium-binding EGF-like modules and C-terminal thrombospondin type 3 repeats. TSP-4 is primarily expressed in heart, skeletal muscle, and tendon tissues. The protein functions as a matricellular signaling molecule that modulates cell adhesion, migration, and proliferation through interactions with integrins (particularly integrin alpha-M-beta-2) and other ECM components. TSP-4 binds heparin and calcium, with calcium binding being important for its conformational stability. A key role is in the adaptive endoplasmic reticulum stress response, where TSP-4 binds to and activates ATF6alpha to promote protective ER stress responses in the heart. TSP-4 is induced during tissue injury and remodeling, contributing to cardioprotective responses to pressure overload. The A387P variant is associated with increased cardiovascular disease risk through enhanced proinflammatory signaling in neutrophils.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0031012 extracellular matrix | IBA GO_REF:0000033 | ACCEPT | Summary: TSP-4 is a secreted matricellular glycoprotein that is incorporated into the extracellular matrix. This is well-established through multiple lines of evidence including its secretion from cells, binding to ECM components, and localization studies. Reason: THBS4/TSP-4 is definitively an extracellular matrix protein. UniProt states it is "Secreted, extracellular space, extracellular matrix" and the deep research confirms TSP-4 is secreted to the extracellular space and incorporated into the ECM, where it binds collagenous and non-collagenous components [THBS4-deep-research-falcon.md]. The IBA annotation is phylogenetically well-supported. Supporting Evidence: PMID:7852353 Recombinant thrombospondin-4 has been purified from the culture supernatant by heparin-Sepharose and anti-thrombospondin-4 antibody-Affi-gel affinity chromatography file:human/THBS4/THBS4-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0034976 response to endoplasmic reticulum stress | IBA GO_REF:0000033 | ACCEPT | Summary: TSP-4 plays a key role in the adaptive ER stress response. It binds ATF6alpha in the ER lumen and promotes its activation and nuclear translocation, leading to upregulation of protective ER stress response factors. Reason: This is a well-established core function of TSP-4. The 2012 Cell paper by Lynch et al. definitively established this mechanism, showing that TSP-4 binds ATF6alpha and promotes a protective ER stress response. The IBA annotation is appropriate. Supporting Evidence: PMID:22682248 Thbs bind the ER lumenal domain of activating transcription factor 6Ξ± (Atf6Ξ±) to promote its nuclear shuttling |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: TSP-4 is a calcium-binding protein with EGF-like calcium-binding domains and type 3 repeats that coordinate calcium ions. Calcium binding affects the conformational stability of the protein. Reason: Calcium binding is a well-established property of TSP-4, supported by IDA evidence (PMID:7852353, PMID:16246837) as well as domain architecture containing calcium-binding EGF-like modules. The IEA annotation is correct and consistent with experimental evidence. Supporting Evidence: PMID:7852353 The observation of a calcium-dependent change in the electron microscopic appearance of thrombospondin-4 is consistent with limited tryptic digestion data that indicate that thrombospondin-4 is resistant to digestion in the presence of calcium. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: TSP-4 is a secreted protein that localizes to the extracellular region. This is a broad but accurate localization term. Reason: TSP-4 is secreted and localizes to the extracellular region. This is supported by UniProt subcellular localization annotations and multiple experimental studies. The IEA annotation is correct, though more specific terms (extracellular matrix, extracellular space) are also annotated. Supporting Evidence: PMID:7852353 Recombinant thrombospondin-4 has been purified from the culture supernatant by heparin-Sepharose and anti-thrombospondin-4 antibody-Affi-gel affinity chromatography |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | ACCEPT | Summary: TSP-4 is resident in the ER/SR compartment where it functions in the adaptive ER stress response through interaction with ATF6alpha. This is particularly important in cardiomyocytes. Reason: TSP-4 resides in the ER compartment, particularly in cardiomyocytes, where it participates in the ER stress response. This is well-established from mouse studies that are expected to translate to human based on sequence conservation. Supporting Evidence: PMID:22682248 We observed prominent Thbs4 protein localization within the ER/SR compartment of adult cardiomyocytes of the heart, with some mild accumulation in the extracellular space or ECM |
| GO:0006986 response to unfolded protein | IEA GO_REF:0000043 | ACCEPT | Summary: TSP-4 participates in the unfolded protein response through its role in activating ATF6alpha, which is one of the three main UPR signaling branches. Reason: TSP-4 activates ATF6alpha, one of the three primary UPR pathways. The ATF6 branch aids in resolution of misfolded proteins. This IEA annotation from UniProt keywords is consistent with experimental evidence. Supporting Evidence: PMID:22682248 Engagement of the ER stress response acutely reduces protein synthesis in the ER, enhances protein degradation of damaged or misfolded proteins, and selectively induces expression of protective proteins |
| GO:0007155 cell adhesion | IEA GO_REF:0000120 | ACCEPT | Summary: TSP-4 mediates cell adhesion through interactions with integrins and cell surface proteoglycans. It supports attachment and spreading of various cell types including myoblasts and neutrophils. Reason: Cell adhesion is a well-documented function of TSP-4. UniProt describes it as "Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions." Multiple studies demonstrate TSP-4 supports cell attachment. Supporting Evidence: PMID:7519904 Thrombospondin-4 (TSP-4) is also present in skeletal muscle and a fusion protein containing the carboxy-terminal domain of TSP-4 also supported myoblast adhesion, although this protein was less active on a molar basis than the TSP-1 fusion protein |
| GO:0007165 signal transduction | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: TSP-4 activates multiple signaling pathways including MAPK signaling through integrin engagement and ATF6alpha-mediated ER stress signaling. Reason: While TSP-4 does participate in signal transduction (e.g., activating p38MAPK and JNK through integrin alpha-M-beta-2, and ATF6alpha signaling), this is a very general term. The more specific signaling functions are better captured by other annotations. Keep as non-core since signaling is an outcome of its ECM/receptor interactions rather than a primary molecular function. Supporting Evidence: PMID:16099885 Despite the similarity in these responses, the P387 variant induced more robust tyrosine phosphorylation of the stress-related mitogen-activated protein kinases (MAPKs): p38MAPK and c-Jun NH2-terminal kinase (JNK), as well as signal transducer and activator of transcription-1 (STAT1) and heat shock protein 27 (HSP27) than the A387 variant |
| GO:0008083 growth factor activity | IEA GO_REF:0000043 | ACCEPT | Summary: TSP-4 has mitogenic activity and can stimulate cell proliferation, particularly through interaction with PTBP3/ROD1. Reason: TSP-4 has been shown to have mitogenic activity. UniProt annotates it with the "Growth factor" and "Mitogen" keywords. PMID:19441079 demonstrated that PTBP3 binds to the C-terminal peptide of TSP-4 and is involved in its mitogenic activity. Supporting Evidence: PMID:19441079 Regulator of differentiation 1 (ROD1) binds to the amphipathic C-terminal peptide of thrombospondin-4 and is involved in its mitogenic activity. |
| GO:0008201 heparin binding | IEA GO_REF:0000117 | ACCEPT | Summary: TSP-4 binds heparin, which was used for purification of the recombinant protein by heparin-Sepharose chromatography. Reason: Heparin binding is experimentally established for TSP-4. Lawler et al. (1995) used heparin-Sepharose chromatography to purify recombinant TSP-4, demonstrating this binding activity. There is also IDA evidence (PMID:7852353) for this term. Supporting Evidence: PMID:7852353 Recombinant thrombospondin-4 has been purified from the culture supernatant by heparin-Sepharose and anti-thrombospondin-4 antibody-Affi-gel affinity chromatography |
| GO:0016529 sarcoplasmic reticulum | IEA GO_REF:0000120 | ACCEPT | Summary: TSP-4 localizes to the sarcoplasmic reticulum in cardiomyocytes, consistent with its role in cardiac ER stress response. Reason: TSP-4 is found in the ER/SR compartment of cardiomyocytes. Given that cardiac muscle cells have specialized sarcoplasmic reticulum, this localization is appropriate for the cardioprotective functions of TSP-4. Supporting Evidence: PMID:22682248 We observed prominent Thbs4 protein localization within the ER/SR compartment of adult cardiomyocytes of the heart, with some mild accumulation in the extracellular space or ECM |
| GO:0048771 tissue remodeling | IEA GO_REF:0000043 | ACCEPT | Summary: TSP-4 is induced during tissue injury and actively participates in tissue remodeling, particularly in the heart during pressure overload and injury. Reason: Tissue remodeling is a well-established function of TSP-4. UniProt describes its role in "adaptive responses of the heart to pressure overload and in myocardial function and remodeling." TSP-4 is induced during tissue damage and modulates ECM reconstruction. Supporting Evidence: PMID:22682248 Thrombospondin (Thbs) proteins are induced in sites of tissue damage or active remodeling. |
| GO:0051781 positive regulation of cell division | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: TSP-4 has mitogenic activity and can promote cell proliferation in certain contexts. Reason: While TSP-4 has mitogenic activity (UniProt keyword), its effects on cell proliferation are context-dependent. For example, the P387 variant suppresses endothelial cell proliferation. This is not a primary function but rather a secondary effect in specific cellular contexts. Supporting Evidence: PMID:12952849 Both variant fragments increased the proliferation of human aortic smooth muscle cells. |
| GO:0005615 extracellular space | IEA GO_REF:0000107 | ACCEPT | Summary: TSP-4 is secreted and found in the extracellular space. This is well-supported by multiple lines of evidence. Reason: TSP-4 is secreted into the extracellular space. This is supported by UniProt annotations and experimental studies showing secretion and extracellular localization. Supporting Evidence: PMID:7852353 Recombinant thrombospondin-4 has been purified from the culture supernatant by heparin-Sepharose and anti-thrombospondin-4 antibody-Affi-gel affinity chromatography |
| GO:0031012 extracellular matrix | IEA GO_REF:0000107 | ACCEPT | Summary: Duplicate annotation for extracellular matrix localization, which is correct for TSP-4. Reason: This is a duplicate of the IBA annotation. TSP-4 is definitively an ECM protein. Multiple evidence codes supporting the same term is acceptable. Supporting Evidence: PMID:17927980 thrombospondin-4, whereas type IV collagen alpha3, type V collagen, fibrillin-1 and -2, thrombospondin-1, and endostatin were present in the corneal BM |
| GO:0034103 regulation of tissue remodeling | IEA GO_REF:0000107 | ACCEPT | Summary: TSP-4 regulates tissue remodeling processes, particularly in the heart during pressure overload and injury responses. Reason: TSP-4 plays a regulatory role in tissue remodeling. UniProt states it is "involved in adaptive responses of the heart to pressure overload and in myocardial function and remodeling." This is more specific than general tissue remodeling and is appropriate. Supporting Evidence: PMID:22682248 Here we describe a function for Thbs as ER-resident effectors of an adaptive ER stress response |
| GO:0034976 response to endoplasmic reticulum stress | IEA GO_REF:0000107 | ACCEPT | Summary: Duplicate annotation for ER stress response, well-supported by experimental evidence. Reason: This is a duplicate of the IBA annotation. The ER stress response role is well-established through ATF6alpha interaction. Supporting Evidence: PMID:22682248 Thbs bind the ER lumenal domain of activating transcription factor 6Ξ± (Atf6Ξ±) to promote its nuclear shuttling |
| GO:0048266 behavioral response to pain | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TSP-4 may contribute to neuropathic pain states through effects on spinal presynaptic hypersensitivity after peripheral nerve injury. Reason: UniProt indicates TSP-4 "May contribute to spinal presynaptic hypersensitivity and neuropathic pain states after peripheral nerve injury" based on similarity. This is not a core function but a specialized role in the nervous system that warrants keeping the annotation as non-core. Supporting Evidence: UniProt:P35443 May contribute to spinal presynaptic hypersensitivity and neuropathic pain states after peripheral nerve injury. |
| GO:0031012 extracellular matrix | ISS GO_REF:0000024 | ACCEPT | Summary: Third annotation for extracellular matrix localization by sequence similarity. Reason: TSP-4 is an extracellular matrix protein. Multiple evidence codes supporting the same accurate annotation is acceptable. Supporting Evidence: PMID:7852353 The thrombospondins are a family of extracellular calcium binding proteins that are involved in cell proliferation, adhesion, and migration |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | ACCEPT | Summary: TSP-4 was detected in exosomes isolated from expressed prostatic secretions in a high-throughput proteomics study. Reason: This HDA annotation from a proteomics study detecting TSP-4 in exosomes is valid. Secreted proteins like TSP-4 can be found in exosomal fractions. Supporting Evidence: PMID:23533145 In pooled EPS-urine exosome samples, ~900 proteins were detected. |
| GO:0005515 protein binding | IPI PMID:22682248 A thrombospondin-dependent pathway for a protective ER stres... | MODIFY | Summary: TSP-4 interacts with ATF6alpha through its type 3 repeat domain to promote ATF6alpha activation. Reason: "Protein binding" is too vague and does not convey the specific functional interaction. TSP-4 has well-characterized interactions with ATF6alpha and integrins. A more specific term should be used. Proposed replacements: integrin binding protein-macromolecule adaptor activity Supporting Evidence: PMID:22682248 Thbs bind the ER lumenal domain of activating transcription factor 6Ξ± (Atf6Ξ±) to promote its nuclear shuttling |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | ACCEPT | Summary: Duplicate annotation for ER localization by sequence similarity. Reason: ER localization is well-established for TSP-4, particularly in cardiomyocytes where it functions in ER stress response. Supporting Evidence: PMID:22682248 We observed prominent Thbs4 protein localization within the ER/SR compartment of adult cardiomyocytes of the heart, with some mild accumulation in the extracellular space or ECM |
| GO:0016529 sarcoplasmic reticulum | ISS GO_REF:0000024 | ACCEPT | Summary: Duplicate annotation for sarcoplasmic reticulum localization by sequence similarity. Reason: SR localization is established in cardiomyocytes. Supporting Evidence: PMID:22682248 We observed prominent Thbs4 protein localization within the ER/SR compartment of adult cardiomyocytes of the heart, with some mild accumulation in the extracellular space or ECM |
| GO:0034103 regulation of tissue remodeling | ISS GO_REF:0000024 | ACCEPT | Summary: Duplicate annotation for regulation of tissue remodeling by sequence similarity. Reason: TSP-4 regulates tissue remodeling, particularly cardiac remodeling during pressure overload. Supporting Evidence: PMID:22682248 Thbs4 cardiac-specific transgenic mice were protected from myocardial injury, whereas Thbs4(-/-) mice were sensitized to cardiac maladaptation. |
| GO:0034976 response to endoplasmic reticulum stress | ISS GO_REF:0000024 | ACCEPT | Summary: Duplicate annotation for ER stress response by sequence similarity. Reason: This is well-established for TSP-4 through its ATF6alpha interaction. Supporting Evidence: PMID:22682248 Here we describe a function for Thbs as ER-resident effectors of an adaptive ER stress response |
| GO:0048266 behavioral response to pain | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Duplicate annotation for pain response by sequence similarity. Reason: This is based on similarity to mouse studies suggesting a role in neuropathic pain. Keep as non-core function. Supporting Evidence: UniProt:P35443 May contribute to spinal presynaptic hypersensitivity and neuropathic pain states after peripheral nerve injury. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-382054 | ACCEPT | Summary: TSP-4 is in the extracellular region where it can bind to PDGF according to Reactome pathway annotation. Reason: TSP-4 is a secreted protein found in the extracellular region. The Reactome pathway annotation relates to PDGF signaling. Supporting Evidence: Reactome:R-HSA-382054 PDGF binds to various types of collagens, thrombospondin and osteopontin |
| GO:0005509 calcium ion binding | IDA PMID:7852353 Characterization of human thrombospondin-4. | ACCEPT | Summary: Direct experimental demonstration of calcium binding by TSP-4 through electron microscopy showing calcium-dependent conformational changes and tryptic digestion protection. Reason: This IDA annotation is well-supported by the original publication showing calcium-dependent changes in TSP-4 structure and protection from proteolysis. Supporting Evidence: PMID:7852353 The observation of a calcium-dependent change in the electron microscopic appearance of thrombospondin-4 is consistent with limited tryptic digestion data that indicate that thrombospondin-4 is resistant to digestion in the presence of calcium. These data indicate that thrombospondin-4 is a pentameric protein that binds to heparin and calcium. |
| GO:0008201 heparin binding | IDA PMID:7852353 Characterization of human thrombospondin-4. | ACCEPT | Summary: Direct experimental demonstration of heparin binding through purification of TSP-4 using heparin-Sepharose chromatography. Reason: This IDA annotation is well-supported by the purification method demonstrating functional heparin binding. Supporting Evidence: PMID:7852353 Recombinant thrombospondin-4 has been purified from the culture supernatant by heparin-Sepharose and anti-thrombospondin-4 antibody-Affi-gel affinity chromatography |
| GO:0001938 positive regulation of endothelial cell proliferation | IDA PMID:12952849 Thrombospondin-4 and its variants expression and differentia... | KEEP AS NON CORE | Summary: TSP-4 A387 variant supports endothelial cell proliferation, while the P387 variant suppresses it. The effect is variant-dependent. Reason: The effects of TSP-4 on endothelial cell proliferation are complex and variant-dependent. The common A387 form supports EC proliferation while P387 suppresses it. This is not a core function but rather a context-dependent biological effect. Supporting Evidence: PMID:12952849 (P387)TSP-4 and its fragment (residues 326 to 722), but not the A(387) forms, suppressed EC adhesion and proliferation. |
| GO:0005178 integrin binding | IDA PMID:16099885 Mechanism and effect of thrombospondin-4 polymorphisms on ne... | ACCEPT | Summary: TSP-4 binds integrin alpha-M-beta-2 (Mac-1) through its EGF-like domains, mediating neutrophil adhesion and signaling. Reason: Integrin binding is a core molecular function of TSP-4. The 2005 Blood paper definitively established integrin alpha-M-beta-2 as a TSP-4 receptor through multiple lines of evidence. Supporting Evidence: PMID:16099885 Integrin Ξ± M Ξ² 2 was identified as the TSP-4 receptor mediating these responses, and the 3 epidermal growth factor (EGF)βlike domains of TSP-4 harboring the SNPs interacted with the Ξ± M I-domain |
| GO:0005509 calcium ion binding | IDA PMID:16246837 Biophysical characterization of the signature domains of thr... | ACCEPT | Summary: Detailed biophysical characterization of calcium binding by TSP-4 signature domain using multiple methods including CD spectroscopy and atomic absorption. Reason: This IDA provides detailed biophysical evidence for calcium binding properties of TSP-4, including quantification of binding sites and cooperativity. Supporting Evidence: PMID:16246837 Titrations of the spectra demonstrated lower cooperativity and affinity for binding of calcium to thrombospondin-4 compared with thrombospondin-2 |
| GO:0005604 basement membrane | IDA PMID:17927980 Characterization of extracellular matrix components in the l... | ACCEPT | Summary: TSP-4 was detected in the basement membrane of the limbal epithelium of the eye by immunohistochemistry. Reason: This IDA annotation is supported by immunohistochemical detection of TSP-4 in the basement membrane zone of limbal and conjunctival epithelium. Supporting Evidence: PMID:17927980 thrombospondin-4, whereas type IV collagen alpha3, type V collagen, fibrillin-1 and -2, thrombospondin-1, and endostatin were present in the corneal BM |
| GO:0005615 extracellular space | IDA PMID:12952849 Thrombospondin-4 and its variants expression and differentia... | ACCEPT | Summary: TSP-4 is secreted by vascular cells into the extracellular space. Reason: The paper demonstrates TSP-4 expression and secretion by vascular cells. Supporting Evidence: PMID:12952849 TSP-4 expression was demonstrated in human endothelial cells (ECs) and vascular smooth muscle cells from brain blood vessels and coronary arteries. |
| GO:0005615 extracellular space | IDA PMID:18802666 Flexible heteroarotinoid (Flex-Het) SHetA2 inhibits angiogen... | ACCEPT | Summary: TSP-4 secretion was measured in cancer and normal cell cultures, demonstrating its presence in the extracellular space. Reason: The study measured secreted TSP-4 protein levels in conditioned media by immunoprecipitation and western blot. Supporting Evidence: PMID:18802666 SHetA2 altered secretion of thrombospondin-4 (TSP-4), vascular endothelial growth factor A (VEGF) and fibroblast growth factor (bFGF) proteins from normal and cancerous ovarian and renal cultures. |
| GO:0016525 negative regulation of angiogenesis | IEP PMID:18802666 Flexible heteroarotinoid (Flex-Het) SHetA2 inhibits angiogen... | UNDECIDED | Summary: TSP-4 was implicated in angiogenesis regulation based on expression pattern changes during drug treatment affecting angiogenesis. Reason: The evidence is indirect (IEP - expression pattern). TSP-4 expression was altered by an anti-angiogenic drug, but the paper suggests TSP-4 may have complex effects on angiogenesis. Unlike TSP-1, TSP-4 lacks type 1 repeats responsible for anti-angiogenic activity. More recent literature suggests TSP-4 can be pro-angiogenic in some contexts. This annotation needs further review. Supporting Evidence: PMID:18802666 Initially, TSP-4 was not considered to be anti-angiogenic because it lacks the protein structures in TSP-1 called type 1 repeats that are responsible for the anti-angiogenesis mechanism [20, 21] |
| GO:0050731 positive regulation of peptidyl-tyrosine phosphorylation | IDA PMID:16099885 Mechanism and effect of thrombospondin-4 polymorphisms on ne... | ACCEPT | Summary: TSP-4, particularly the P387 variant, induces tyrosine phosphorylation of signaling proteins including MAPKs and FAK in neutrophils upon integrin engagement. Reason: The paper directly demonstrates that TSP-4 induces tyrosine phosphorylation of multiple proteins including p38MAPK, JNK, STAT1, and HSP27, with the P387 variant being more potent. Supporting Evidence: PMID:16099885 Despite the similarity in these responses, the P387 variant induced more robust tyrosine phosphorylation of the stress-related mitogen-activated protein kinases (MAPKs): p38MAPK and c-Jun NH2-terminal kinase (JNK), as well as signal transducer and activator of transcription-1 (STAT1) and heat shock protein 27 (HSP27) than the A387 variant |
| GO:0051451 myoblast migration | IDA PMID:7519904 Cell-type specific adhesive interactions of skeletal myoblas... | MODIFY | Summary: TSP-4 C-terminal domain supports myoblast adhesion, which is a prerequisite for migration. Reason: The paper primarily demonstrates myoblast adhesion to TSP-4, not specifically migration. While adhesion is related to migration, the evidence more directly supports cell adhesion. The annotation should be modified to a more accurate term. Proposed replacements: cell adhesion cell-substrate adhesion Supporting Evidence: PMID:7519904 Thrombospondin-4 (TSP-4) is also present in skeletal muscle and a fusion protein containing the carboxy-terminal domain of TSP-4 also supported myoblast adhesion, although this protein was less active on a molar basis than the TSP-1 fusion protein |
| GO:0071603 endothelial cell-cell adhesion | IDA PMID:12952849 Thrombospondin-4 and its variants expression and differentia... | ACCEPT | Summary: TSP-4 affects endothelial cell adhesion, with the P387 variant suppressing adhesion compared to the A387 form. Reason: The paper demonstrates that TSP-4 modulates endothelial cell adhesion, though the effects are variant-dependent. The A387 form supports EC adhesion while P387 suppresses it. Supporting Evidence: PMID:12952849 (P387)TSP-4 and its fragment (residues 326 to 722), but not the A(387) forms, suppressed EC adhesion and proliferation. |
| GO:0090023 positive regulation of neutrophil chemotaxis | IDA PMID:16099885 Mechanism and effect of thrombospondin-4 polymorphisms on ne... | ACCEPT | Summary: TSP-4 supports neutrophil migration through integrin alpha-M-beta-2 binding and induces IL-8 secretion which promotes chemotaxis. Reason: The paper demonstrates that TSP-4 supports neutrophil migration and induces IL-8 secretion (a chemotactic cytokine), with the P387 variant inducing 2-fold more IL-8 than A387. Supporting Evidence: PMID:16099885 Additionally, cells adherent to P387 TSP-4 variant released 4-fold more H2O2 and secreted 2-fold more interleukin 8 (IL-8) as compared with the A387 |
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Download this section (compressed HTML)Q: What are the specific structural differences between A387 and P387 TSP-4 variants that account for their differential effects on cell signaling? The A387P polymorphism has significant functional effects on proinflammatory signaling but biophysical studies show minimal overall structural changes.
Q: Does TSP-4 have chaperone-like activity for other ECM proteins in addition to its ATF6alpha regulatory function? The type 3 repeat domain has been implicated in ECM protein processing and COMP mutations in this domain cause ER retention of collagen.
Q: What is the relative contribution of TSP-4 pro-angiogenic versus anti-angiogenic effects in different tissue contexts? Unlike TSP-1, TSP-4 lacks anti-angiogenic type 1 repeats but its role in angiogenesis regulation remains unclear.
Experiment: Structural studies (cryo-EM or X-ray crystallography) of full-length TSP-4 pentamer to understand quaternary structure. This would reveal domain arrangement and how A387P affects local structure.
Experiment: Comparison of TSP-4 A387 and P387 effects on cardiac ER stress response in human iPSC-derived cardiomyocytes. This would establish whether variant effects on integrin signaling translate to cardiac ATF6alpha pathway differences.
Experiment: Investigation of TSP-4 interaction with other integrins beyond alpha-M-beta-2. This would identify complete integrin receptor repertoire for TSP-4.
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