Stimulation of Platelet Activation and Aggregation by a Carboxyl-terminal Peptide from Thrombospondin Binding to the Integrin-associated Protein Receptor

Dorahy, Douglas J.; Thorne, Rick F.; Fecondo, John V.; Burns, Gordon F.

doi:10.1074/jbc.272.2.1323

Cited by 72 publications

(56 citation statements)

References 45 publications

(32 reference statements)

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“…We detected a modest enrichment of genes involved in ''cell-to-cell signaling and interaction'' (range, P = 4.52 3 10 À2 to 1.17 3 10 À1 , Benjamini-Hochberg corrected for multiple testing; n = 10). Notably, these genes included THBS1 (encoding thrombospondin 1), WASL (Wiskott-Aldrich syndrome-like), and EDN1 (endothelin 1), which have a marked role in the activation of blood platelets (Dorahy et al 1997;Falet et al 2002;Jagroop et al 2005). This suggests the involvement of non-cell-autonomous mechanisms for the regulation of platelet count, whereby extrinsic factors expressed by MOs or their progeny regulate the differentiation and proliferation of the hematopoietic stem cells toward MKs and the removal of senescent platelets from the circulation by liverresiding MO-derived macrophages.…”

Section: Enrichment Patterns Of Snps Associated With Closely Related mentioning

confidence: 99%

Maps of open chromatin highlight cell type–restricted patterns of regulatory sequence variation at hematological trait loci

et al. 2013

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Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by metaanalyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell typespecific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits.

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Section: Enrichment Patterns Of Snps Associated With Closely Related mentioning

confidence: 99%

Maps of open chromatin highlight cell type–restricted patterns of regulatory sequence variation at hematological trait loci

et al. 2013

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“…Under some conditions, TSP1 promotes platelet aggregation [92], but recombinant domains and peptides derived from TSP1 can either increase or delay platelet aggregation [93][94][95][96]. TSP1 also regulates the processing of the platelet adhesion factor von Willebrand factor (vWF) by ADAMTS13 [97], which is associated with increased collagen-and vWF-mediated aggregation of TSP-1 null platelets under static and shear conditions [98].…”

Section: Tsp1 Regulation Of No Signaling In Plateletsmentioning

confidence: 99%

Thrombospondins: from structure to therapeutics

Isenberg

Frazier

Roberts

2008

Cell. Mol. Life Sci.

118

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Thrombospondin-1 is secreted protein that modulates vascular cell behavior via several cell surface receptors. In vitro, nanomolar concentrations of thrombospondin-1 are required to alter endothelial and vascular smooth muscle cell adhesion, proliferation, motility, and survival. Yet, much lower levels of thrombospondin-1 are clearly functional in vivo. This discrepancy was explained with the discovery that the potency of thrombospondin-1 increases more than 100-fold in the presence of physiological levels of NO. Thrombospondin-1 binding to CD47 inhibits NO signaling by preventing cGMP synthesis and activation of its target cGMP-dependent protein kinase. This potent antagonism of NO signaling allows thrombospondin-1 to acutely constrict blood vessels, accelerate platelet aggregation and, if sustained, inhibit angiogenic responses. Acute antagonism of NO signaling by thrombospondin-1 is important for hemostasis but becomes detrimental for tissue survival of ischemic injuries. New therapeutic approaches targeting thrombospondin-1 or CD47 can improve recovery from ischemic injuries and overcome a deficit in NO-responsiveness in aging.

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“…12,16,17 In platelets, IAP is associated with ␣IIb␤3 and ␣2␤1 integrins that bind to fibrinogen and collagen, respectively. 15,18 It was reported that 4N1-1 and the more soluble peptide 4N1K (Lys-ArgPhe-Tyr-Val-Val-M-Lys-Lys) induce aggregation 19 and spreading of platelets on immobilized fibronectin and collagen. 15,18 The ability of the C-terminal peptide of TSP1 to modulate integrin function depends on its interaction with IAP, since spreading of platelets on fibrinogen and collagen was decreased after treatment with an antifunctional IAP antibody and in platelets from mice deficient in IAP.…”

Section: Introductionmentioning

confidence: 99%

C-terminal peptide of thrombospondin-1 induces platelet aggregation through the Fc receptor γ-chain–associated signaling pathway and by agglutination

Tulasne

Judd

Johansen

et al. 2001

Blood

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A peptide from the C-terminal domain of thrombospondin-1 (Arg-Phe-Tyr-Val-ValMet-Trp-Lys; known as 4N1-1) has been reported to induce platelet aggregation and to bind to the integrin-associated protein (IAP), which is also known as CD47. In this study, it was discovered that 4N1-1 or its derivative peptide, 4N1K, induces rapid phosphorylation of the Fc receptor (FcR) ␥ chain, Syk, SLP-76, and phospholipase C ␥2 in human platelets. A specific inhibitor of Src family kinases, 4-amino-4-(4-methylphenyl)-7-(t-butyl) pyrazola[3,4-d]pyrimidine, prevented phosphorylation of these proteins, abolished platelet secretion, and reduced aggregation by approximately 50%. A similar inhibition of aggregation to 4N1-1 was obtained in the presence of Arg-Gly-Asp-Ser in mouse platelets deficient in FcR ␥ chain or SLP-76 and in patients with type I Glanzmann thrombasthenia. These results show that 4N1-1 signals through a pathway similar to that used by the collagen receptor glycoprotein (GP) VI. The ␣IIb␤3-independent aggregation induced by 4N1-1 was also observed in fixed platelets and platelets from patients with Bernard-Soulier syndrome, which are deficient in GPIb␣. Surprisingly, the ability of 4N1-1 to stimulate aggregation and tyrosine phosphorylation was not altered in platelets pretreated with anti-IAP antibodies and in IAP-deficient mice. These results show that the C-terminal peptide of thrombospondin induces platelet aggregation through the FcR ␥-chain signaling pathway and through agglutination. The latter pathway is independent of signaling events and does not use GPIb␣ or IntroductionPlatelet aggregation and clot formation are initiated when platelets are activated by soluble activators such as thrombin or by binding to components of the subendothelial matrix, such as von Willebrand factor (vWF) or collagen. These events lead to a change in platelet shape and secretion of dense and ␣ granules. Platelet aggregation is supported by binding of fibrinogen to activated ␣IIb␤3 and by binding of vWF to ␣IIb␤3 and the glycoprotein (GP) Ib-IX-V complex. 1 Thrombospondin 1 (TSP1) was first discovered as a glycoprotein associated with the surface of thrombin-stimulated platelets. 2 TSP1 is stored in ␣ granules and is released on activation, after which it becomes bound to the surface of the activated platelet. Anti-TSP1 antibodies can inhibit platelet aggregation induced by thrombin and collagen, and it has been proposed that TSP1 acts by stabilizing platelet aggregates initiated by interactions between fibrinogen and ␣IIb␤3. [3][4][5] TSP1 binds to a large number and wide variety of receptors on the platelet surface. Proteolytic digestion of TSP1 and expression of domains as recombinant proteins or synthetic peptides has enabled identification of several sequences that support these interactions, including a heparin-binding domain in the N-terminal region, which binds to proteoglycans 6 ; a region within the type 1 repeats, which binds to CD36 7 ; and an Arg-Gly-Asp sequence within the last of the type III repeats, which bind ...

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Stimulation of Platelet Activation and Aggregation by a Carboxyl-terminal Peptide from Thrombospondin Binding to the Integrin-associated Protein Receptor

Cited by 72 publications

References 45 publications

Maps of open chromatin highlight cell type–restricted patterns of regulatory sequence variation at hematological trait loci

Maps of open chromatin highlight cell type–restricted patterns of regulatory sequence variation at hematological trait loci

Thrombospondins: from structure to therapeutics

C-terminal peptide of thrombospondin-1 induces platelet aggregation through the Fc receptor γ-chain–associated signaling pathway and by agglutination

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