Thrombospondin: a versatile multifunctional glycoprotein.

Silverstein, Roy L.; Leung, LL; Nachman, Ralph L.

doi:10.1161/01.atv.6.3.245

Cited by 81 publications

(49 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although platelets from patients with GPS allowed studies on the role of α-granules in platelet function tests in vitro, the sometimes severe thrombocytopenia in the human subjects often makes the assessment difficult (12, 13). As a consequence, the contribution of secreted adhesive proteins to plateletmediated processes in vivo has remained poorly understood since early reports pointing to roles of fibrinogen and thrombospondin in secretion-dependent platelet aggregation (37,38). Our studies unambiguously show a role of secreted proteins both in platelet aggregation in vitro and in thrombus formation under flow.…”

Section: Discussionsupporting

confidence: 50%

Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice

Deppermann¹,

Cherpokova²,

Nurden³

et al. 2013

J. Clin. Invest.

166

159

View full text Add to dashboard Cite

Platelets are anuclear organelle-rich cell fragments derived from bone marrow megakaryocytes (MKs) that safeguard vascular integrity. The major platelet organelles, α-granules, release proteins that participate in thrombus formation and hemostasis. Proteins stored in α-granules are also thought to play a role in inflammation and wound healing, but their functional significance in vivo is unknown. Mutations in NBEAL2 have been linked to gray platelet syndrome (GPS), a rare bleeding disorder characterized by macrothrombocytopenia, with platelets lacking α-granules. Here we show that Nbeal2-knockout mice display the characteristics of human GPS, with defective α-granule biogenesis in MKs and their absence from platelets. Nbeal2 deficiency did not affect MK differentiation and proplatelet formation in vitro or platelet life span in vivo. Nbeal2-deficient platelets displayed impaired adhesion, aggregation, and coagulant activity ex vivo that translated into defective arterial thrombus formation and protection from thrombo-inflammatory brain infarction following focal cerebral ischemia. In a model of excisional skin wound repair, Nbeal2-deficient mice exhibited impaired development of functional granulation tissue due to severely reduced differentiation of myofibroblasts in the absence of α-granule secretion. This study demonstrates that platelet α-granule constituents are critically required not only for hemostasis but also thrombosis, acute thrombo-inflammatory disease states, and tissue reconstitution after injury.

show abstract

Section: Discussionsupporting

confidence: 50%

Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice

Deppermann¹,

Cherpokova²,

Nurden³

et al. 2013

J. Clin. Invest.

166

159

View full text Add to dashboard Cite

show abstract

“…3 " 6 Platelets constitute the main reservoir of TSP in the circulation; TSP is released by platelets upon activation and plays a major role in hemostasis by promoting irreversible platelet macroaggregate formation. 78 In addition, there is some evidence that binding of secreted TSP to the platelet surface contributes to the amplification of the signaling process and is required for maximal platelet secretion.…”

mentioning

confidence: 99%

Selective inhibition of platelet macroaggregate formation by a recombinant heparin-binding domain of human thrombospondin.

Legrand

Morandi

Mendelovitz

et al. 1994

Arterioscler Thromb

View full text Add to dashboard Cite

Thrombospondin (TSP) is a platelet a-granule adhesive protein that plays a critical role in the stabilization of thrombus by promoting the formation of platelet macroaggregates. We have recently shown that a monoclonal antibody (mAb) to the NH 2 -terminal heparin-binding domain of TSP, MAE, inhibits platelet aggregation induced by thrombin in a dose-dependent manner. In this study, we have expressed in Escherichia coli two recombinant proteins comprising residues 1 to 174 (TSP18) and 1 to 242 (TSP28) of TSP. After purification, both proteins reacted equally well with mAb MAII, whereas the reactivity of TSP18 for heparin was lower than that of TSP28 or native TSP. At micromolar concentrations, TSP18 and TSP28 inhibited the second wave of platelet aggregation and the concomitant release of [

show abstract

“…Discussion tant at 5 min (mean _+ S.D., n--6). Conversion of the TSP-I monomer into TSP-lf was accompanied by the generation of Formation of platelet macroaggregates is clearly dependent a smaller fragment with Mr=28200 + 1450 (n=3), which was upon exocytosis and surface expression and organization of identified as the amino-terminal HBD (CG-HBD) since it was fibrinogen and TSP-1 [3,4]. Thus, using a-thrombin as the recognized by the monoclonal antibody MAil [7] (Fig.…”

Section: Cg-induced Platelet Aggregationmentioning

confidence: 99%

“…2B). agonist, it was originally shown that TSP-1 stabilizes the bindThe most striking feature, however, was that, being generated ing of fibrinogen to its membrane receptor, the Cqlb133 integrin during the course of platelet exocytosis and aggregation, the [4]. Recent studies have indicated that the amino-terminal CG-HBD was almost entirely released into the extracellular heparin binding domain (HBD) of TSP-1 may interact with milieu, with only traces (<5%) detected in the cell extracts membrane-bound fibrinogen [9,11], whereas there is also a (Fig.…”

Section: Cg-induced Platelet Aggregationmentioning

confidence: 99%

“…Each subunit has a modular organization typical of multiexpression of c~-granule adhesive proteins such as fihrinogen (Fg) functional adhesive proteins, and contains specific domains and thrombospondin-1 (TSP-1). Because Fg and TSP-1 are that support interactions of TSP-1 with cell surface glycopropotential substrates for the enzymatic activity of CG, we tein receptors, sulfated proteoglycans and membrane lipids, investigated the fate of these proteins during CG-induced platelet and various matrix proteins [4][5][6][7]. Regarding platelet aggregaaggregation using an immunoblot technique.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Proteolysis of thrombospondin during cathepsin‐G‐induced platelet aggregation: functional role of the 165‐kDa carboxy‐terminal fragment

et al. 1996

View full text Add to dashboard Cite

The serine-proteinase eathepsin G (CG) is a potent SDS-polyacrylamide gel electrophoresis (SDS-PAGE) analyagonist of platelet aggregation inducing the release and surface sis. Each subunit has a modular organization typical of multiexpression of c~-granule adhesive proteins such as fihrinogen (Fg) functional adhesive proteins, and contains specific domains and thrombospondin-1 (TSP-1). Because Fg and TSP-1 are that support interactions of TSP-1 with cell surface glycopropotential substrates for the enzymatic activity of CG, we tein receptors, sulfated proteoglycans and membrane lipids, investigated the fate of these proteins during CG-induced platelet and various matrix proteins [4][5][6][7]. Regarding platelet aggregaaggregation using an immunoblot technique. Only a small tion, particular attention has been paid to the amino-terminal proportion of secreted Fg was proteolyzed by CG and platelet domain of TSP-1 which contains high-affinity binding site(s) aggregation was efficiently inhibited by anti-fibrinogen Fab for heparin, thus commonly designated as the heparin-binding fragments. In contrast, TSP-1 was extensively proteolyzed on domain (HBD) [7]. This domain can be cleaved by various aggregated platelets releasing in the milieu a fragment with M, ~ 28 000, corresponding to the amino-terminal heparinserine-proteinases, producing a fragment with Mr in the range binding domain (HBD). Several antibodies, directed against 25 000-35 000 [7,8]. A role for the HBD in platelet-to-platelet the cell-associated earboxy-terminal TSP-lf fragment interactions is currently supported by the following observa-(M, ~ 165 000) impaired the formation of stable macroaggretions: (i) some antibodies directed at epitopes within the HBD gates, indicating that this fragment may contribute to platelet as well as recombinant HBD polypeptides are potent inhibiaggregation in the absence of the HBD.tots of ct-thrombin-induced platelet aggregation, and can specifically inhibit the interaction of purified TSP-1 with ad-

show abstract

Thrombospondin: a versatile multifunctional glycoprotein.

Cited by 81 publications

References 49 publications

Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice

Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice

Selective inhibition of platelet macroaggregate formation by a recombinant heparin-binding domain of human thrombospondin.

Proteolysis of thrombospondin during cathepsin‐G‐induced platelet aggregation: functional role of the 165‐kDa carboxy‐terminal fragment

Contact Info

Product

Resources

About