Eph kinases and ephrins support thrombus growth and stability by regulating integrin outside-in signaling in platelets

Prévost, Nicolas; Woulfe, Donna S.; Jiang, Hong; Stalker, Timothy J.; Marchese, Patrizia; Ruggeri, Zaverio M.; Brass, Lawrence F.

doi:10.1073/pnas.0404065102

Cited by 134 publications

(104 citation statements)

References 36 publications

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“…The contacts that develop allow interactions to occur among molecules on the surface of adjacent platelets. A well described example involves the integrin ␣ IIb ␤ 3 , but contact-dependent events can also occur when a ligand on the surface of one platelet binds to a receptor on another, as when ephrinB1 binds to EphA4 and EphB1 (30,31). The present studies evolved from an ongoing effort to identify additional molecules on the platelet surface that can participate in communication between platelets once platelet activation has begun.…”

Section: Discussionmentioning

confidence: 99%

Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury

Zhu¹,

Bergmeier

Wu³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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175

221

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Semaphorin 4D (sema4D; CD100) is an integral membrane protein and the ligand for two receptors, CD72 and plexin-B1. Soluble sema4D has been shown to evoke angiogenic responses from endothelial cells and impair monocyte migration, but the origin of soluble sema4D, particularly at sites of vascular injury, has been unclear. Here we show that platelets express sema4D and both of its receptors and provide evidence that these molecules promote thrombus formation. We also show that the surface expression of sema4D and CD72 increases during platelet activation, followed by the gradual shedding of the sema4D extracellular domain. Shedding is blocked by metalloprotease inhibitors and abolished in mouse platelets that lack the metalloprotease ADAM17 (TACE). Mice that lack sema4D exhibit delayed arterial occlusion after vascular injury in vivo, and their platelets show impaired collagen responses in vitro. In resting platelets, as in B lymphocytes, CD72 is associated with the protein tyrosine phosphatase SHP-1. Platelet activation causes dissociation of the complex, as does the addition of soluble sema4D. These findings suggest a dual role for sema4D in vascular responses to injury. As thrombus formation begins, platelet-associated sema4D can bind to its receptors on nearby platelets, promoting thrombus formation. As thrombus formation continues, sema4D is shed from the platelet surface and becomes available to interact with receptors on endothelial cells and monocytes, as well as continuing to interact with platelets.signaling ͉ thrombosis ͉ metalloprotease ͉ CD72 ͉ plexin-B1 P latelet activation typically begins with the exposure of collagen within a damaged vessel wall or the local generation of thrombin, but the establishment of a stable thrombus requires the recruitment of additional platelets and the development of stable contacts between platelets (1). Platelet activation also results in the release from platelets of molecules that can affect nearby cells, including endothelial cells and leukocytes as well as other platelets. In a continuing search for molecules that might contribute to contact-dependent events during thrombus formation, we screened human platelets for members of the semaphorin family. Although sempahorins are best known as regulators of neurite outgrowth and vascular development, individual family members have been shown to participate in a variety of events. Class IV semaphorin [semaphorin 4D (sema4D; CD100)] is a type I integral membrane protein first reported on T cells where it supports B cell development by binding to CD72 (2-4). However, sema4D receptors are not limited to B cells. Prior work has shown that a soluble sema4D extracellular domain fragment can activate endothelial cells by its other known receptor, plexin-B1. This causes endothelial migration, actin rearrangement, and the formation of tube-like structures in vitro, responses that are relevant for wound healing and angiogenesis (5-11). Soluble sema4D has also been shown to inhibit monocyte (12) and dendritic cell (13) migration. ...

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Section: Discussionmentioning

confidence: 99%

Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury

Zhu¹,

Bergmeier

Wu³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

175

221

View full text Add to dashboard Cite

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“…Ephrins are known to modulate ECM/integrin-mediated adhesion (Huynh-Do et al, 1999, 2002Chong and Jiang, 2005;Prevost et al, 2005;Foo et al, 2006). Alternatively, ephrinB2 signals could affect production or secretion of fibronectin, or influence a fibronectin-selective proteinase.…”

Section: How Does Loss Of a Pdz Binding Site On Ephrinb2 Affect The Ementioning

confidence: 99%

Role for ephrinB2 in postnatal lung alveolar development and elastic matrix integrity

Wilkinson

Schittny

Reinhardt

et al. 2008

Developmental Dynamics

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Alveoli are formed in the lung by the insertion of secondary tissue folds, termed septa, which are subsequently remodeled to form the mature alveolar wall. Secondary septation requires interplay between three cell types: endothelial cells forming capillaries, contractile interstitial myofibroblasts, and epithelial cells. Here, we report that postnatal lung alveolization critically requires ephrinB2, a ligand for Eph receptor tyrosine kinases expressed by the microvasculature. Mice homozygous for the hypomorphic knockin allele ephrinB2 ⌬V/⌬V , encoding mutant ephrinB2 with a disrupted C-terminal PDZ interaction motif, show severe postnatal lung defects including an almost complete absence of lung alveoli and abnormal and disorganized elastic matrix. Lung alveolar formation is not sensitive to loss of ephrinB2 cytoplasmic tyrosine phosphorylation sites. Postnatal day 1 mutant lungs show extracellular matrix alterations without differences in proportions of major distal cell populations. We conclude that lung alveolar formation relies on endothelial ephrinB2 function. Developmental Dynamics 237:2220 -2234, 2008.

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“…90 The family of Eph receptor tyrosine kinases and their ligands, known as ephrins, provide another mechanism of signaling promoted by direct contact between platelets. 88,91 Human platelets express EphA4, EphB1 and ephrinB. The former is constitutively associated with αIIbβ3 in both resting and activated platelets.…”

Section: Stabilization Phasementioning

confidence: 99%

Platelet receptors and signaling in the dynamics of thrombus formation

Rivera¹,

Lozano²,

et al. 2009

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Hemostasis and pathological thrombus formation are dynamic processes that require a co-ordinated series of events involving platelet membrane receptors, bidirectional intracellular signals, and release of platelet proteins and inflammatory substances. This review aims to summarize current knowledge in the key steps in the dynamics of thrombus formation, with special emphasis on the crucial participation of platelet receptors and signaling in this process. Initial tethering and firm adhesion of platelets to the exposed subendothelium is mediated by glycoprotein (GP) Ib/IX/V complex and collagen receptors, GP VI and α2β1 integrin, in the platelet surface, and by VWF and fibrillar collagen in the vascular site. Interactions between these elements are largely influenced by flow and trigger signaling events that reinforce adhesion and promote platelet activation. Thereafter, soluble agonists, ADP, thrombin, TxA2, produced/released at the site of vascular injury act in autocrine and paracrine mode to amplify platelet activation and to recruit circulating platelets to the developing thrombus. Specific interactions of these agonists with their G-protein coupled receptors generate inside-out signaling leading to conformational activation of integrins, in particular αIIbβ3, increasing their ligand affinity. Binding of αIIbβ3 to its ligands, mainly fibrinogen, supports processes such as clot retraction and platelet aggregation. Stabilization of thrombi is supported by the late wave of signaling events promoted by close contact between aggregated platelets. The best known contact-dependent signaling is outside-in signaling through αIIbβ3, but new ones are being clarified such as those mediated by interaction of Eph receptors with ephrins, or by Sema 4D and Gas-6 binding to their receptors. Finally, newly identified mechanisms appear to control thrombus growth, including back-shifting of activated integrins and actuation of compensatory molecules such as ESAM or PECAM-1. The expanding knowledge of thrombotic disease is expected to translate into the development of new drugs to help management and prevention of thrombosis.Key words: platelet, receptors, thrombus formation.Citation: Rivera J, Lozano ML, Navarro-Núñez L, Vicente V. Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica 2009; 94:700-711. doi:10.3324/haematol.2008 This is an open-access paper. ABSTRACT Platelet receptors and signaling in the dynamics of thrombus formationJosé Rivera, María Luisa Lozano, Leyre Navarro-Núñez, and Vicente Vicente Unit of Hematology and Clinical Oncology, Centro Regional de Hemodonación, University of Murcia, Spain © F e r r a t a S t o r t i F o u n d a t i o nand metastasis, or immunological host defense. 1Internally, platelets contain a cytoskeleton, a dense tubular system, few mitochondrias, glycogen granules, dense (δ) and α storage granules and peroxisomes. The α-granules retain relevant proteins for the hemostatic function of platelets, such as von Willebrand factor (VWF), fibrinogen, P-selectin,...

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Eph kinases and ephrins support thrombus growth and stability by regulating integrin outside-in signaling in platelets

Cited by 134 publications

References 36 publications

Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury

Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury

Role for ephrinB2 in postnatal lung alveolar development and elastic matrix integrity

Platelet receptors and signaling in the dynamics of thrombus formation

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