Platelet aggregation induces platelet aggregate stability via SLAM family receptor signaling

Nanda, Nisha; André, Patrick; Bao, Ming; Clauser, Karl R.; DeGuzman, Francis; Howie, Duncan; Conley, Pamela B.; Terhorst, Cox; Phillips, David R.

doi:10.1182/blood-2005-01-0333

Cited by 91 publications

(85 citation statements)

References 25 publications

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“…21,23,24 Platelets from these knock-out mice share an impaired ability to aggregate with ADP, suggesting that a common mechanism is responsible for the decreased thrombus stability. One possibility is that P2Y 12 activity is a prerequisite for late contactdependent signaling via these proteins or, alternatively, that diminished platelet-platelet contact may lead to reduced ADP secretion and paracrine activation via P2Y 12 .…”

Section: Discussionmentioning

confidence: 99%

“…These include the P2Y 1 and P2Y 12 receptors, 10,20 Gas6 and Gas6-receptors, 21 ephrins and Eph kinases, 22 CD40 ligand (CD40L), 23 and signaling lymphocytic activation molecule (SLAM). 24 Mice deficient in 1 of these components exhibit an intriguing similarity in phenotype (ie, all showing diminished thrombus formation and increased embolization). In essence, these findings raise the possibility that thrombi are intrinsically unstable, and may require multiple postaggregation events to become stabilized.…”

Section: Introductionmentioning

confidence: 99%

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Continuous signaling via PI3K isoforms β and γ is required for platelet ADP receptor function in dynamic thrombus stabilization

Cosemans¹,

Munnix²,

Wetzker³

et al. 2006

Blood

143

149

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Signaling from collagen and G proteincoupled receptors leads to platelet adhesion and subsequent thrombus formation. Paracrine agonists such as ADP, thromboxane, and Gas6 are required for platelet aggregate formation. We hypothesized that thrombi are intrinsically unstable structures and that their stabilization requires persistent paracrine activity and continuous signaling, maintaining integrin ␣ IIb ␤ 3 activation. Here, we studied the disassembly of human and murine thrombi formed on collagen under high shear conditions. Platelet aggregates rapidly disintegrated (1) in the absence of fibrinogen-containing plasma; (2) by blocking or inhibiting ␣ IIb ␤ 3 ; (3) by blocking P2Y 12 receptors; (4) by suppression of phosphoinositide 3-kinase (PI3K) ␤. In murine blood, absence of PI3K␥ led to formation of unstable thrombi, leading to dissociation of multiplatelet aggregates. In addition, blocking PI3K␤ delayed initial thrombus formation and reduced individual platelet-platelet contact. Similarly without flow, agonist-induced aggregation was reversed by late suppression of P2Y 12 or PI3K isoforms, resulting in single platelets that had inactivated ␣ IIb ␤ 3 and no longer bound fibrinogen. Together, the data indicate that continuous outside-in signaling via P2Y 12 and both PI3K␤ and PI3K␥ isoforms is required for perpetuated ␣ IIb IntroductionPlatelet plug formation at sites of vascular injury is considered to consist of 3 phases: initiation, propagation, and perpetuation. 1,2 The initiation phase involves platelet adhesion to von Willebrand factor (VWF) and to collagen exposed in the vessel wall. In the propagation phase, activated platelets secrete mediators such as ADP, thromboxane A 2 (TxA 2 ), and Gas6, which activate other platelets to form aggregates. In the perpetuation phase, fibrin formation and less well-understood postaggregation events are assumed to accomplish stabilization of the thrombus.At arterial shear rates, the thrombotic process is initiated by the tethering of platelets via glycoprotein (GP) Ib-IX-V to VWF, bound to collagen. 3 In human and murine platelets, 2 interacting collagen receptors, GPVI and integrin ␣ 2 ␤ 1 , mediate stable adhesion to collagen. [4][5][6][7] The signaling receptor GPVI triggers series of activation events, including integrin ␣ IIb ␤ 3 activation (providing binding sites, for example, for fibrinogen) and Ca 2ϩ mobilization and secretion, which all function to recruit other platelets. 8,9 During the propagation phase of thrombus formation, released ADP and TxA 2 in a paracrine way pursue the activation process, mediated by P2Y 1 , P2Y 12 , and TP␣ receptors. 8,10,11 The Gq-coupled P2Y 1 and TP␣ receptors evoke Ca 2ϩ mobilization and protein kinase C activity. The P2Y 12 signaling pathway involves Gimediated inhibition of adenylyl cyclase, which lowers cyclic AMP and indirectly enhances Ca 2ϩ signal generation. 12-14 P2Y 12 signaling via Gi also leads to activation of the phosphoinositide 3-kinase (PI3K) and protein kinase B signaling pathways. However, it is still unc...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Continuous signaling via PI3K isoforms β and γ is required for platelet ADP receptor function in dynamic thrombus stabilization

Cosemans¹,

Munnix²,

Wetzker³

et al. 2006

Blood

143

149

View full text Add to dashboard Cite

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“…Treatment of human T cells with CD84-Ig enhances TCR-induced IFN-␥ secretion presumably through homophilic engagement of cell surface CD84 (10). It has also been demonstrated that CD84 homophilic engagement induces platelet stimulation (11).…”

mentioning

confidence: 98%

Structure of CD84 provides insight into SLAM family function

Yan

Malashkevich

Fedorov

et al. 2007

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

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The signaling lymphocyte activation molecule (SLAM) family includes homophilic and heterophilic receptors that modulate both adaptive and innate immune responses. These receptors share a common ectodomain organization: a membrane-proximal immunoglobulin constant domain and a membrane-distal immunoglobulin variable domain that is responsible for ligand recognition. CD84 is a homophilic family member that enhances IFN-␥ secretion in activated T cells. Our solution studies revealed that CD84 strongly self-associates with a Kd in the submicromolar range. These data, in combination with previous reports, demonstrate that the SLAM family homophilic affinities span at least three orders of magnitude and suggest that differences in the affinities may contribute to the distinct signaling behavior exhibited by the individual family members. The 2.0 Å crystal structure of the human CD84 immunoglobulin variable domain revealed an orthogonal homophilic dimer with high similarity to the recently reported homophilic dimer of the SLAM family member NTB-A. Structural and chemical differences in the homophilic interfaces provide a mechanism to prevent the formation of undesired heterodimers among the SLAM family homophilic receptors. These structural data also suggest that, like NTB-A, all SLAM family homophilic dimers adopt a highly kinked organization spanning an end-to-end distance of Ϸ140 Å. This common molecular dimension provides an opportunity for all two-domain SLAM family receptors to colocalize within the immunological synapse and bridge the T cell and antigen-presenting cell.homophilic ͉ dimer ͉ affinity

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“…Signaling lymphocytic activation molecule (SLAM; CD150) and CD84 are members of the CD2 family of homophilic adhesion molecules that have been studied extensively in lymphocytes, but have now been shown to be expressed in platelets as well (41)(42)(43). The members of the family are type 1 membrane glycoproteins in the Ig superfamily.…”

Section: Junctional Adhesion Molecules In the Igmentioning

confidence: 99%