RASA3 is a critical inhibitor of RAP1-dependent platelet activation

Stefanini, Lucia; Paul, David S.; Robledo, Raymond F.; Chan, E. Ricky; Getz, Todd M.; Campbell, Robert A.; Kechele, Daniel O.; Casari, Caterina; Piatt, Raymond; Caron, Kathleen M.; Mackman, Nigel; Weyrich, Andrew S.; Parrott, Matthew C.; Boulaftali, Yacine; Adams, Mark D.; Peters, Luanne L.; Bergmeier, Wolfgang

doi:10.1172/jci77993

Cited by 119 publications

(159 citation statements)

References 75 publications

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“…25 Once a IIb b 3 has been activated, integrin-dependent signaling promotes clot retraction, increasing packing density and slowing solute transport.…”

Section: The Platelet Signaling Network Is An Integrating Enginementioning

confidence: 99%

“…[26][27][28] For Rap1b, the primary GAP is Rasa3. 25,29 Network integration occurs in part by regulating the balance of GEF and GAP activity. The availability of RGS10 and RGS18 is regulated by spinophilin (SPL), which sequesters both in resting platelets, and by 14-3-3g, which binds RGS proteins in activated platelets.…”

Section: The Platelet Signaling Network Is An Integrating Enginementioning

confidence: 99%

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Platelets and hemostasis: a new perspective on an old subject

Brass¹,

Diamond

Stalker³

2016

Blood Advances

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This article has a companion Counterpoint by Kapur and Semple. This is an exciting time for clinicians and scientists interested in platelet biology. Improved imaging methods allow platelets to be observed in action in animal models in real time at ever greater resolution. Expanding proteomic and genetic data sets lend themselves to better understanding platelet activation. New gene editing methods make it easier, faster, and less expensive to test new ideas using transgenic animal models. Combining systems biology approaches with computational methods encourages a broader perspective on platelet activation and makes it possible to develop ideas in silico that can then be tested in vivo. One result has been an opportunity to revisit prevailing wisdom about the hemostatic response, extending and occasionally refuting what has come before.Systems biology is the study of complex interactions, some of whose properties can be understood only when multiple cells or multiple pathways are considered. Here we will consider 2 examples in which improved methods and a systems-oriented approach have provided insights into the most basic of platelet functions: participation in the hemostatic response to injury. The first example considers the ways in which the simple act of piling up of platelets at a site of injury helps to calibrate the hemostatic response by altering the environment in which platelet activation occurs. The second example considers how individual signaling events within platelets form an integrated network whose properties emerge from the individual pathways.

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“…25 Once a IIb b 3 has been activated, integrin-dependent signaling promotes clot retraction, increasing packing density and slowing solute transport.…”

Section: The Platelet Signaling Network Is An Integrating Enginementioning

confidence: 99%

Section: The Platelet Signaling Network Is An Integrating Enginementioning

confidence: 99%

Platelets and hemostasis: a new perspective on an old subject

Brass¹,

Diamond

Stalker³

2016

Blood Advances

View full text Add to dashboard Cite

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“…The active GTP‐bound Gαi‐subunit dissociates from the β and γ subunits and binds to AC leading to diminished cAMP synthesis (Figure 3 and Table 1). Simultaneously Gi triggers the phosphatidylinositol 3‐kinase (PI3K) pathway, which converts phosphatidylinositol 4,5‐bisphosphate to phosphatidylinositol 3,4,5‐trisphosphate at the plasma membrane leading to the activation of the kinase Akt and inhibition of the Rap1‐GAP RASA3, key activating pathways in platelets 20, 21, 22. The synergism between P2Y12 function and blockage of cyclic nucleotide pathways has been shown for both, cAMP and cGMP components, although cGMP regulation by P2Y12 is not well understood 9, 23.…”

Section: Interactions At Receptor Levelmentioning

confidence: 99%

“…During platelet activation Rap1GAP2 S9 phosphorylation enhances 14‐3‐3 binding, whereas PKA/PKG‐mediated S7 phosphorylation does the opposite (Figure 7). 92 Platelet activation has also been shown to inhibit the function of RASA3, a highly expressed GAP of Rap1 in platelets, in a PI3K‐dependent manner 21, 22. Vasodilator‐stimulated phosphoprotein (VASP) is an actin filament and focal adhesion binding protein and was one of the first substrates of PKA/PKG to be identified in platelets.…”

Section: Interactions Involving Small G‐proteinsmentioning

confidence: 99%

Cyclic nucleotide‐dependent inhibitory signaling interweaves with activating pathways to determine platelet responses

Nagy

Smolenski

2018

Research and Practice in Thrombosis and Haemostasis

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Platelets are regulated by extracellular cues that impact on intracellular signaling. The endothelium releases prostacyclin and nitric oxide which stimulate the synthesis of cyclic nucleotides cAMP and cGMP leading to platelet inhibition. Other inhibitory mechanisms involve immunoreceptor tyrosine‐based inhibition motif‐containing receptors, intracellular receptors and receptor desensitization. Inhibitory cyclic nucleotide pathways are traditionally thought to represent a passive background system keeping platelets in a quiescent state. In contrast, cyclic nucleotides are increasingly seen to be dynamically involved in most aspects of platelet regulation. This review focuses on crosstalk between activating and cyclic nucleotide‐mediated inhibitory pathways highlighting emerging new hub structures and signaling mechanisms. In particular, interactions of plasma membrane receptors like P2Y12 and GPIb/IX/V with the cyclic nucleotide system are described. Furthermore, differential regulation of the RGS18 complex, second messengers, protein kinases, and phosphatases are presented, and control over small G‐proteins by guanine‐nucleotide exchange factors and GTPase‐activating proteins are outlined. Possible clinical implications of signaling crosstalk are discussed.

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“…For firm platelet adhesion to occur, RASA3 activity has to be down-modulated. Critical for the down-modulation of Rasa3 activity is signaling via the Gi-coupled receptor for ADP, P2Y12[61]. Thus, similar to the GPCR dual receptor systems, RAP activation is a two-step process.…”

Section: Classical Hemostasis – Balancing Platelet Adhesiveness In CImentioning

confidence: 99%

Platelets at the vascular interface

Bergmeier

Stefanini

2018

Research and Practice in Thrombosis and Haemostasis

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In this brief review paper, we will summarize the State-of-the-Art on how platelet reactivity is regulated in circulation and at sites of vascular injury. Our review discusses recent and ongoing work, presented at this year’s International Society on Thrombosis and Haemostasis (ISTH) meeting, on the role of platelets in (1) classical hemostasis at sites of mechanical injury, and (2) the maintenance of vascular integrity at sites of inflammation.

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RASA3 is a critical inhibitor of RAP1-dependent platelet activation

Cited by 119 publications

References 75 publications

Platelets and hemostasis: a new perspective on an old subject

Platelets and hemostasis: a new perspective on an old subject

Cyclic nucleotide‐dependent inhibitory signaling interweaves with activating pathways to determine platelet responses

Platelets at the vascular interface

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