Loss of pleckstrin defines a novel pathway for PKC-mediated exocytosis

Lian, Lurong; Wang, Yanfeng; Flick, Matthew J.; Choi, John K.; Scott, Edward W.; Degen, Jay L.; Lemmon, Mark A.; Abrams, Charles S.

doi:10.1182/blood-2008-09-178913

Cited by 48 publications

(56 citation statements)

References 54 publications

(50 reference statements)

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“…PKC is known to play a key role in G q -dependent platelet secretion and aggregation (34,36,45,46). PKC-dependent platelet activation requires its effector pleckstrin (47). AYPGKF at high concentrations induces aggregation of PKC inhibitor-treated platelets (Fig.…”

Section: Discussionmentioning

confidence: 99%

The Src Family Kinases and Protein Kinase C Synergize to Mediate Gq-dependent Platelet Activation

Xiang

Zhang

Stefanini

et al. 2012

Journal of Biological Chemistry

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Background:The role of SFKs in G protein-coupled receptor-mediated platelet activation is not well understood. Results: AYPGKF induced G q /Ca 2ϩ -dependent SFK phosphorylation, and AYPGKF-elicited platelet activation was partially inhibited by PP2 but was completely abolished by PKC inhibitors plus SFK inhibitors. Conclusion: Ca 2ϩ /SFKs/PI3K and PKC represent alternative pathways mediating AYPGKF-dependent platelet activation. Significance: This work increases understanding of important SFK functions in platelet activation.

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Section: Discussionmentioning

confidence: 99%

The Src Family Kinases and Protein Kinase C Synergize to Mediate Gq-dependent Platelet Activation

Xiang

Zhang

Stefanini

et al. 2012

Journal of Biological Chemistry

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“…For the actin assembly experiment, platelets were analyzed on a FACSCalibur (BD PharMingen) using FlowJo software (Tree Star, Ashland, OR) as described previously. 24 Analysis of focal adhesion kinase (FAK) was performed by layering 4 3 10 8 platelets over 0.1% fibrinogen-coated 10-cm tissue culture dishes in the presence of 0.5 U/mL thrombin. After incubation at 37°C for 15 minutes, the cells were lysed in RIPA buffer and immunoblotted with either anti-pFAK (Cell Signaling Technology) or anti-FAK (Millipore Corp., Billerica, MA) antibodies.…”

Section: Platelet Integrin Function Ex Vivo and In Vivo Assaysmentioning

confidence: 99%

Platelets lacking PIP5KIγ have normal integrin activation but impaired cytoskeletal-membrane integrity and adhesion

Wang¹,

Zhao²,

Suzuki³

et al. 2013

Blood

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“…16 DAG is a well-established activator of protein kinase C (PKC) and therefore granule release in platelets. 17,18 PKC-dependent integrin activation depends on positive feedback by the Gi-coupled P2Y12 receptor, 19 which again leads to the activation of Rap1. 11,12,20 Importantly, CalDAG-GEFI-mediated Rap1 activation is rapid but reversible, while P2Y12-mediated Rap1 activation occurs with a delay but is more stable.…”

Section: Introductionmentioning

confidence: 99%

“…16 DAG is a well-established activator of protein kinase C (PKC) and therefore granule release in platelets. 17,18 PKC-dependent integrin activation depends on positive feedback For personal use only. on May 9, 2018. by guest www.bloodjournal.org From by the Gi-coupled P2Y12 receptor, 19 which again leads to the activation of Rap1.…”

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confidence: 99%

The kinetics of αIIbβ3 activation determines the size and stability of thrombi in mice: implications for antiplatelet therapy

Stolla

Stefanini

Roden

et al. 2011

Blood

115

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Two major pathways contribute to Rasproximate-1-mediated integrin activation in stimulated platelets. Calcium and diacyglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI, Ras-GRP2) mediates the rapid but reversible activation of integrin ␣IIb␤3, while the adenosine diphosphate receptor P2Y12, the target for antiplatelet drugs like clopidogrel, facilitates delayed but sustained integrin activation. To establish CalDAG-GEFI as a target for antiplatelet therapy, we compared how each pathway contributes to thrombosis and hemostasis in mice. Ex vivo, thrombus formation at arterial or venous shear rates was markedly reduced in CalDAG-GEFI ؊/؊ blood, even in the presence of exogenous adenosine diphosphate and thromboxane A 2 . In vivo, thrombosis was virtually abolished in arterioles and arteries of CalDAG-GEFI ؊/؊ mice, while small, hemostatically active thrombi formed in venules. Specific deletion of the C1-like domain of CalDAG-GEFI in circulating platelets also led to protection from thrombus formation at arterial flow conditions, while it only marginally increased blood loss in mice. In comparison, thrombi in the micro-and macrovasculature of clopidogrel-treated wild-type mice grew rapidly and frequently embolized but were hemostatically inactive. Together, these data suggest that inhibition of the catalytic or the C1 regulatory domain in CalDAG-GEFI will provide strong protection from atherothrombotic complications while maintaining a better safety profile than P2Y12 inhibitors like clopidogrel. (Blood. 2011; 117(3):1005-1013) IntroductionArterial thrombosis in the coronary or cerebrovascular circulation is the principal pathological process underlying acute coronary syndrome and ischemic stroke, which together represent the leading cause of morbidity and mortality in industrialized countries. 1 Platelet activation is a central event in the pathogenesis of arterial thrombosis. Currently, the most powerful antiplatelet agents used in the clinic are inhibitors of cyclooxygenase-1 (acetylsalicylic acid, aspirin), the platelet adenosine diphosphate (ADP) receptor P2Y12 (eg, clopiodgrel or Plavix), and integrin ␣IIb␤3 (eg, abciximab or Reopro). 2,3 These agents have all been shown to improve clinical outcomes in large-scale randomized controlled trials. However, all therapies have limitations that include uncertainty about optimal dosing, questions about resistance, and issues regarding the lack of reversibility in situations where bleeding risks are high.␣IIb␤3, the platelet fibrinogen receptor, is the best-studied member of the integrin family. 4,5 Like most integrins, especially those regulating adhesion and trafficking of blood cells, it is expressed in a low-affinity state on resting platelets. Engagement of agonist receptors on the platelet surface triggers intracellular signaling events, which lead to inside-out activation of ␣IIb␤3. Deficiency in ␣IIb␤3 completely inhibits the ability of platelets to aggregate and adhere to sites of injury. 6,7 Consequently, inhibitors to integrin ␣IIb␤3 show...

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Loss of pleckstrin defines a novel pathway for PKC-mediated exocytosis

Cited by 48 publications

References 54 publications

The Src Family Kinases and Protein Kinase C Synergize to Mediate Gq-dependent Platelet Activation

The Src Family Kinases and Protein Kinase C Synergize to Mediate Gq-dependent Platelet Activation

Platelets lacking PIP5KIγ have normal integrin activation but impaired cytoskeletal-membrane integrity and adhesion

The kinetics of αIIbβ3 activation determines the size and stability of thrombi in mice: implications for antiplatelet therapy

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