Integrin Signaling: The Platelet Paradigm

Shattil, Sanford J.; Kashiwagi, Hirokazu; Pampori, Nisar A.

doi:10.1182/blood.v91.8.2645.2645_2645_2657

Cited by 644 publications

(352 citation statements)

References 183 publications

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“…As platelets are activated, focal adhesions form a network of cytoskeletal and signaling proteins that stabilize cell adhesion and platelet aggregates. Src and Syk are phosphorylated early in platelet activation, whereas Fak requires GPIIb/IIIa ligation for its activation (7). Grb2 and Shc are both adaptor proteins without catalytic activity.…”

Section: Discussionmentioning

confidence: 99%

“…Phospholipase D (PLD) is also activated, probably downstream of PKC (6) and catalyzes the formation of phospatidic acid (PA), mainly from phosphatidylcholine. Subsequently, the af®nity of GPIIb/IIIa changes, allowing it to bind ®brinogen, and focal adhesions are formed as Src, Fak, Syk, Grb2, phosphatidyl inositol-3-kinase (PI-3-K) and other important enzymes and adaptor proteins are recruited and assembled into mature focal adhesions, connected to actin stress ®bers (7).…”

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confidence: 99%

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Defective platelet aggregation in polycythaemia vera is not caused by impaired calcium signaling, phospholipase D activation or decreased amounts of focal adhesion proteins

Blanc

Berg

Palmblad³

et al. 2000

European J of Haematology

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We have previously demonstrated that platelets in polycythaemia vera (PV) exhibit decreased aggregation after stimulation with platelet activating factor (PAF) and reduced expression of GPIIIa on both resting and stimulated platelets. In the present study, we investigated if these results were related to changes in the mobilization of intracellular calcium, activation of phospholipase D (PLD) or amounts of GPIIIa and the intracellular tyrosine kinases Fak, Syk, Grb2, Shc and rhoA. Intracellular calcium levels were not different in resting platelets from 14 PV patients and 15 healthy controls (median 43 nmol/L, range 10-114, vs. 36 nmol/L, range 10-119). After stimulation with PAF (1 micromol/L) an equal increase was seen (125 nmol/L for PV platelets, range 67-257, vs. 113 nmol/L for controls, range 60-250). Also formation of phosphatidyl ethanol (PEt) was similar after exposure to 0.5 U/ml thrombin (0.28% PEt of total phospholipid, range 0.16-1.10, vs. 0.24 for controls, range 0.11-2.3) and 1 micromol/L PMA (0.25, range 0.16-0.32, vs. 0.14, range 0.09-0.6). In contrast to the reduced amount of GPIIIa on the surface of PV platelets, immunoblotting on whole cell lysates showed no reduction in PV patients compared to controls, indicating the possibility of an impaired incorporation of GPIIIa to the cell membrane. Levels of Fak, Syk, Shc, Grb2 and rhoA appeared equal in patients and controls. Similar intracellular proteins were tyrosine phosphorylated after stimulation with thrombin, PAF and PMA. In summary, defective platelet aggregation after stimulation with PAF is caused by neither defective mobilization of intracellular calcium nor, in contrast to the situation in PV granulocytes, an impaired activation of PLD. Moreover, no apparent differences in the intracellular amounts of Fak, Syk Shc, Grb2 and rhoA could be detected between PV and control platelets.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Defective platelet aggregation in polycythaemia vera is not caused by impaired calcium signaling, phospholipase D activation or decreased amounts of focal adhesion proteins

Blanc

Berg

Palmblad³

et al. 2000

European J of Haematology

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“…The binding of fibrinogen to the surface GPIIb/IIIa complex is a critical step for platelet aggregation (Shattil et al, 1998;Salanova et al, 2007). Inhibiting NF-κB activation reduces the outside-in/inside-out signalling of GPIIb/IIIa and fibrinogen binding (Malaver et al, 2009).…”

Section: Figurementioning

confidence: 99%

Antiplatelet activity of nifedipine is mediated by inhibition of NF‐κB activation caused by enhancement of PPAR‐β/‐γ activity

Shih

Lin

Ding

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEThe transcription factor NF-κB, stimulates platelet aggregation through a non-genomic mechanism. Nifedipine, a voltage-gated L-type calcium channel blocker, is widely used to treat hypertension. Nifedipine also displays antiplatelet activity, but the underlying mechanisms involved remain unclear. This study was designed to investigate whether the antiplatelet effects of nifedipine are mediated by regulating NF-κB-dependent responses. EXPERIMENTAL APPROACHPlatelet aggregation was measured turbidimetrically using an aggregometer. NF-κB and PPAR activation, intracellular Ca 2+ mobilization, PKCα activity, surface glycoprotein IIb/IIIa (GPIIb/IIIa) expression and platelet activation-related signalling pathways were determined in control and nifedipine-treated platelets in the presence or absence of PPAR antagonists or betulinic acid, a NF-κB activator. KEY RESULTSExposure of platelets to nifedipine significantly increased the PPAR-β/-γ activity in activated human platelets. Treatment with nifedipine reduced collagen-induced NF-κB events, including the phosphorylation of IκB kinase-β, IκBα and p65NF-κB, which were markedly attenuated by GSK0660, a PPAR-β antagonist, or GW9662, a PPAR-γ antagonist. Furthermore, the interaction of PPAR-β/-γ with NF-κB and the PPAR-β/-γ-up-regulated NO/cGMP/PKG1 cascade may contribute to inhibition of NF-κB activation by nifedipine. Suppressing PPAR-β/-γ activity or increasing NF-κB activation greatly reversed the inhibitory effect of nifedipine on collagen-induced platelet aggregation, intracellular Ca 2+ mobilization, PKCα activity and surface GPIIb/IIIa expression. CONCLUSIONS AND IMPLICATIONSPPAR-β/-γ-dependent inhibition of NF-κB activation contributes to the antiplatelet activity of nifedipine. These findings provide a novel mechanism underlying the beneficial effects of nifedipine on platelet hyperactivity-related vascular and inflammatory diseases.

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“…The integrin αIIbβ3 plays an important role in hemostasis mediating platelet adhesion, aggregation and bidirectional signaling. 182,183 Little is known about the molecular mechanisms underlying the regulation of αIIb-mediated outside-in signaling. Recently, it has been shown that this signaling is enhanced in platelets of a patient lacking the terminal 39 residues of the β3 CYTO domain, as detected by thromboxane production and granule secretion, and requires ligand cross-linking of αIIbβ3 and platelet aggregation.…”

Section: Multichain Receptorsmentioning

confidence: 99%

The SCHOOL of nature. III. From mechanistic understanding to novel therapies

Sigalov

2010

Self/Nonself

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Integrin Signaling: The Platelet Paradigm

Cited by 644 publications

References 183 publications

Defective platelet aggregation in polycythaemia vera is not caused by impaired calcium signaling, phospholipase D activation or decreased amounts of focal adhesion proteins

Defective platelet aggregation in polycythaemia vera is not caused by impaired calcium signaling, phospholipase D activation or decreased amounts of focal adhesion proteins

Antiplatelet activity of nifedipine is mediated by inhibition of NF‐κB activation caused by enhancement of PPAR‐β/‐γ activity

The SCHOOL of nature. III. From mechanistic understanding to novel therapies

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