Editors' ChoicePlatelet Biology

Platelet NF-κB–PKA Complex

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Science Signaling  15 Jun 2010:
Vol. 3, Issue 126, pp. ec182
DOI: 10.1126/scisignal.3126ec182

Platelets are small anucleate cells derived from cytoplasmic extensions of megakaryocytes. They play a critical role in blood clotting and the response to endothelial injury. Maintenance of the proper balance between platelet activation and platelet inhibition is critical because disruption of this balance can cause thrombotic or bleeding disorders, respectively. Gambaryan et al. provide evidence for a role for cAMP-independent protein kinase A (PKA) activity in mediating an inhibitory signal in human platelets in response to thrombin or collagen. Although collagen or thrombin failed to stimulate an increase in either the concentration of cAMP or cGMP, phosphorylation of several PKA substrates, such as VASP (vasodilator-stimulated phosphoprotein) and Rap1GAP2 (Rap1 GTPase-activating protein 2), was stimulated in human platelets. Phosphorylation of VASP on the PKA site was blocked by the inhibitor of the catalytic subunit of PKA, H-89, but not by Rp-8-Br-cAMPS, which is a competitive inhibitor of the cAMP binding sites on the regulatory subunit of PKA. Thus, this activation of PKA by collagen or thrombin appeared to be independent of cAMP. Previous work has suggested that PKA could associate with the IKK (inhibitor of NF-κB kinase) complex, which regulates the activation of nuclear factor κB (NF-κB). The authors showed that human platelets contain all three IKK family members, a subset of NF-κB proteins, and several IκB proteins, suggesting that, despite their lack of a nucleus, the IKK complex has a role in platelets. The catalytic subunit of PKA coimmunoprecipitated with IκBα in human platelets, and this interaction was reduced in platelets exposed to collagen or thrombin. Exposure of platelets to the IKK inhibitor VII prevented thrombin-induced dissociation of PKA from the IKK complex, decreased phosphorylation of VASP, increased integrin activation, and potentiated platelet aggregation. Thus, the authors propose that PKA released from the IKK complex participates in a negative feedback pathway in response to either collagen or thrombin. Unanswered questions remain regarding what roles the other components of the IKK complex or NF-κB play in this process.

S. Gambaryan, A. Kobsar, N. Rukoyatkina, S. Herterich, J. Geiger, A. Smolenski, S. M. Lohmann, U. Walter, Thrombin and collagen induce a feedback inhibitory signaling pathway in platelets involving dissociation of the catalytic subunit of protein kinase A from an NFκB-IκB complex. J. Biol. Chem. 285, 18352–18363 (2010). [Abstract] [Full Text]

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