Protein kinase C mediates platelet secretion and thrombus formation through protein kinase D2

Author:

Konopatskaya Olga1,Matthews Sharon A.2,Harper Matthew T.1,Gilio Karen3,Cosemans Judith M. E. M.3,Williams Christopher M.1,Navarro Maria N.2,Carter Deborah A.1,Heemskerk Johan W. M.3,Leitges Michael4,Cantrell Doreen2,Poole Alastair W.1

Affiliation:

1. School of Physiology & Pharmacology, Bristol Heart Institute, Bristol, United Kingdom;

2. Department of Cell Biology and Immunology, College of Life Sciences, University of Dundee, Dundee, United Kingdom;

3. Department of Biochemistry, Maastricht University, Maastricht, the Netherlands; and

4. Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway

Abstract

Abstract Platelets are highly specialized blood cells critically involved in hemostasis and thrombosis. Members of the protein kinase C (PKC) family have established roles in regulating platelet function and thrombosis, but the molecular mechanisms are not clearly understood. In particular, the conventional PKC isoform, PKCα, is a major regulator of platelet granule secretion, but the molecular pathway from PKCα to secretion is not defined. Protein kinase D (PKD) is a family of 3 kinases activated by PKC, which may represent a step in the PKC signaling pathway to secretion. In the present study, we show that PKD2 is the sole PKD member regulated downstream of PKC in platelets, and that the conventional, but not novel, PKC isoforms provide the upstream signal. Platelets from a gene knock-in mouse in which 2 key phosphorylation sites in PKD2 have been mutated (Ser707Ala/Ser711Ala) show a significant reduction in agonist-induced dense granule secretion, but not in α-granule secretion. This deficiency in dense granule release was responsible for a reduced platelet aggregation and a marked reduction in thrombus formation. Our results show that in the molecular pathway to secretion, PKD2 is a key component of the PKC-mediated pathway to platelet activation and thrombus formation through its selective regulation of dense granule secretion.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference42 articles.

1. Antiplatelet therapies for the treatment of cardiovascular disease.;Michelson;Nat Rev Drug Discov,2010

2. PKCalpha regulates platelet granule secretion and thrombus formation in mice.;Konopatskaya;J Clin Invest,2009

3. Regulation of outside-in signaling in platelets by integrin-associated protein kinase C beta.;Buensuceso;J Biol Chem,2005

4. A role for PKCtheta in outside-in alpha(IIb)beta3 signaling.;Soriani;J Thromb Haemost,2006

5. Protein kinase Cδ differentially regulates platelet functional responses.;Chari;Arterioscler Thromb Vasc Biol,2009

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