Essential Role of Protein Kinase Cδ in Platelet Signaling, αIIbβ3 Activation, and Thromboxane A2 Release

The protein kinase C (PKC) family is an essential signaling mediator in platelet activation and aggregation. However, the relative importance of the major platelet PKC isoforms and their downstream effectors in platelet signaling and function remain unclear. Using isolated human platelets, we report that PKCδ, but not PKCα or PKCβ, is required for collagen-induced phospholipase C-dependent signaling, activation of αIIbβ3, and platelet aggregation. Analysis of PKCδ phosphorylation and translocation to the membrane following activation by both collagen and thrombin indicates that it is positively regulated by αIIbβ3 outside-in signaling. Moreover, PKCδ triggers activation of the mitogen-activated protein kinase-kinase (MEK)/extracellular-signal regulated kinase (ERK) and the p38 MAPK signaling. This leads to the subsequent release of thromboxane A2, which is essential for collagen-induced but not thrombin-induced platelet activation and aggregation. This study adds new insight to the role of PKCs in platelet function, where PKCδ signaling, via the MEK/ERK and p38 MAPK pathways, is required for the secretion of thromboxane A2. The protein kinase C (PKC) family is an essential signaling mediator in platelet activation and aggregation. However, the relative importance of the major platelet PKC isoforms and their downstream effectors in platelet signaling and function remain unclear. Using isolated human platelets, we report that PKCδ, but not PKCα or PKCβ, is required for collagen-induced phospholipase C-dependent signaling, activation of αIIbβ3, and platelet aggregation. Analysis of PKCδ phosphorylation and translocation to the membrane following activation by both collagen and thrombin indicates that it is positively regulated by αIIbβ3 outside-in signaling. Moreover, PKCδ triggers activation of the mitogen-activated protein kinase-kinase (MEK)/extracellular-signal regulated kinase (ERK) and the p38 MAPK signaling. This leads to the subsequent release of thromboxane A2, which is essential for collagen-induced but not thrombin-induced platelet activation and aggregation. This study adds new insight to the role of PKCs in platelet function, where PKCδ signaling, via the MEK/ERK and p38 MAPK pathways, is required for the secretion of thromboxane A2. Platelets are required for normal hemostasis but are also actively involved in thrombosis, restenosis, and inflammatory reactions. Platelet interactions with other components of the blood and with the vascular wall represent a fundamental aspect of platelet function. These interactions are primarily mediated by specific cell adhesion molecules that induce adhesion to other platelets, leukocytes, endothelial cells, and the extracellular matrix, leading to platelet activation and amplification of the thrombo-inflammatory reactions (1Frojmovic M.M. Am. Heart J. 1998; 135: S119-S131Crossref PubMed Google Scholar, 2Hynes R.O. Thromb. 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The initial binding of platelets to damaged blood vessels, which does not necessitate activation, is predominantly mediated by the interactions of platelet glycoprotein (GP) 2The abbreviations used are: GP, glycoprotein; PKC, protein kinase C; PLC, phospholipase C; TxA2, thromboxane A2; DAG, diacylglycerol; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase. 2The abbreviations used are: GP, glycoprotein; PKC, protein kinase C; PLC, phospholipase C; TxA2, thromboxane A2; DAG, diacylglycerol; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase. Ib-IX-V (leucinrich) with von Willebrand Factor (6Berndt M.C. Shen Y. Dopheide S.M. Gardiner E.E. Andrews R.K. Thromb. Haemostasis. 2001; 86: 178-188Crossref PubMed Scopus (241) Google Scholar) at high shear and α2β1 with collagen at low shear (7Clemetson K.J. Clemetson J.M. Thromb. 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Park J. Israels S.J. McNicol A. Lint D. Cragoe Jr., E.J. Blood. 1989; 74: 2405-2413Crossref PubMed Google Scholar). However, the role of individual PKC isoforms in platelet function remains to be elucidated. For instance, although it is well established that collagen-induced platelet activation and aggregation through GPVI is mediated by tyrosine kinase Syk and activation of PLCγ2 (32Blake R.A. Schieven G.L. Watson S.P. FEBS Lett. 1994; 353: 212-216Crossref PubMed Scopus (124) Google Scholar, 33Yanaga F. Poole A. Asselin J. Blake R. Schieven G.L. Clark E.A. Law C.L. Watson S.P. Biochem. J. 1995; 311: 471-478Crossref PubMed Scopus (131) Google Scholar), there is limited information concerning the roles of specific PKC isoforms and their downstream effectors in this process. This study was to the role of in particular PKCδ, in platelet activation and aggregation. Using thrombin and collagen, and potent platelet we to that PKCδ is essential for collagen-induced but not thrombin-induced platelet aggregation and activation of integrin This study also that PKCδ is positively regulated by αIIbβ3 outside-in signaling and is involved in the release of through the MEK/ERK and p38 MAPK signaling pathways, which is required for collagen-induced but not thrombin-induced platelet activation and aggregation. of the signaling from The was from The αIIbβ3 and from and for PKCδ, and p38 MAPK from Cell and The PKCδ was from whereas the and p38 from cell signaling. is a PKC that PKCδ more and and more and In platelets, its used at as a specific of the novel PKCδ (25Murugappan S. Tuluc F. Dorsam R.T. Shankar H. Kunapuli S.P. J. Biol. Chem. 2004; 279: 2360-2367Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, D. Poole J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of blood was from from to with platelet function for at the in with the of the of the Heart The platelets as J.G. A. Y. J. 2001; Google Scholar, A. S.A. Y. J. PubMed Scopus Google Scholar). the platelets by of and to a of an cell in which The platelets to at for Platelet of platelets was a J.G. A. Y. J. 2001; Google Scholar, A. S.A. Y. J. PubMed Scopus Google Scholar). The platelets with for at The at Platelet aggregation was and the of the and platelets for the with at in the or of the was by the of a 4 and for The by in and to The with at at 4 with the and with at by of platelet reactions by the of an of and and the to for The platelet at for at 4 to the from the membrane The membrane in for and both by as activation and translocation by as J.G. A. Y. J. 2001; Google Scholar, A. S.A. Y. J. PubMed Scopus Google Scholar), and the of αIIbβ3 The platelets with for at to cell The with for 1 at and with of for αIIbβ3 activation was by in platelet to of the an was The platelets and by their and and platelets from each and platelets from the with in and to platelets with and with with in for 1 The with in normal with for with for 1 and of with a and with a and a was used for is and with the in and to the platelets as with or with and at The was by the of an of of and the at for at 4 the of TxA2, was a thromboxane to the at three different The are as the of multiple in the by of with for multiple whereas of different by of The with of PLC in Platelet and activates platelets via a tyrosine that in tyrosine phosphorylation of of PLCγ in turn, to the of second inositol and DAG, which intracellular Ca2+ and PKC isoforms, (14Morton L.F. Peachey A.R. Barnes M.J. Biochem. J. 1989; 258: 157-163Crossref PubMed Scopus (69) Google Scholar, 15Santoro S.A. Walsh J.J. Staatz W.D. 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J. J. Cell Biol. 1994; PubMed Google Scholar, J. S. L.F. Barnes M.J. Farndale J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, F. M. S. E. M. FEBS Lett. PubMed Scopus Google Scholar). the MEK/ERK and p38 MAPK may be downstream effectors of PKCδ involved in platelet activation and aggregation. in with the MAPK kinase for MEK/ERK and for collagen-induced but not thrombin-induced platelet aggregation and activation of αIIbβ3 The other MEK/ERK and p38 and not Furthermore, we the phosphorylation of and p38 platelet that both agonists to and However, thrombin to collagen, as with the phosphorylation of was to the phosphorylation of both and whereas the phosphorylation of p38 In and the phosphorylation of that PLC and PKCδ are involved in this signaling In the phosphorylation of it that the MEK/ERK and p38 signaling are downstream effectors of PKCδ in triggers activation of the and p38 MAPK signaling phosphorylation of and p38 by collagen and platelets with collagen or thrombin at the to to and with and of kinase was with and p38 of and and thrombin-induced phosphorylation of and or indicates that was used for and whereas was used for The by and the are as the relative of The are of at three of in PKCδ is well established that collagen induces platelet aggregation through a that is primarily mediated by the release of and M.J. J. S.A. D. Blood. PubMed Scopus Google Scholar, McNicol A. R. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, G.J. Blood. 1994; PubMed Google Scholar) and that thrombin-induced platelet aggregation to be was that we the role of and secretion in thrombin-induced PKCδ signaling. we first to the importance of in collagen-induced but not thrombin-induced platelet aggregation and activation of integrin αIIbβ3 the and the Moreover, the also collagen-induced but not thrombin-induced platelet aggregation that the secretion of to be essential for collagen-induced platelet activation and we the role of PKCδ and the other signaling involved in this process. in both and thrombin-induced by PLC, PKCδ, and p38 However, of the integrin αIIbβ3 with or the secretion of by that PKCδ, in to its and downstream PLC and the pathways, are essential for and However, the secretion of is for the activation of αIIbβ3 and the aggregation of platelets in to collagen but not to In platelets, the PKC family is an signaling mediator required for activation, secretion of granule and aggregation. In the we the role of individual PKC isoforms in platelet activation and aggregation induced by agonists such as collagen and The major are: activation of PKCδ is essential for collagen-induced but not platelet activation of αIIbβ3 and the of PKCδ, as by its phosphorylation and translocation to the platelet membrane activation by both collagen and thrombin, is positively regulated by αIIbβ3 outside-in and PKCδ triggers activation of the MEK/ERK and p38 MAPK signaling and the subsequent release of TxA2, which are essential for collagen-induced but not thrombin-induced platelet activation and aggregation. is well established that collagen the adhesion and activation of platelets at of vascular via α2β1 and GPVI de S. J.J. Blood. 1994; PubMed Google Scholar, B. F. Ruggeri Z.M. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). 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Indeed, PLC platelet αIIbβ3 activation, and translocation following platelet the of PLC in and thrombin-induced platelet activation and we the role of individual PKC isoforms in platelet function. the of PKCs in was with a PKC that and thrombin-induced platelet a role for PKCs in this process. to that collagen-induced platelet aggregation was mediated by PKCδ and not by the conventional PKCα or isoforms, whereas platelet aggregation to be multiple PKC Indeed, of thrombin-induced platelet aggregation was with the or the conventional PKC isoforms and and the novel PKCδ isoform not In it that PKCδ with the tyrosine kinase to platelet function D. Poole J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). However, in that platelets by the which is to both and GPVI In collagen, a was to platelet activation, and signaling mediated through GPVI and α2β1 that PKCδ may roles in platelet related to the signaling by specific Platelet aggregation is a process that is by the of αIIbβ3 receptors platelets, via a fibrinogen that PKCδ is required to this we its in the activation of integrin αIIbβ3 and in the translocation of to the platelet collagen-induced activation of αIIbβ3 was PKCδ, which the of platelets to in the of the other PKCδ thrombin-induced platelet aggregation αIIbβ3 These the of a αIIbβ3 required to platelet aggregation. translocation to the platelet a of granule also be used as an of platelet The PKC family to be involved in this process through its to a of platelet involved in the secretion of granule such as platelet 1 and 4 M. R.A. 1988; PubMed Scopus Google Scholar, G.L. Blood. 1999; PubMed Google Scholar, J. G.L. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). we have that PKCδ does not to be required for collagen-induced translocation and to have a in this process in thrombin signaling. These new to the of platelet also that the novel and and atypical but not the conventional and and the novel PKCs are involved in this process D. Y. Thromb. Haemostasis. PubMed Scopus Google Scholar). of PKC is an essential required for kinase the importance of PKCδ in platelet function, it was that we study the phosphorylation of PKCδ activation of platelets by collagen and have PKCδ to be by platelet such as thrombin, and (25Murugappan S. Tuluc F. Dorsam R.T. Shankar H. Kunapuli S.P. J. Biol. Chem. 2004; 279: 2360-2367Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, D. Poole J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. B. 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The importance of αIIbβ3 outside-in signaling in the of PKCδ was the translocation of the from the to the cell membrane activation aspect of PKC In platelets, PKCδ to be in the and to to the cell activation by collagen and In in which αIIbβ3 outside-in signaling was translocation of PKCδ to the cell membrane activation was the of PKCδ by αIIbβ3 be of in platelet function. established the role of PKCδ in platelet activation and we the of the MAPK signaling in platelet that agonists such as collagen and thrombin and p38 in it also that the PKC family may be involved in this process J. J. J. Cell Biol. 1994; PubMed Google Scholar, J. S. L.F. Barnes M.J. Farndale J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, F. M. S. E. M. FEBS Lett. PubMed Scopus Google Scholar). However, the role of the MAPK signaling in platelet function remains unclear. we have that collagen-induced but not thrombin-induced platelet aggregation and activation of αIIbβ3 are the MAPK signaling as by the MAPK kinase and These are in with a study that is not involved in thrombin platelet although it plays an role in collagen-induced platelet aggregation A. C.L. Israels S.J. Biochem. 1998; PubMed Scopus Google Scholar). In we that and p38 are by collagen and thrombin, and more established the for PKCδ and PLC activation in this process. Moreover, we that of αIIbβ3 the phosphorylation of and which indicates that the of PKCδ phosphorylation by αIIbβ3 outside-in signaling is not required for the activation and phosphorylation of PKCδ and downstream such as the MAPK signaling These that the αIIbβ3 outside-in signaling involved in the of PKCδ most a signaling downstream of PKCδ, other that MEK/ERK and such as and TxA2, have to be involved in collagen-induced platelet it was for to the role of in PKCδ signaling. we first to the importance of and most in collagen-induced but not in thrombin-induced platelet aggregation and activation of Furthermore, we that both and thrombin-induced release by platelets PKCδ signaling, in to its and downstream These that the signaling is involved in the and release of in platelets, which to be essential for collagen-induced but not thrombin-induced platelet function. of αIIbβ3 or the release of TxA2, we that the αIIbβ3 outside-in signaling involved in the of PKCδ does not lead to the activation of and the subsequent of In this it that proteinase-activated release by platelets was by PKCδ S. Shankar H. S. Dorsam R.T. J. Kunapuli S.P. Blood. PubMed Scopus Google Scholar). we and the by which this platelet not in but also in signaling. In this study adds new to the role of PKCδ in platelet signaling and function the binding of platelet receptors to collagen, phosphorylation of the tyrosine Syk and lead in to the activation of PKCδ, through the of PKCδ triggers activation of the MEK/ERK and p38 signaling pathways, which in the and release of of in platelets is well to and activation of platelets at of vascular In this we have that the release of is essential for collagen-induced αIIbβ3 activation and platelet aggregation. In platelet signaling, PKCδ is also required for the release of TxA2, and this platelet in a In to collagen-induced platelet signaling, this release does not to be essential for platelet function. binding of fibrinogen to αIIbβ3 triggers outside-in signaling, which in to a which in turn PKCδ However, this second of PKCδ phosphorylation does not to the for and with the

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