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• W2108349218 endingPage "2016" @default.
• W2108349218 startingPage "2007" @default.
• W2108349218 abstract "SummaryThe mitogen‐activated protein (MAP) kinases ERK2, p38 and JNK1 are present in platelets and are activated by various stimuli, such as thrombin, collagen, von Willebrand factor (VWF) and ADP. Until recently, MAP kinases were only studied in the conventional model of agonist‐induced platelet aggregation mediated by fibrinogen and integrin αIIbβ3. However, this approach is likely to be too limited for a physiological understanding of platelet MAP kinases and their signaling pathways. Recent studies with varying blood‐flow conditions and animal models of thrombosis have provided deeper insight into the role of MAP kinases in thrombus formation and the dependence of these kinases on shear conditions. This review summarizes and discusses the physiological functions of these kinases in hemostasis and thrombosis as revealed by various technical approaches. The mitogen‐activated protein (MAP) kinases ERK2, p38 and JNK1 are present in platelets and are activated by various stimuli, such as thrombin, collagen, von Willebrand factor (VWF) and ADP. Until recently, MAP kinases were only studied in the conventional model of agonist‐induced platelet aggregation mediated by fibrinogen and integrin αIIbβ3. However, this approach is likely to be too limited for a physiological understanding of platelet MAP kinases and their signaling pathways. Recent studies with varying blood‐flow conditions and animal models of thrombosis have provided deeper insight into the role of MAP kinases in thrombus formation and the dependence of these kinases on shear conditions. This review summarizes and discusses the physiological functions of these kinases in hemostasis and thrombosis as revealed by various technical approaches. Mitogen‐activated protein (MAP) kinases control major cellular responses in eukaryotic organisms and contribute to proliferation, migration, differentiation and apoptosis. In humans, at least six distinct MAP kinase subfamilies have been defined on the basis of sequence similarity: extracellular signal‐regulated kinases 1 and 2 (ERK1/2); c‐Jun amino‐terminal kinases (JNK1/2/3); p38 MAP kinase (p38α/β/γ/δ); ERK5, which is also known as big MAP kinase; ERK3s (ERK3, p97 MAPK, ERK4); and ERK7s (ERK7, ERK8) [1Pearson G. Robinson F. Beers Gibson T. Xu B.E. Karandikar M. Berman K. Cobb M.H. Mitogen‐activated protein (MAP) kinase pathways: regulation and physiological functions.Endocr Rev. 2001; 22: 153-83Crossref PubMed Scopus (3538) Google Scholar]. ERK1/2, JNKs and p38 MAP kinases have been studied in the most detail. Growth factors preferentially activate ERK1/2, whereas JNK and p38 kinases are more responsive to stress stimuli. Each subfamily can be activated by a different protein cascade involving the sequential activation of a specific MAP kinase kinase kinase (MAPKKK). In a typical signaling pathway, Ras or Rho family small GTPases stimulate MAP kinase kinase kinase kinase (MAPKKKK), which in turn activates the serine/threonine MAPKKK, leading to phosphorylation and activation of the tyrosine/threonine MAP kinase kinase (MAPKK). The MAP kinase is then activated through the phosphorylation of threonine (Thr) and tyrosine (Tyr) residues separated by one amino acid (Thr‐X‐Tyr). Upon activation, MAP kinases phosphorylate the Ser and Thr residues of target substrates, such as key cytoplasmic and nuclear proteins, including phospholipases, cytoskeletal proteins, transcription factors and protein kinases known as MAPK‐activated protein kinases (MKs). Recently, MAP kinase pathways have become the focus of growing research into the multiple platelet signaling pathways. There is now firm evidence that MAP kinases – ERK1/2, p38 and JNK1 – are present and active in platelets [2Bugaud F. Nadal‐Wollbold F. Levy‐Toledano S. Rosa J.P. Bryckaert M. Regulation of c‐jun‐NH2 terminal kinase and extracellular‐signal regulated kinase in human platelets.Blood. 1999; 94: 3800-5Crossref PubMed Google Scholar, 3Kramer R.M. Roberts E.F. Strifler B.A. Johnstone E.M. Thrombin induces activation of p38 MAP kinase in human platelets.J Biol Chem. 1995; 270: 27395-8Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 4Papkoff J. Chen R.H. Blenis J. Forsman J. p42mitogen‐activated protein kinase and p90 ribosomal S6 kinase are selectively phosphorylated and activated during thrombin‐induced platelet activation and aggregation.Mol Cell Biol. 1994; 14: 463-72Crossref PubMed Google Scholar]. This review summarizes current knowledge of the properties and regulation of MAP kinases in platelets and discusses the physiological functions of these kinases in hemostasis and thrombosis. ERK1/2 activation In 1994, two MAP kinases – ERK1/2 – were identified in platelets [4Papkoff J. Chen R.H. Blenis J. Forsman J. p42mitogen‐activated protein kinase and p90 ribosomal S6 kinase are selectively phosphorylated and activated during thrombin‐induced platelet activation and aggregation.Mol Cell Biol. 1994; 14: 463-72Crossref PubMed Google Scholar]. ERK2 is phosphorylated and activated by thrombin [5Nadal‐Wollbold F. Pawlowski M. Levy‐Toledano S. Berrou E. Rosa J.P. Bryckaert M. Platelet ERK2 activation by thrombin is dependent on calcium and conventional protein kinases C but not Raf‐1 or B‐Raf.FEBS Lett. 2002; 531: 475-82Crossref PubMed Scopus (65) Google Scholar] and other agonists, including collagen [6Roger S. Pawlowski M. Habib A. Jandrot‐Perrus M. Rosa J.P. Bryckaert M. Costimulation of the Gi‐coupled ADP receptor and the Gq‐coupled TXA2 receptor is required for ERK2 activation in collagen‐induced platelet aggregation.FEBS Lett. 2004; 556: 227-35Crossref PubMed Scopus (69) Google Scholar, 7Oury C. Toth‐Zsamboki E. Vermylen J. Hoylaerts M.F. P2X(1)‐mediated activation of extracellular signal‐regulated kinase 2 contributes to platelet secretion and aggregation induced by collagen.Blood. 2002; 100: 2499-505Crossref PubMed Scopus (92) Google Scholar], von Willebrand factor (VWF) [8Li Z. Xi X. Du X. A mitogen‐activated protein kinase‐dependent signaling pathway in the activation of platelet integrin alpha IIbbeta3.J Biol Chem. 2001; 276: 42226-32Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 9Garcia A. Quinton T.M. Dorsam R.T. Kunapuli S.P. Src family kinase‐mediated and Erk‐mediated thromboxane A2 generation are essential for VWF/GPIb‐induced fibrinogen receptor activation in human platelets.Blood. 2005; 106: 3410-4Crossref PubMed Scopus (97) Google Scholar] and ADP [10Garcia A. Shankar H. Murugappan S. Kim S. Kunapuli S.P. Regulation and functional consequences of ADP receptor‐mediated ERK2 activation in platelets.Biochem J. 2007; 404: 299-308Crossref PubMed Scopus (71) Google Scholar]. However, little or no ERK1 phosphorylation occurs in response to induction by strong agonists, such as thrombin or collagen, possibly as a result of the smaller amounts of ERK1 than ERK2 in platelets [10Garcia A. Shankar H. Murugappan S. Kim S. Kunapuli S.P. Regulation and functional consequences of ADP receptor‐mediated ERK2 activation in platelets.Biochem J. 2007; 404: 299-308Crossref PubMed Scopus (71) Google Scholar, 11Borsch‐Haubold A.G. Kramer R.M. Watson S.P. Cytosolic phospholipase A2 is phosphorylated in collagen‐ and thrombin‐stimulated human platelets independent of protein kinase C and mitogen‐activated protein kinase.J Biol Chem. 1995; 270: 25885-92Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar]. Little is known about the molecular basis of the signaling pathway involved in ERK2 activation. ERK2 activation by high doses of thrombin, is independent of the activities of both serine/threonine kinases Raf‐1 and B‐Raf [5Nadal‐Wollbold F. Pawlowski M. Levy‐Toledano S. Berrou E. Rosa J.P. Bryckaert M. Platelet ERK2 activation by thrombin is dependent on calcium and conventional protein kinases C but not Raf‐1 or B‐Raf.FEBS Lett. 2002; 531: 475-82Crossref PubMed Scopus (65) Google Scholar], despite the presence of both in platelets, but is dependent on protein kinase C (PKC) [5Nadal‐Wollbold F. Pawlowski M. Levy‐Toledano S. Berrou E. Rosa J.P. Bryckaert M. Platelet ERK2 activation by thrombin is dependent on calcium and conventional protein kinases C but not Raf‐1 or B‐Raf.FEBS Lett. 2002; 531: 475-82Crossref PubMed Scopus (65) Google Scholar] and, particularly, PKC delta [12Yacoub D. Theoret J.F. Villeneuve L. Abou‐Saleh H. Mourad W. Allen B.G. Merhi Y. Essential role of protein kinase C delta in platelet signaling, alpha IIb beta 3 activation, and thromboxane A2 release.J Biol Chem. 2006; 281: 30024-35Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar] as well as on the threonine/tyrosine kinase, MEK1/2 [5Nadal‐Wollbold F. Pawlowski M. Levy‐Toledano S. Berrou E. Rosa J.P. Bryckaert M. Platelet ERK2 activation by thrombin is dependent on calcium and conventional protein kinases C but not Raf‐1 or B‐Raf.FEBS Lett. 2002; 531: 475-82Crossref PubMed Scopus (65) Google Scholar] (Fig. 1). This observation does not exclude the possibility of Raf‐dependent activation of the ERK pathway being induced by other agonists in platelets. The tyrosine kinase Src, which is activated by thrombin, may also be involved in ERK2 activation in platelets [13Shankar H. Garcia A. Prabhakar J. Kim S. Kunapuli S.P. P2Y12 receptor‐mediated potentiation of thrombin‐induced thromboxane A2 generation in platelets occurs through regulation of Erk1/2 activation.J Thromb Haemost. 2006; 4: 638-47Crossref PubMed Scopus (99) Google Scholar] (Fig. 1). The link between PKC/MEK1/2/ERK and Src remains to be established. The activation of ERK2 by collagen, the most thrombogenic component of the subendothelial layer, has also been assessed. At low doses of collagen, the prior release of ATP triggers P2X1‐mediated Ca2+ influx, activating ERK2 via the P2X1/PKC/MEK1/2 pathway (Fig. 1), enhancing myosin light chain kinase (MLCK) phosphorylation (Fig. 2A) [7Oury C. Toth‐Zsamboki E. Vermylen J. Hoylaerts M.F. P2X(1)‐mediated activation of extracellular signal‐regulated kinase 2 contributes to platelet secretion and aggregation induced by collagen.Blood. 2002; 100: 2499-505Crossref PubMed Scopus (92) Google Scholar, 14Toth‐Zsamboki E. Oury C. Cornelissen H. De Vos R. Vermylen J. Hoylaerts M.F. P2X1‐mediated ERK2 activation amplifies the collagen‐induced platelet secretion by enhancing myosin light chain kinase activation.J Biol Chem. 2003; 278: 46661-7Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar]. At higher doses of collagen, ERK2 activation becomes dependent on costimulation of the P2Y12 ADP receptor (P2Y12‐R) and the Gq‐coupled TXA2 receptor [6Roger S. Pawlowski M. Habib A. Jandrot‐Perrus M. Rosa J.P. Bryckaert M. Costimulation of the Gi‐coupled ADP receptor and the Gq‐coupled TXA2 receptor is required for ERK2 activation in collagen‐induced platelet aggregation.FEBS Lett. 2004; 556: 227-35Crossref PubMed Scopus (69) Google Scholar] or directly dependent on collagen receptors (GPVI and α2β1) (personal data) (Fig. 1). These findings are consistent with the hypothesis that collagen‐induced platelet activation leads to concomitant ERK signaling through both the ATP‐gated P2X1 ion channel and the P2Y12‐ and collagen receptors. In response to ADP alone, ERK2 activation is observed in specific experimental conditions. ERK2 activation was not detected in the presence of Ca2+ in the extracellular medium [6Roger S. Pawlowski M. Habib A. Jandrot‐Perrus M. Rosa J.P. Bryckaert M. Costimulation of the Gi‐coupled ADP receptor and the Gq‐coupled TXA2 receptor is required for ERK2 activation in collagen‐induced platelet aggregation.FEBS Lett. 2004; 556: 227-35Crossref PubMed Scopus (69) Google Scholar, 15Falker K. Lange D. Presek P. ADP secretion and subsequent P2Y12 receptor signalling play a crucial role in thrombin‐induced ERK2 activation in human platelets.Thromb Haemost. 2004; 92: 114-23Crossref PubMed Google Scholar]. By contrast, in the absence of Ca2+, ERK2 is activated through Src kinase pathways, via concomitant pathways triggered through the P2Y1‐ and P2Y12‐Rs (Fig. 1) [10Garcia A. Shankar H. Murugappan S. Kim S. Kunapuli S.P. Regulation and functional consequences of ADP receptor‐mediated ERK2 activation in platelets.Biochem J. 2007; 404: 299-308Crossref PubMed Scopus (71) Google Scholar]. In this study, the authors reported that extracellular Ca2+ negatively regulated ERK2 activation and, consequently, TXA2 generation [10Garcia A. Shankar H. Murugappan S. Kim S. Kunapuli S.P. Regulation and functional consequences of ADP receptor‐mediated ERK2 activation in platelets.Biochem J. 2007; 404: 299-308Crossref PubMed Scopus (71) Google Scholar], consistent with the absence of ERK2 activation previously observed in the presence of Ca2+ (Fig. 2A) [6Roger S. Pawlowski M. Habib A. Jandrot‐Perrus M. Rosa J.P. Bryckaert M. Costimulation of the Gi‐coupled ADP receptor and the Gq‐coupled TXA2 receptor is required for ERK2 activation in collagen‐induced platelet aggregation.FEBS Lett. 2004; 556: 227-35Crossref PubMed Scopus (69) Google Scholar, 15Falker K. Lange D. Presek P. ADP secretion and subsequent P2Y12 receptor signalling play a crucial role in thrombin‐induced ERK2 activation in human platelets.Thromb Haemost. 2004; 92: 114-23Crossref PubMed Google Scholar]. Finally, the role of low doses of agonists, such as thrombin or VWF, sufficient for binding to glycoprotein (GP)Ib [8Li Z. Xi X. Du X. A mitogen‐activated protein kinase‐dependent signaling pathway in the activation of platelet integrin alpha IIbbeta3.J Biol Chem. 2001; 276: 42226-32Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 16Marshall S.J. Senis Y.A. Auger J.M. Feil R. Hofmann F. Salmon G. Peterson J.T. Burslem F. Watson S.P. GPIb‐dependent platelet activation is dependent on Src kinases but not MAP kinase or cGMP‐dependent kinase.Blood. 2004; 103: 2601-9Crossref PubMed Scopus (76) Google Scholar, 17Li Z. Zhang G. Feil R. Han J. Du X. Sequential activation of p38 and ERK pathways by cGMP‐dependent protein kinase leading to activation of the platelet integrin alphaIIb beta3.Blood. 2006; 107: 965-72Crossref PubMed Scopus (133) Google Scholar], remains a matter of debate. Marshall et al. reported no ERK2 activation in response to the interaction of VWF with GPIb [16Marshall S.J. Senis Y.A. Auger J.M. Feil R. Hofmann F. Salmon G. Peterson J.T. Burslem F. Watson S.P. GPIb‐dependent platelet activation is dependent on Src kinases but not MAP kinase or cGMP‐dependent kinase.Blood. 2004; 103: 2601-9Crossref PubMed Scopus (76) Google Scholar], whereas other studies have reported that GPIb stimulation activates ERK2 pathways via the cGMP‐dependent protein kinase (PKG) and p38 [8Li Z. Xi X. Du X. A mitogen‐activated protein kinase‐dependent signaling pathway in the activation of platelet integrin alpha IIbbeta3.J Biol Chem. 2001; 276: 42226-32Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 17Li Z. Zhang G. Feil R. Han J. Du X. Sequential activation of p38 and ERK pathways by cGMP‐dependent protein kinase leading to activation of the platelet integrin alphaIIb beta3.Blood. 2006; 107: 965-72Crossref PubMed Scopus (133) Google Scholar] or via Src/PLCγ2/ERK (Fig. 1) [9Garcia A. Quinton T.M. Dorsam R.T. Kunapuli S.P. Src family kinase‐mediated and Erk‐mediated thromboxane A2 generation are essential for VWF/GPIb‐induced fibrinogen receptor activation in human platelets.Blood. 2005; 106: 3410-4Crossref PubMed Scopus (97) Google Scholar]. These divergent findings may reflect differences in the conditions of platelet activation by VWF/GPIb or thrombin/GPIb, in the presence or absence of ADP and TXA2. Indeed, VWF‐GPIb interaction induces a weak signal sufficient to initiate integrin αIIbβ3 activation, but the release of ADP and TXA2 is required for subsequent full platelet activation. Regulation of ERK2 activation by the integrin αIIbβ3 Alike integrins in proliferative cells [18Chen Q. Kinch M.S. Lin T.H. Burridge K. Juliano R.L. Integrin‐mediated cell adhesion activates mitogen‐activated protein kinases.J Biol Chem. 1994; 269: 26602-5Abstract Full Text PDF PubMed Google Scholar], αIIbβ3 would thus be expected to engage MAP kinases in platelets. Unexpectedly, αIIbβ3 engagement downregulates ERK2 activation in platelets by hindering both ERK2 phosphorylation and activity [19Nadal F. Levy‐Toledano S. Grelac F. Caen J.P. Rosa J.P. Bryckaert M. Negative regulation of mitogen‐activated protein kinase activation by integrin alphaIIbbeta3 in platelets.J Biol Chem. 1997; 272: 22381-4Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar]. αIIbβ3 engagement initiates selective dephosphorylation of the Thr residue of ERK2 [20Pawlowski M. Ragab A. Rosa J.P. Bryckaert M. Selective dephosphorylation of the threonine(183) residue of ERK2 upon (alpha)llb(beta)3 engagement in platelets.FEBS Lett. 2002; 521: 145-51Crossref PubMed Scopus (12) Google Scholar], presumably through the activity of a serine/threonine phosphatase, such as PP1 and/or PP2A. Vijayan et al. reported the association of the PP1C phosphatase with αIIbβ3 and showed its dissociation and concomitant activation during platelet aggregation [21Vijayan K.V. Liu Y. Li T.T. Bray P.F. Protein phosphatase 1 associates with the integrin alphaIIb subunit and regulates signaling.J Biol Chem. 2004; 279: 33039-42Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar]. This group subsequently confirmed that αIIbβ3 engagement leads to serine/threonine phosphatase activation during platelet aggregation, as revealed by the dephosphorylation of ERK2 and myosin light chain (MLC) [22Vijayan K.V. Liu Y. Sun W. Ito M. Bray P.F. The Pro33 isoform of integrin beta3 enhances outside‐in signaling in human platelets by regulating the activation of serine/threonine phosphatases.J Biol Chem. 2005; 280: 21756-62Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar]. These observations are consistent with the hypothesis that MAP kinases are downregulated by αIIbβ3 engagement, but further studies are required to determine the significance of this phenomenon. These studies were carried out in conditions of aggregation in the presence of Ca2+, suggesting that the inhibitory effect of external Ca2+ on ERK2 in platelet aggregation [10Garcia A. Shankar H. Murugappan S. Kim S. Kunapuli S.P. Regulation and functional consequences of ADP receptor‐mediated ERK2 activation in platelets.Biochem J. 2007; 404: 299-308Crossref PubMed Scopus (71) Google Scholar] may be as a result of the engagement of αIIbβ3 and PP2A. ERK2 in hemostasis and thrombosis Pharmacological approach and platelet aggregation: The role of ERK1/2 was first investigated using two inhibitors of MEK1/2 activity (Table 1). Caution should be exercised in evaluating data obtained with PD98059 which inhibits cyclooxygenase‐1 (COX‐1) directly, and thereby TXA2 formation [23Borsch‐Haubold A.G. Pasquet S. Watson S.P. Direct inhibition of cyclooxygenase‐1 and ‐2 by the kinase inhibitors SB 203580 and PD 98059. SB 203580 also inhibits thromboxane synthase.J Biol Chem. 1998; 273: 28766-72Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar]. However, U0126 is specific for MEK1/2 and has no effect on other kinases (Table 1).Table 1Inhibitors of MEK1/2, p38 and JNK used in platelet studies Open table in a new tab The role of ERK2 in collagen‐induced platelet aggregation is well established. In experiments with U0126, ERK2 activation has been shown to be involved in the platelet aggregation induced by low doses of type I collagen, requiring the prior release of ATP. ATP, which triggers P2X1‐mediated Ca2+ influx, activates ERK2, increasing MLCK phosphorylation (Fig. 2A) [7Oury C. Toth‐Zsamboki E. Vermylen J. Hoylaerts M.F. P2X(1)‐mediated activation of extracellular signal‐regulated kinase 2 contributes to platelet secretion and aggregation induced by collagen.Blood. 2002; 100: 2499-505Crossref PubMed Scopus (92) Google Scholar, 14Toth‐Zsamboki E. Oury C. Cornelissen H. De Vos R. Vermylen J. Hoylaerts M.F. P2X1‐mediated ERK2 activation amplifies the collagen‐induced platelet secretion by enhancing myosin light chain kinase activation.J Biol Chem. 2003; 278: 46661-7Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar]. At higher doses of collagen and with a peptide inhibitor of MEK1/2 (Table 1), ERK2 activation is essential for collagen‐induced platelet aggregation (Fig. 2A) dependent on costimulation of the P2Y12‐R of ADP and the Gq‐coupled TXA2 receptor [6Roger S. Pawlowski M. Habib A. Jandrot‐Perrus M. Rosa J.P. Bryckaert M. Costimulation of the Gi‐coupled ADP receptor and the Gq‐coupled TXA2 receptor is required for ERK2 activation in collagen‐induced platelet aggregation.FEBS Lett. 2004; 556: 227-35Crossref PubMed Scopus (69) Google Scholar]. These findings are consistent with collagen‐induced platelet activation leading to concomitant ERK signaling through both the ATP‐gated P2X1 ion channel and the P2Y12‐R of ADP, enhancing platelet aggregation and secretion. However, the ERK2 pathway is bypassed at high doses of collagen when platelet aggregation is independent of ADP and TXA2 [6Roger S. Pawlowski M. Habib A. Jandrot‐Perrus M. Rosa J.P. Bryckaert M. Costimulation of the Gi‐coupled ADP receptor and the Gq‐coupled TXA2 receptor is required for ERK2 activation in collagen‐induced platelet aggregation.FEBS Lett. 2004; 556: 227-35Crossref PubMed Scopus (69) Google Scholar, 24Borsch‐Haubold A.G. Kramer R.M. Watson S.P. Inhibition of mitogen‐activated protein kinase kinase does not impair primary activation of human platelets.Biochem J. 1996; 318: 207-12Crossref PubMed Scopus (71) Google Scholar]. Local production of a high concentration of thrombin is directly involved in amplifying thrombus formation. Under these conditions, platelet activation occurs independently of ERK2 [12Yacoub D. Theoret J.F. Villeneuve L. Abou‐Saleh H. Mourad W. Allen B.G. Merhi Y. Essential role of protein kinase C delta in platelet signaling, alpha IIb beta 3 activation, and thromboxane A2 release.J Biol Chem. 2006; 281: 30024-35Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 13Shankar H. Garcia A. Prabhakar J. Kim S. Kunapuli S.P. P2Y12 receptor‐mediated potentiation of thrombin‐induced thromboxane A2 generation in platelets occurs through regulation of Erk1/2 activation.J Thromb Haemost. 2006; 4: 638-47Crossref PubMed Scopus (99) Google Scholar, 24Borsch‐Haubold A.G. Kramer R.M. Watson S.P. Inhibition of mitogen‐activated protein kinase kinase does not impair primary activation of human platelets.Biochem J. 1996; 318: 207-12Crossref PubMed Scopus (71) Google Scholar]. Borsch‐Haubold et al. were the first to report that PD98059 in the presence of COX‐1 inhibitors [24Borsch‐Haubold A.G. Kramer R.M. Watson S.P. Inhibition of mitogen‐activated protein kinase kinase does not impair primary activation of human platelets.Biochem J. 1996; 318: 207-12Crossref PubMed Scopus (71) Google Scholar] does not block the aggregation, secretion and complete phosphorylation of cytosolic phospholipase A2 (cPLA2) after activation by thrombin. The lack of ERK2 involvement in platelet aggregation induced by thrombin was confirmed in studies with U0126 [25Davies S.P. Reddy H. Caivano M. Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors.Biochem J. 2000; 351: 95-105Crossref PubMed Scopus (0) Google Scholar], but impairing PLA2 phosphorylation at Ser‐505 and TXA2 generation [13Shankar H. Garcia A. Prabhakar J. Kim S. Kunapuli S.P. P2Y12 receptor‐mediated potentiation of thrombin‐induced thromboxane A2 generation in platelets occurs through regulation of Erk1/2 activation.J Thromb Haemost. 2006; 4: 638-47Crossref PubMed Scopus (99) Google Scholar] (Fig. 2A). Thus, ERK2 required for PLA2 phosphorylation does not appear to be directly involved in platelet aggregation at high doses of agonists, such as thrombin or collagen [11Borsch‐Haubold A.G. Kramer R.M. Watson S.P. Cytosolic phospholipase A2 is phosphorylated in collagen‐ and thrombin‐stimulated human platelets independent of protein kinase C and mitogen‐activated protein kinase.J Biol Chem. 1995; 270: 25885-92Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 12Yacoub D. Theoret J.F. Villeneuve L. Abou‐Saleh H. Mourad W. Allen B.G. Merhi Y. Essential role of protein kinase C delta in platelet signaling, alpha IIb beta 3 activation, and thromboxane A2 release.J Biol Chem. 2006; 281: 30024-35Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar]. The role of the ERK2 pathway in platelet aggregation dependent on GPIb‐VWF interaction has also been investigated. It is difficult to compare the signaling pathways in blood flow and platelet aggregation conditions. Nevertheless, the activation and the role of ERK2 in the presence of small amounts of VWF with ristocetin – sufficient for binding to GPIb – have been studied, using various inhibitors of MEK1/2 in the presence or absence of COX‐1 blockers. Conflicting and confusing conclusions have been drawn from these studies (Fig. 2A) [8Li Z. Xi X. Du X. A mitogen‐activated protein kinase‐dependent signaling pathway in the activation of platelet integrin alpha IIbbeta3.J Biol Chem. 2001; 276: 42226-32Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 16Marshall S.J. Senis Y.A. Auger J.M. Feil R. Hofmann F. Salmon G. Peterson J.T. Burslem F. Watson S.P. GPIb‐dependent platelet activation is dependent on Src kinases but not MAP kinase or cGMP‐dependent kinase.Blood. 2004; 103: 2601-9Crossref PubMed Scopus (76) Google Scholar, 17Li Z. Zhang G. Feil R. Han J. Du X. Sequential activation of p38 and ERK pathways by cGMP‐dependent protein kinase leading to activation of the platelet integrin alphaIIb beta3.Blood. 2006; 107: 965-72Crossref PubMed Scopus (133) Google Scholar]. Several studies have reported that ERK2 activation by GPIb stimulation leads to integrin αIIbβ3 activation [8Li Z. Xi X. Du X. A mitogen‐activated protein kinase‐dependent signaling pathway in the activation of platelet integrin alpha IIbbeta3.J Biol Chem. 2001; 276: 42226-32Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 9Garcia A. Quinton T.M. Dorsam R.T. Kunapuli S.P. Src family kinase‐mediated and Erk‐mediated thromboxane A2 generation are essential for VWF/GPIb‐induced fibrinogen receptor activation in human platelets.Blood. 2005; 106: 3410-4Crossref PubMed Scopus (97) Google Scholar, 17Li Z. Zhang G. Feil R. Han J. Du X. Sequential activation of p38 and ERK pathways by cGMP‐dependent protein kinase leading to activation of the platelet integrin alphaIIb beta3.Blood. 2006; 107: 965-72Crossref PubMed Scopus (133) Google Scholar] and involves a PKG‐p38 pathway [8Li Z. Xi X. Du X. A mitogen‐activated protein kinase‐dependent signaling pathway in the activation of platelet integrin alpha IIbbeta3.J Biol Chem. 2001; 276: 42226-32Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 17Li Z. Zhang G. Feil R. Han J. Du X. Sequential activation of p38 and ERK pathways by cGMP‐dependent protein kinase leading to activation of the platelet integrin alphaIIb beta3.Blood. 2006; 107: 965-72Crossref PubMed Scopus (133) Google Scholar] or a Src/PLCγ2/ERK pathway (Fig. 1) [9Garcia A. Quinton T.M. Dorsam R.T. Kunapuli S.P. Src family kinase‐mediated and Erk‐mediated thromboxane A2 generation are essential for VWF/GPIb‐induced fibrinogen receptor activation in human platelets.Blood. 2005; 106: 3410-4Crossref PubMed Scopus (97) Google Scholar]. In these conditions, ERK2 within the Src/PLCγ2/ERK pathway acts indirectly on integrin αIIbβ3 activation, through TXA2 generation [9Garcia A. Quinton T.M. Dorsam R.T. Kunapuli S.P. Src family kinase‐mediated and Erk‐mediated thromboxane A2 generation are essential for VWF/GPIb‐induced fibrinogen receptor activation in human platelets.Blood. 2005; 106: 3410-4Crossref PubMed Scopus (97) Google Scholar]. In contrast, Marshall et al. were unable to confirm the activation of ERK2 in platelet aggregation induced by VWF and ristocetin and the blocking of platelet aggregation in the presence of ERK2 inhibitors [16Marshall S.J. Senis Y.A. Auger J.M. Feil R. Hofmann F. Salmon G. Peterson J.T. Burslem F. Watson S.P. GPIb‐dependent platelet activation is dependent on Src kinases but not MAP kinase or cGMP‐dependent kinase.Blood. 2004; 103: 2601-9Crossref PubMed Scopus (76) Google Scholar]. There may be explanations for these discrepancies. The VWF‐GPIb interaction induces a weak signal, sufficient to initiate integrin αIIbβ3 activation, but requires the subsequent release of ADP and TXA2 to reach full platelet activation. It is possible that these divergent findings may originate from differences in the experimental conditions used for platelet preparation and activation, affecting ADP and TXA2. ERK2 in static adhesion and in blood flow In blood flow conditions, various adhesive ligands and receptors are involved in platelet adhesion and thrombus formation [26Varga‐Szabo D. Pleines I. Nieswandt B. Cell adhesion mechanisms in platelets.Arterioscler Thromb Vasc Biol. 2008; 28: 403-12Crossref PubMed Scopus (452) Google Scholar]. At lower shear rates (<500 s−1), platelet adhesion and aggregation are mediated by collagen receptors (GPVI and α2β1) and fibrinogen binding to αIIbβ3, respectively. Between 1000 s−1 and 10 000 s−1, the initial formation of aggregates of platelets is dependent on VWF, GPIb and αIIbβ3, whereas the formation of stable aggregates is dependent on VWF, fibrinogen and fibronectin [27Jackson S.P. The growing complexity of platelet aggregation.Blood. 2007; 109: 5087-95Crossref PubMed Scopus (492) Google Scholar]. At higher shear rates (>10 000 s−1), platelet aggregation, which precedes platelet adhesion, is independent of platelet activation and is mediated by interaction between VWF and GPIb [27Jackson S.P." @default.
• W2108349218 created "2016-06-24" @default.
• W2108349218 creator A5045322922 @default.
• W2108349218 creator A5053217321 @default.
• W2108349218 creator A5053873308 @default.
• W2108349218 creator A5073545087 @default.
• W2108349218 date "2008-12-01" @default.
• W2108349218 modified "2023-10-16" @default.
• W2108349218 title "Mitogen‐activated protein kinases in hemostasis and thrombosis" @default.
• W2108349218 cites W1505462836 @default.
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• W2108349218 cites W1592287085 @default.
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