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• W2095395004 abstract "Primary hemostasis is initiated by the adhesion of platelets to the exposed subendothelial matrix, a process that also initiates platelet activation and stimulates multiple platelet signaling pathways 1.Ruggeri Z.M. Platelets in atherothrombosis.Nat Med. 2002; 8: 1227-34Crossref PubMed Scopus (1355) Google Scholar. One of the earliest events in platelet activation is the mobilization of stored Ca2+, which is then able to form a complex with calmodulin (CaM) and subsequently activate a large number of CaM‐binding proteins, including the myosin light chain kinase. The latter phosphorylates the myosin light chain, leading to a rapid rearrangement of the cytoskeleton that results in a shape change from discoid to fully spread cells. Another target of the Ca2+–CaM complex is Ca2+–CaM‐dependent kinase kinase β (CAMKKβ) 2.Hook S.S. Means A.R. Ca2+/CaM‐dependent kinases: from activation to function.Annu Rev Pharmacol Toxicol. 2001; 41: 471-505Crossref PubMed Scopus (414) Google Scholar, which, in turn, phosphorylates and activates AMP‐activated protein kinase (AMPK) 3.Hawley S.A. Pan D.A. Mustard K.J. Ross L. Bain J. Edelman A.M. Frenguelli B.G. Hardie D.G. Calmodulin‐dependent protein kinase kinase‐beta is an alternative upstream kinase for AMP‐activated protein kinase.Cell Metab. 2005; 2: 9-19Abstract Full Text Full Text PDF PubMed Scopus (1274) Google Scholar, 4.Hurley R.L. Anderson K.A. Franzone J.M. Kemp B.E. Means A.R. Witters L.A. The Ca2+/calmodulin‐dependent protein kinase kinases are AMP‐activated protein kinase kinases.J Biol Chem. 2005; 280: 29060-6Abstract Full Text Full Text PDF PubMed Scopus (810) Google Scholar. The latter kinase is generally referred to as a ‘metabolite‐sensing kinase’, as it is activated in many different cell types by increased intracellular concentrations of AMP (and ADP). Indeed, AMPK is activated following heat shock, vigorous exercise, hypoxia–ischemia, and starvation, and appears to be a metabolic master switch, phosphorylating key target proteins that control flux through metabolic pathways; for recent detailed reviews, see 5.Carling D. Mayer F.V. Sanders M.J. Gamblin S.J. AMP‐activated protein kinase: nature's energy sensor.Nat Chem Biol. 2011; 7: 512-18Crossref PubMed Scopus (311) Google Scholar, 6.Hardie D.G. Ross F.A. Hawley S.A. AMPK: a nutrient and energy sensor that maintains energy homeostasis.Nat Rev Mol Cell Biol. 2012; 13: 251-62Crossref PubMed Scopus (2918) Google Scholar. In addition to the allosteric activation of AMPK by binding of AMP to its γ regulatory subunit, the kinase can also be activated by the phosphorylation of the catalytic α subunit on Thr172. AMPK activity increases > 100‐fold in response to phosphorylation, and there appear to be two main AMPK kinases, i.e. liver kinase B1 (LKB1) – the activity of which provides a high basal level of phosphorylation at Thr172 that is modulated by the binding of AMP – and CaMKKβ. Relatively little information is available regarding the role played by AMPK in platelets, other than that the kinase is present, that it can be activated by insulin, and that its inhibition abrogates the insulin‐induced attenuation of platelet activation 7.Fleming I. Schulz C. Fichtlscherer B. Kemp B.E. Fisslthaler B. Busse R. AMP‐activated protein kinase (AMPK) regulates the insulin‐induced activation of the nitric oxide synthase in human platelets.Thromb Haemost. 2003; 90: 863-7Crossref PubMed Google Scholar. AMPK is a heterotrimeric serine/threonine protein kinase consisting of a catalytic subunit (α) and two regulatory subunits (β and γ) that exist as multiple isoforms and splice variants, resulting in the generation of 12 possible heterotrimeric combinations. Exactly which of these combinations predominates in platelets is unclear. In this issue of the Journal of Thrombosis and Haemostasis, Onselaer et al. 8.Onselaer M.‐.B. Oury C. Hunter R.W. Eeckhoudt S. Barile N. Lecut C. Morel N. Viollet B. Jacquet L.‐.M. Bertrand L. Sakamoto K. Vanoverscheide J.‐.L. Beauloye C. Horman S. CAMKKβ/AMPKα1 pathway regulates phosphorylation of cytoskeletal targets in thrombin‐stimulated human platelets.J Thromb Haemost. 2014; 12: 973-86Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar report that the α1 isoform is the main catalytic AMPK subunit present in human platelets, and that it is specifically activated by thrombin via the CAMKKβ‐dependent pathway to affect cytoskeleton remodeling during platelet activation. These observations apparently contradict an earlier report that the phosphorylation of AMPKα2 plays an important role in the regulation of murine platelet activation by phosphorylating the Src‐family kinase Fyn 9.Randriamboavonjy V. Isaak J. Frömel T. Viollet B. Fisslthaler B. Preissner K.T. Fleming I. AMPK α2 subunit is involved in platelet signaling, clot retraction, and thrombus stability.Blood. 2010; 116: 2134-40Crossref PubMed Scopus (37) Google Scholar. Moreover, AMPKα2 deletion attenuated the threonine phosphorylation of Fyn, as well as the subsequent tyrosine phosphorylation of its substrate, β3 integrin 9.Randriamboavonjy V. Isaak J. Frömel T. Viollet B. Fisslthaler B. Preissner K.T. Fleming I. AMPK α2 subunit is involved in platelet signaling, clot retraction, and thrombus stability.Blood. 2010; 116: 2134-40Crossref PubMed Scopus (37) Google Scholar. Is there a way to resolve these observations? A recent analysis of the platelet transcriptome in highly purified human and mouse platelets revealed that there may be species‐dependent differences in platelet AMPKα subunit isoform expression, with human platelets only containing RNA for the α1 subunit, but murine platelets containing RNA for both α subunits 10.Rowley J.W. Oler A. Tolley N.D. Hunter B. Low E.N. Nix D.A. Yost C.C. Zimmerman G.A. Weyrich A.S. Genome wide RNA‐seq analysis of human and mouse platelet transcriptomes.Blood. 2011; 118: e101-11Crossref PubMed Scopus (413) Google Scholar. However, both the α1 and α2 subunits are expressed in human megakaryocytes, which donate RNA to the daughter platelets, and the platelet RNA analyses were based on data obtained from only two subjects. Certainly, more detailed analyses of AMPK subunit expression in human platelets are warranted. There have been reports that the α subunits are preferentially activated by different kinases. Indeed, whereas CAMKKβ was reported to be the main upstream kinase for AMPKα1 3.Hawley S.A. Pan D.A. Mustard K.J. Ross L. Bain J. Edelman A.M. Frenguelli B.G. Hardie D.G. Calmodulin‐dependent protein kinase kinase‐beta is an alternative upstream kinase for AMP‐activated protein kinase.Cell Metab. 2005; 2: 9-19Abstract Full Text Full Text PDF PubMed Scopus (1274) Google Scholar, 11.Stahmann N. Woods A. Carling D. Heller R. Thrombin activates AMP‐activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin‐dependent protein kinase kinase beta.Mol Cell Biol. 2006; 26: 5933-45Crossref PubMed Scopus (186) Google Scholar, LKB1 has been linked to the phosphorylation of AMPKα2 12.Sakamoto K. McCarthy A. Smith D. Green K.A. Grahame H.D. Ashworth A. Alessi D.R. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction.EMBO J. 2005; 24: 1810-20Crossref PubMed Scopus (442) Google Scholar, 13.Sakamoto K. Zarrinpashneh E. Budas G.R. Pouleur A.C. Dutta A. Prescott A.R. Vanoverschelde J.L. Ashworth A. Jovanovic A. Alessi D.R. Bertrand L. Deficiency of LKB1 in heart prevents ischemia‐mediated activation of AMPKalpha2 but not AMPKalpha1.Am J Physiol Endocrinol Metab. 2006; 290: E780-8Crossref PubMed Scopus (178) Google Scholar. However, the latter is likely to be an oversimplification, and is not a universally observed phenomenon. Onselaer et al. 8.Onselaer M.‐.B. Oury C. Hunter R.W. Eeckhoudt S. Barile N. Lecut C. Morel N. Viollet B. Jacquet L.‐.M. Bertrand L. Sakamoto K. Vanoverscheide J.‐.L. Beauloye C. Horman S. CAMKKβ/AMPKα1 pathway regulates phosphorylation of cytoskeletal targets in thrombin‐stimulated human platelets.J Thromb Haemost. 2014; 12: 973-86Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar reported that the thrombin‐induced aggregation of human platelets was associated with the CAMKKβ‐dependent phosphorylation of several cytoskeletal proteins, including myosin light chain, cofilin, and vasodilator‐stimulated phosphoprotein (VASP). The authors also reported that platelets from AMPKα1−/− mice showed reduced thrombin‐induced aggregation and decreased cytoskeletal protein phosphorylation. However, whether AMPKα1 directly phosphorylates these proteins, or whether an intermediate kinase is involved, was not determined. Both of these are possible, as the phosphorylation of the small actin‐depolymerizing protein cofilin is indirectly regulated by AMPK 14.Lee Y.M. Lee J.O. Jung J.H. Kim J.H. Park S.H. Park J.M. Kim E.K. Suh P.G. Kim H.S. Retinoic acid leads to cytoskeletal rearrangement through AMPK‐Rac1 and stimulates glucose uptake through AMPK‐p38 MAPK in skeletal muscle cells.J Biol Chem. 2008; 283: 33969-74Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 15.Miranda L. Carpentier S. Platek A. Hussain N. Gueuning M.A. Vertommen D. Ozkan Y. Sid B. Hue L. Courtoy P.J. Rider M.H. Horman S. AMP‐activated protein kinase induces actin cytoskeleton reorganization in epithelial cells.Biochem Biophys Res Commun. 2010; 396: 656-61Crossref PubMed Scopus (56) Google Scholar. AMPK has been shown to phosphorylate VASP at one of the three well‐characterized protein kinase A (PKA)/protein kinase G phosphorylation sites 16.Blume C. Benz P.M. Walter U. Ha J. Kemp B.E. Renne T. AMP‐activated protein kinase impairs endothelial actin cytoskeleton assembly by phosphorylating vasodilator‐stimulated phosphoprotein.J Biol Chem. 2007; 282: 4601-12Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, as well as at a novel site 17.Thompson D.‐.M. Ascione M.P. Grange J. Nelson C. Hansen M.D. Phosphorylation of VASP by AMPK alters actin binding and occurs at a novel site.Biochem Biophys Res Commun. 2011; 414: 215-19Crossref PubMed Scopus (23) Google Scholar. However, the situation has recently become more complicated, because, at least in hepatocytes, VASP phosphorylation has been placed upstream of that of AMPK 18.Tateya S. Rizzo‐De Leon N. Handa P. Cheng A.M. Morgan‐Stevenson V. Ogimoto K. Kanter J.E. Bornfeldt K.E. Daum G. Clowes A.W. Chait A. Kim F. VASP increases hepatic fatty acid oxidation by activating AMPK in mice.Diabetes. 2013; 62: 1913-22Crossref PubMed Scopus (23) Google Scholar. As an index of AMPK activation in a thrombin‐regulated process in vivo, Onslaer et al. 8.Onselaer M.‐.B. Oury C. Hunter R.W. Eeckhoudt S. Barile N. Lecut C. Morel N. Viollet B. Jacquet L.‐.M. Bertrand L. Sakamoto K. Vanoverscheide J.‐.L. Beauloye C. Horman S. CAMKKβ/AMPKα1 pathway regulates phosphorylation of cytoskeletal targets in thrombin‐stimulated human platelets.J Thromb Haemost. 2014; 12: 973-86Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar compared the phosphorylation of the AMPK substrate acetyl‐CoA carboxylase (ACC) in platelets from a small number of patients during major cardiac surgery and after surgery. The concept behind this was that, during cardiopulmonary bypass surgery, patients are given heparin to prevent thrombin generation. The authors found that ACC phosphorylation was significantly higher in platelets sampled postoperatively, and they concluded that this phenomenon was related to the presence of thrombin. Clearly, it is difficult to exclude the possibility that other factors affected AMPK activation and ACC phosphorylation under these conditions. Although the work of Onslaer et al. 8.Onselaer M.‐.B. Oury C. Hunter R.W. Eeckhoudt S. Barile N. Lecut C. Morel N. Viollet B. Jacquet L.‐.M. Bertrand L. Sakamoto K. Vanoverscheide J.‐.L. Beauloye C. Horman S. CAMKKβ/AMPKα1 pathway regulates phosphorylation of cytoskeletal targets in thrombin‐stimulated human platelets.J Thromb Haemost. 2014; 12: 973-86Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar clearly highlights the potential importance of AMPK signaling in platelet function, their work also leaves several questions unanswered. For example, the authors' observation that the CAMKKβ–AMPKα1 pathway could only be activated by thrombin is more than unexpected. Indeed, given that the main stimulus for CAMKKβ activation is an increase in the intracellular Ca2+ level, other Ca2+‐elevating agonists would be expected to elicit the same response. However, the stimulation of human platelets with other platelet agonists did not activate CAMKKβ, even though they increased platelet Ca2+ levels. This led Onslaer et al. to suggest that the thrombin‐induced activation of CAMKKβ involves an alternative, as yet unidentified, Ca2+‐independent mechanism. The ability of the CAMKK inhibitor STO‐690 to inhibit platelet aggregation also contradicts an earlier study, which found that the inhibitor potentiated thrombin‐induced platelet aggregation 9.Randriamboavonjy V. Isaak J. Frömel T. Viollet B. Fisslthaler B. Preissner K.T. Fleming I. AMPK α2 subunit is involved in platelet signaling, clot retraction, and thrombus stability.Blood. 2010; 116: 2134-40Crossref PubMed Scopus (37) Google Scholar. Onslaer et al. suggest that the discrepancy between their study and the previous one could be related to the incubation time, as inhibition was only seen when STO‐690 was incubated for a very short period (2 min). It should be noted, however, that Onslaer et al. 8.Onselaer M.‐.B. Oury C. Hunter R.W. Eeckhoudt S. Barile N. Lecut C. Morel N. Viollet B. Jacquet L.‐.M. Bertrand L. Sakamoto K. Vanoverscheide J.‐.L. Beauloye C. Horman S. CAMKKβ/AMPKα1 pathway regulates phosphorylation of cytoskeletal targets in thrombin‐stimulated human platelets.J Thromb Haemost. 2014; 12: 973-86Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar used a buffer containing prostaglandin E1 during platelet isolation to prevent aggregation. This is relevant because prostaglandin E1 has marked effects on thrombin‐induced platelet aggregation and the platelet phosphoproteome, including the myosin light chain 19.Aburima A. Wraith K.S. Raslan Z. Law R. Magwenzi S. Naseem K.M. cAMP signaling regulates platelet myosin light chain (MLC) phosphorylation and shape change through targeting the RhoA–Rho kinase–MLC phosphatase signaling pathway.Blood. 2013; 122: 3533-45Crossref PubMed Scopus (84) Google Scholar and VASP 20.Nolte C. Eigenthaler M. Schanzenbacher P. Walter U. Comparison of vasodilatory prostaglandins with respect to cAMP‐mediated phosphorylation of a target substrate in intact human platelets.Biochem Pharmacol. 1991; 42: 253-62Crossref PubMed Scopus (16) Google Scholar. Thus, even though the compound was removed prior to functional analyses, it cannot be ruled out that the activation of cAMP–PKA signaling in platelets may have affected the response observed. Part of the confusion may also be related to the methods used to isolate and purify platelets, as the authors took no particular care to prevent the activation of calpain, a protease that rapidly cleaves and alters the activity of several platelet signaling molecules, including kinases 21.Kuchay S.M. Kim N. Grunz E.A. Fay W.P. Chishti A.H. Double knockouts reveal that protein tyrosine phosphatase 1B is a physiological target of calpain‐1 in platelets.Mol Cell Biol. 2007; 27: 6038-52Crossref PubMed Scopus (66) Google Scholar, 22.Srivastava K. Dash D. Changes in membrane microenvironment and signal transduction in platelets from NIDDM patients – a pilot study.Clin Chim Acta. 2002; 317: 213-20Crossref PubMed Scopus (13) Google Scholar, 23.Randriamboavonjy V. Isaak J. Elgheznawy A. Pistrosch F. Frömel T. Yin X. Badenhoop K. Heide H. Mayr M. Fleming I. Calpain inhibition stabilizes the platelet proteome and reactivity in diabetes.Blood. 2012; 120: 415-23Crossref PubMed Scopus (50) Google Scholar. Following the authors' line of argument, AMPK activation would be expected to promote platelet aggregation and thrombosis – at least that induced by thrombin. Taking this a step further would mean that strategies to increase AMPK activation would carry a potentially higher risk of thrombosis. This is particularly relevant in the case of diabetes, which is linked to altered AMPK expression and activity. Indeed, in untreated diabetic subjects, platelet reactivity is already a problem, and these patients generally receive metformin – a well‐described AMPK activator 24.Hardie D.G. AMPK: a target for drugs and natural products with effects on both diabetes and cancer.Diabetes. 2013; 62: 2164-72Crossref PubMed Scopus (328) Google Scholar. However, rather than promoting platelet hyper‐reactivity, metformin improves platelet reactivity in diabetic patients 25.Grant P.J. Beneficial effects of metformin on haemostasis and vascular function in man.Diabetes Metab. 2003; 29: 6S44-52Crossref PubMed Google Scholar, 26.Formoso G. De Filippis E.A. Michetti N. Di Fulvio P. Pandolfi A. Bucciarelli T. Ciabattoni G. Nicolucci A. Davi G. Consoli A. Decreased in vivo oxidative stress and decreased platelet activation following metformin treatment in newly diagnosed type 2 diabetic subjects.Diabetes Metab Res Rev. 2008; 24: 231-7Crossref PubMed Scopus (59) Google Scholar. Certainly, in the light of the findings outlined by Onslaer et al., additional studies on the role of AMPK signaling in platelets from such patients are warranted. The authors state that they have no conflict of interest." @default.
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• W2095395004 title "Energy and motion: AMP‐activated protein kinase α1 and its role in platelet activation" @default.
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