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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4229-4236. Prepublished online as a Blood First Edition Paper on January 23, 2007; DOI 10.1182/blood-2006-04-020024. This Article Full Text (PDF) All Versions of this Article: blood-2006-04-020024v1 109/10/4229    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chang, Y. Articles by Debili, N. Search for Related Content PubMed PubMed Citation Articles by Chang, Y. Articles by Debili, N. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 27, 2006 Accepted January 6, 2007 Proplatelet formation is regulated by the Rho/ROCK pathway Yunhua Chang, Frederic Aurade, Frederic Larbret, Yanyan Zhang, Jean-Pierre Le Couedic, Laurence Momeux, Jerome Larghero, Jacques Bertoglio, Fawzia Louache, Elisabeth Cramer, William Vainchenker, and Najet Debili* INSERM, U790, Pavillon de Recherche 1, Institute Gustave Roussy, Villejuif, France University Paris XI, IFR54, Institute Gustave Roussy, Villejuif, France Institute Gustave Roussy, Villejuif, France INSERM, U567, Institut Cochin, Departement d'Hematologie, Paris, France INSERM, EMI00-03, Laboratoire de Biologie Cellulaire Hematopoietique, Hopital Saint-Louis, Paris, France INSERM, U749, Faculte de Pharmacie, Chatenay-Malabry, France * Corresponding author; email: denali{at}igr.fr. Platelets are released by megakaryocytes (MKs) via cytoplasmic extensions called proplatelets which require profound changes in the microtubule and actin organization. Here, we provide evidence that the Rho/ROCK pathway, a well known regulator of actin cytoskeleton, acts as a negative regulator of proplatelet formation (PPF). Rho is expressed at a high level during the entire MK differentiation including human CD34+ cells. Thrombopoietin stimulates its activity, but at a higher extent in immature than in mature MKs. Overexpression of a dominant negative or a spontaneously active RhoA leads to an increase or a decrease in PPF indicating that Rho activation inhibits PPF. This inhibitory effect is mediated through the main Rho effector, Rho kinase (ROCK), the inhibition of which also increases PPF. Furthermore, inhibition of Rho or ROCK in MKs leads to a decrease in myosin light chain 2 (MLC2) phosphorylation which is required for myosin contractility. Interestingly, inhibition of the MLC kinase also decreases MLC2 phosphorylation while increasing PPF. Taken together, our results suggest that MLC2 phosphorylation is regulated by both ROCK and MLC kinase and plays an important role in platelet biogenesis by controlling proplatelet formation and fragmentation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. Gilles, D. Bluteau, S. Boukour, Y. Chang, Y. Zhang, T. Robert, P. Dessen, N. Debili, O. A. Bernard, W. Vainchenker, et al. MAL/SRF complex is involved in platelet formation and megakaryocyte migration by regulating MYL9 (MLC2) and MMP9 Blood, November 5, 2009; 114(19): 4221 - 4232. [Abstract] [Full Text] [PDF] A. E. Geddis The regulation of proplatelet production Haematologica, June 1, 2009; 94(6): 756 - 759. [Full Text] [PDF] A. Eckly, C. Strassel, M. Freund, J.-P. Cazenave, F. Lanza, C. Gachet, and C. Leon Abnormal megakaryocyte morphology and proplatelet formation in mice with megakaryocyte-restricted MYH9 inactivation Blood, April 2, 2009; 113(14): 3182 - 3189. [Abstract] [Full Text] [PDF] L. Lordier, A. Jalil, F. Aurade, F. Larbret, J. Larghero, N. Debili, W. Vainchenker, and Y. Chang Megakaryocyte endomitosis is a failure of late cytokinesis related to defects in the contractile ring and Rho/Rock signaling Blood, October 15, 2008; 112(8): 3164 - 3174. [Abstract] [Full Text] [PDF] S. Kunishima, M. Hamaguchi, and H. Saito Differential expression of wild-type and mutant NMMHC-IIA polypeptides in blood cells suggests cell-specific regulation mechanisms in MYH9 disorders Blood, March 15, 2008; 111(6): 3015 - 3023. [Abstract] [Full Text] [PDF] A. T. Nurden and P. Nurden Inherited thrombocytopenias Haematologica, September 1, 2007; 92(9): 1158 - 1164. [Full Text] [PDF] A. T. Nurden ROCK and Rho(ll) in bone marrow Blood, July 1, 2007; 110(1): 5 - 6. [Full Text] [PDF] Z. Chen, O. Naveiras, A. Balduini, A. Mammoto, M. A. Conti, R. S. Adelstein, D. Ingber, G. Q. Daley, and R. A. Shivdasani The May-Hegglin anomaly gene MYH9 is a negative regulator of platelet biogenesis modulated by the Rho-ROCK pathway Blood, July 1, 2007; 110(1): 171 - 179. [Abstract] [Full Text] [PDF]

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