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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.

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HEMATOPOIESIS

Proplatelet formation is regulated by the Rho/ROCK pathway

Yunhua Chang1,2,6, Frédéric Auradé1,2,6, Frédéric Larbret2,6, Yanyan Zhang1,2,6, Jean-Pierre Le Couedic1,2,6, Laurence Momeux3, Jerôme Larghero4, Jacques Bertoglio5, Fawzia Louache1,2,6, Elisabeth Cramer3, William Vainchenker1,2,6, and Najet Debili1,2,6

1 Institut National de la Santé et de la Recherche Médicale (INSERM), Unité (U) 790, Pavillon de Recherche 1, Institut Gustave Roussy, Villejuif, France; 2 Université Paris XI, Institut Fédératif de Recherche (IFR) 54, Institut Gustave Roussy, Villejuif, France; 3 INSERM, U567, Institut Cochin, Département d'Hématologie, Paris, France; 4 Laboratoire de Therapie Cellulaire, Hôpital Saint-Louis, Paris, France; 5 INSERM, U749, Faculté de Pharmacie, Chatenay-Malabry, France; 6 Institut Gustave Roussy, Villejuif, France

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 PPF and fragmentation.


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