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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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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.


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