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Blood, 15 January 2008, Vol. 111, No. 2, pp. 596-604.
Prepublished online as a Blood First Edition Paper on October 9, 2007; DOI 10.1182/blood-2007-05-089680.
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Submitted May 9, 2007
Accepted September 26, 2007
Roles of focal adhesion kinase (FAK) in megakaryopoiesis and platelet function: Studies using a megakaryocyte lineage-specific FAK knockout
Ian S Hitchcock, Norma E Fox, Nicolas Prevost, Katherine Sear, Sanford J Shattil, and Kenneth Kaushansky*
Department of Medicine, University of California San Diego, La Jolla, CA, United States
* Corresponding author; email: kkaushansky{at}ucsd.edu.
Focal adhesion kinase (FAK) plays a key role in mediating signaling downstream of integrins and growth factor receptors. In this study we determined the roles of FAK in vivo by generating a megakaryocyte lineage-specific FAK-null mouse (Pf4-Cre/FAK-floxed). Megakaryocyte and platelet FAK expression was ablated in Pf4-Cre/FAK-floxed mice without affecting expression of the FAK homologue PYK2, although PYK2 phosphorylation was increased in FAK-/- megakaryocytes in response to fibrinogen. Megakaryopoiesis is greatly enhanced in Pf4-Cre/FAK-floxed mice, with significant increases in megakaryocytic progenitors (CFU-MK) and mature megakaryocyte numbers, increased megakaryocyte ploidy and moderate increases in resting platelet number and platelet recovery following a thrombocytopenic stress. Thrombopoietin (TPO)-mediated activation of Lyn kinase, a negative regulator of megakaryopoiesis, is severely attenuated in FAK-null megakaryocytes compared to wild-type controls. In contrast, TPO-mediated activation of positive megakaryopoiesis regulators such as ERK1/2 and AKT is increased in FAK-null megakaryocytes, providing a plausible explanation for the observed increases in megakaryopoiesis in these mice. Re-bleeding times of Pf4-Cre/FAK-floxed mice are significantly increased and FAK-null platelets exhibit diminished spreading on immobilized fibrinogen. These studies establish clear roles for FAK in megakaryocyte growth and platelet function, setting the stage for manipulation of this component of the TPO signaling apparatus for therapeutic benefit.
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