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Blood, 15 January 2008, Vol. 111, No. 2, pp. 482-483. This Article Full Text (PDF) 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 Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Italiano, J. E. Search for Related Content PubMed Articles by Italiano, J. E., Jr Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  INSIDE BLOOD Comment on Hitchcock et al, page 596 Megakaryocyte and platelet biology: getting your FAKs straight Joseph E. Italiano, Jr BRIGHAM AND WOMEN'S HOSPITAL In this issue of Blood, Hitchcock and colleagues show that the nonreceptor tyrosine kinase FAK plays a critical role in regulating megakaryocyte maturation and platelet function in vivo. Nearly a trillion platelets circulate in an adult human. To maintain this level of circulating platelets, each second the megakaryocytes within the bone marrow must produce approximately 1 million platelets. Megakaryopoiesis and platelet production are highly regulated by a number of growth factors. While recent studies have identified the underlying mechanics of megakaryocyte differentiation and have established that thrombopoietin is the principal regulator of thrombopoiesis,1 the conditions that influence megakaryopoiesis in vivo as well as the signaling pathways that contribute to platelet production are not well understood. It has become clear that the bone marrow microenvironment in which megakaryocytes reside contributes to megakaryopoiesis and platelet production.2 Indeed, interactions with extracellular matrices have been shown to influence megakaryocyte development and platelet production.3 The protein tyrosine kinase focal adhesion kinase (FAK) plays a prominent role in integrin signaling and cell migration in response to interactions between the extracellular matrix and integrins; thus, FAK could potentially regulate megakaryocyte development. However, the role of FAK in megakaryocyte development and platelet biogenesis in vivo was not clear, because FAK deletion in mice results in embryonic lethality before the initiation of hematopoiesis. In this issue of Blood, Hitchcock and colleagues report on the generation and characterization of a megakaryocyte lineage-specific FAK knockout mouse that was generated by crossing conditional FAK-floxed mice with the recently described megakaryocyte-lineage specific platelet factor 4 (Pf4)–Cre mouse.4 In a series of elegant experiments, the authors show that FAK plays a central role in megakaryocyte development and platelet biology. The authors begin by showing that specific ablation of FAK from the megakaryocyte lineage results in a significant increase in platelet numbers, increased megakaryocyte progenitor numbers, as well as increased bone marrow megakaryocyte numbers and ploidy. The authors also observed that the thrombopoietin-mediated activation of Lyn kinase, which functions as a negative regulator of megakaryocyte development, is severely attenuated in FAK-null megakaryocytes. The strongest conclusion from their work is that FAK functions as a negative regulator of megakaryopoiesis. These findings suggest that manipulation of FAK may provide a way to increase platelet levels in patients with thrombocytopenia or decrease platelet levels in patients with thrombocytosis. While the majority of this study focused on the function of FAK in megakaryopoiesis, there were also some insights into the role of FAK in platelets. When challenged by localized vascular damage, platelets are rapidly activated to prevent vascular leakage. Platelet activation requires rapid structural changes that remodel the cell cytoskeleton. The other novel finding presented in the article is that FAK–/– platelets display significantly impaired spreading on fibrinogen-coated surfaces when incubated with multiple platelet-agonists. Surprisingly, the impaired spreading was not due to loss of vinculin-rich focal adhesions, suggesting that one of the major roles of FAK in platelets may be reorganization of the cytoskeleton. While many aspects of FAK function remain to be explored, additional studies with megakaryocyte lineage-specific FAK knockout mice are likely to reveal new therapeutic targets that regulate platelet numbers and function. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Kaushansky K. Lineage-specific hematopoietic growth factors. N Engl J Med 2006; 354:2034–2045.[Free Full Text] Larson MK and Watson SP. Regulation of proplatelet formation and platelet release by integrin IIbβ3. Blood 2006; 108:1509–1514.[Abstract/Free Full Text] Avecilla ST, Hattori K, Heissig B, et al. Chemokine-mediated interaction of hematopoietic progenitors with bone marrow vascular niche is required for theombopoiesis. Nat Med 2003; 10:64–71.[CrossRef][Medline] [Order article via Infotrieve] Tiedt R, Schomber T, Hao-Shen H, Skoda RC. Pf4-Cre transgenic mice allow the generation of lineage-restricted gene knockouts for studying megakaryocyte and platelet function in vivo. Blood 2007; 109:1503–1506.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: 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 Prévost, Katherine Sear, Sanford J. Shattil, and Kenneth Kaushansky Blood 2008 111: 596-604. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) 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 Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Italiano, J. E. Search for Related Content PubMed Articles by Italiano, J. E., Jr Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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