IntroductionFocal adhesion kinase (FAK) is an essential nonreceptor protein tyrosine kinase that is expressed ubiquitously and is conserved in mammals and lower eukaryotic organisms. [1][2][3][4] The principal FAK stimulus is integrin engagement (Guan and Shalloway 5 and reviewed in Parsons 6 ), although its direct interaction with, and activation via, platelet-derived and epidermal growth factor receptors suggests that it may also function downstream of other membrane-bound growth factor and cytokine receptors. 7 Autophosphorylation of FAK Tyr397 occurs rapidly following integrin activation, and the resulting phosphorylated residue acts as a docking site for the SH2 domains of Src-family kinases. 8,9 FAK catalytic activity is increased by subsequent Src-mediated phosphorylation of FAK residues Tyr576 and Tyr577, 10 followed by Tyr861 and Tyr925, which act as binding sites for the SH3 domain of p130CAS and the SH2 domain of the adaptor protein GRB2, respectively. 11,12 Tyr925, located in the focal adhesion targeting domain, also mediates interactions with integrin-associated proteins such as talin and paxillin, 13 thereby recruiting FAK to focal adhesion sites.Activated FAK modulates the activity of a broad range of downstream signaling proteins, including phosphoinositide 3-kinase (PI3-K) 14 and phospholipase C (PLC)-␥, 15 as well as a number of small GTPases such as Ras, Rac, and Rho (reviewed in 16 ). Extensive studies indicate that FAK is essential for normal cell migration. FAK-deficient cells migrate poorly in response to chemokines; form an increased number of prominent "immature" focal adhesions, apparently due to decreased focal adhesion turnover; and do not spread normally on extracellular matrices (ECMs). 17,18 Megakaryopoiesis and platelet production are tightly regulated by a number of growth factors and cytokines to maintain a normal number of circulating platelets. The principal regulator of megakaryopoiesis is thrombopoietin (Tpo), 19 although other fac 1 tors such as interleukin-3 and stem-cell factor work in synergy with Tpo during the earlier stages of megakaryocytic progenitor cell expansion. 20 It has become apparent that the microenvironments in which megakaryocytes function are also of critical importance to megakaryopoiesis. 21,22 Indeed, direct cell-cell and cell-ECM interactions have been demonstrated to influence megakaryocyte differentiation and proplatelet formation. [23][24][25] Although FAK is important in regulating cell spreading and migration in response to integrin-ECM interactions, the role of FAK in megakaryopoiesis remains unclear, partly because Fak deletion in mice is lethal at embryonic day 8.5, before the onset of significant definitive hematopoiesis. Although the role of proline-rich tyrosine kinase-2 (PYK2), which shares sequence homology and similar characteristics with FAK, has been characterized in megakaryocytes, 8,[26][27][28] its localization and dependence on intracellular calcium make the 2 proteins functionally different. 29 FAK activation in platelets require...

CMBs are common and associated with neurocognitive dysfunction in pediatric brain tumor survivors treated with radiation.