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Blood, 1 October 2009, Vol. 114, No. 14, pp. 2900-2908. Prepublished online as a Blood First Edition Paper on July 30, 2009; DOI 10.1182/blood-2009-01-200733. This Article Full Text Full Text (PDF) Supplemental Appendix, Table, and Figures All Versions of this Article: blood-2009-01-200733v1 114/14/2900    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Mani, M. Articles by Jahn, T. PubMed PubMed Citation Articles by Mani, M. Articles by Jahn, T. Related Collections Hematopoiesis and Stem Cells Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS AND STEM CELLS Wiskott-Aldrich syndrome protein is an effector of Kit signaling Maheswaran Mani1, Shivkumar Venkatasubrahmanyam2, Mrinmoy Sanyal3, Shoshana Levy3, Atul Butte2, Kenneth Weinberg1, and Thomas Jahn1 1 Division of Stem Cell Transplantation, Department of Pediatrics, 2 Center for Biomedical Informatics Research, and 3 Division of Oncology, Department of Medicine, Stanford University School of Medicine, CA The pleiotropic receptor tyrosine kinase Kit can provide cytoskeletal signals that define cell shape, positioning, and migration, but the underlying mechanisms are less well understood. In this study, we provide evidence that Kit signals through Wiskott-Aldrich syndrome protein (WASP), the central hematopoietic actin nucleation-promoting factor and regulator of the cytoskeleton. Kit ligand (KL) stimulation resulted in transient tyrosine phosphorylation of WASP, as well as interacting proteins WASP-interacting protein and Arp2/3. KL-induced filopodia in bone marrow–derived mast cells (BMMCs) were significantly decreased in number and size in the absence of WASP. KL-dependent regulation of intracellular Ca2+ levels was aberrant in WASP-deficient BMMCs. When BMMCs were derived from WASP-heterozygous female mice using KL as a growth factor, the cultures eventually developed from a mixture of WASP-positive and -negative populations into a homogenous WASP-positive culture derived from the WASP-positive progenitors. Thus, WASP expression conferred a selective advantage to the development of Kit-dependent hematopoiesis consistent with the selective advantage of WASP-positive hematopoietic cells observed in WAS-heterozygous female humans. Finally, KL-mediated gene expression in wild-type and WASP-deficient BMMCs was compared and revealed that approximately 30% of all Kit-induced changes were WASP dependent. The results indicate that Kit signaling through WASP is necessary for normal Kit-mediated filopodia formation, cell survival, and gene expression, and provide new insight into the mechanism in which WASP exerts a strong selective pressure in hematopoiesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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