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Blood, 15 September 2007, Vol. 110, No. 6, pp. 1739-1747. Prepublished online as a Blood First Edition Paper on June 6, 2007; DOI 10.1182/blood-2006-05-020925. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-05-020925v1 110/6/1739    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Jahn, T. Articles by Weinberg, K. Search for Related Content PubMed PubMed Citation Articles by Jahn, T. Articles by Weinberg, K. Related Collections Signal Transduction Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CHEMOKINES, CYTOKINES, AND INTERLEUKINS Lipid rafts are required for Kit survival and proliferation signals Thomas Jahn1, Erica Leifheit1, Stacie Gooch1, Simran Sindhu1, and Kenneth Weinberg1 1 Division of Research Immunology and Bone Marrow Transplantation, Childrens Hospital Los Angeles, CA In addition to its physiologic role as central regulator of the hematopoietic and reproductive systems, the Kit receptor tyrosine kinase (RTK) is pathologically overexpressed in some forms of leukemia and constitutively activated by oncogenic mutations in mast-cell proliferations and gastrointestinal stromal tumors. To gain insight into the general activation and signaling mechanisms of RTKs, we investigated the activation-dependent dynamic membrane distributions of wild-type and oncogenic forms of Kit in hematopoietic cells. Ligand-induced recruitment of wild-type Kit to lipid rafts after stimulation by Kit ligand (KL) and the constitutive localization of oncogenic Kit in lipid rafts are necessary for Kit-mediated proliferation and survival signals. KL-dependent and oncogenic Kit kinase activity resulted in recruitment of the regulatory phosphatidylinositol 3-kinase (PI3-K) subunit p85 to rafts where the catalytical PI3-K subunit p110 constitutively resides. Cholesterol depletion by methyl-ß-cyclodextrin prevented Kit-mediated activation of the PI3-K downstream target Akt and inhibited cellular proliferation by KL-activated or oncogenic Kit, including mutants resistant to the Kit inhibitor imatinib-mesylate. Our data are consistent with the notion that Kit recruitment to lipid rafts is required for efficient activation of the PI3-K/Akt pathway and Kit-mediated proliferation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Kent, M. Copley, C. Benz, B. Dykstra, M. Bowie, and C. Eaves Regulation of Hematopoietic Stem Cells by the Steel Factor/KIT Signaling Pathway Clin. Cancer Res., April 1, 2008; 14(7): 1926 - 1930. [Abstract] [Full Text] [PDF] T. Jahn, S. Sindhu, S. Gooch, P. Seipel, P. Lavori, E. Leifheit, and K. Weinberg Direct interaction between Kit and the interleukin-7 receptor Blood, September 15, 2007; 110(6): 1840 - 1847. [Abstract] [Full Text] [PDF]

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