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Blood, 1 January 2005, Vol. 105, No. 1, pp. 226-232. Prepublished online as a Blood First Edition Paper on August 17, 2004; DOI 10.1182/blood-2004-05-1768. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-05-1768v1 105/1/226    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 Zeng, S. Articles by Longley, J. B. Search for Related Content PubMed PubMed Citation Articles by Zeng, S. Articles by Longley, J. B. Related Collections Hematopoiesis and Stem Cells Immunobiology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Regulation of stem cell factor receptor signaling by Cbl family proteins (Cbl-b/c-Cbl) Shan Zeng, Zhiheng Xu, Stan Lipkowitz, and Jack B. Longley From the Departments of Dermatology and Pathology, College of Physicians and Surgeons, Columbia University, New York, NY; and Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, MD. Activation of the KIT receptor tyrosine kinase contributes to the pathogenesis of several human diseases, but the mechanisms regulating KIT signaling have not been fully characterized. Here, we show that stem cell factor (SCF), the ligand for KIT, induces the interaction between KIT and Cbl proteins and their mutual degradation. Upon SCF stimulation, KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT. We propose a negative feedback loop controlling the SCF-KIT signaling pathway, in which SCF activates KIT. The activated KIT in turn induces phosphorylation and activation of Cbl proteins. The Cbl proteins then bind and direct the degradation of activated KIT, leading to down-regulation of KIT signaling. (Blood. 2005;105:226-232) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Sun, M. Pedersen, and L. Ronnstrand The D816V Mutation of c-Kit Circumvents a Requirement for Src Family Kinases in c-Kit Signal Transduction J. Biol. Chem., April 24, 2009; 284(17): 11039 - 11047. [Abstract] [Full Text] [PDF] C. Reindl, H. Quentmeier, K. Petropoulos, P. A. Greif, T. Benthaus, B. Argiropoulos, G. Mellert, S. Vempati, J. Duyster, C. Buske, et al. CBL Exon 8/9 Mutants Activate the FLT3 Pathway and Cluster in Core Binding Factor/11q Deletion Acute Myeloid Leukemia/Myelodysplastic Syndrome Subtypes Clin. Cancer Res., April 1, 2009; 15(7): 2238 - 2247. [Abstract] [Full Text] [PDF] S. Abbas, G. Rotmans, B. Lowenberg, and P. J.M. Valk Exon 8 splice site mutations in the gene encoding the E3-ligase CBL are associated with core binding factor acute myeloid leukemias Haematologica, October 1, 2008; 93(10): 1595 - 1597. [Full Text] [PDF] I. Bachelet, A. Munitz, B. Berent-Maoz, D. Mankuta, and F. Levi-Schaffer Suppression of Normal and Malignant Kit Signaling by a Bispecific Antibody Linking Kit with CD300a J. Immunol., May 1, 2008; 180(9): 6064 - 6069. [Abstract] [Full Text] [PDF] C. Rathinam, C. B.F. Thien, W. Y. Langdon, H. Gu, and R. A. Flavell The E3 ubiquitin ligase c-Cbl restricts development and functions of hematopoietic stem cells Genes & Dev., April 15, 2008; 22(8): 992 - 997. [Abstract] [Full Text] [PDF] J. Tu, L. Fan, K. Tao, W. Zhu, J. Li, and G. Lu Stem cell factor affects fate determination of human gonocytes in vitro Reproduction, December 1, 2007; 134(6): 757 - 765. [Abstract] [Full Text] [PDF] A. L. Reddi, G. Ying, L. Duan, G. Chen, M. Dimri, P. Douillard, B. J. Druker, M. Naramura, V. Band, and H. Band Binding of Cbl to a Phospholipase C{gamma}1-docking Site on Platelet-derived Growth Factor Receptor beta Provides a Dual Mechanism of Negative Regulation J. Biol. Chem., October 5, 2007; 282(40): 29336 - 29347. [Abstract] [Full Text] [PDF] B. Sargin, C. Choudhary, N. Crosetto, M. H. H. Schmidt, R. Grundler, M. Rensinghoff, C. Thiessen, L. Tickenbrock, J. Schwable, C. Brandts, et al. Flt3-dependent transformation by inactivating c-Cbl mutations in AML Blood, August 1, 2007; 110(3): 1004 - 1012. [Abstract] [Full Text] [PDF] M. A. Caligiuri, R. Briesewitz, J. Yu, L. Wang, M. Wei, K. J. Arnoczky, T. B. Marburger, J. Wen, D. Perrotti, C. D. Bloomfield, et al. Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia Blood, August 1, 2007; 110(3): 1022 - 1024. [Abstract] [Full Text] [PDF]

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