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Prepublished online as a Blood First Edition Paper on September 12, 2002; DOI 10.1182/blood-2002-01-0177. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-01-0177v1 101/3/1094    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 Hashimoto, K. Articles by Kanakura, Y. Search for Related Content PubMed PubMed Citation Articles by Hashimoto, K. Articles by Kanakura, Y. Related Collections Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 February 2003, Vol. 101, No. 3, pp. 1094-1102 NEOPLASIA Necessity of tyrosine 719 and phosphatidylinositol 3'-kinase-mediated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the Asp814Val mutation Koji Hashimoto, Itaru Matsumura, Tohru Tsujimura, Dae-Ki Kim, Hideki Ogihara, Hirokazu Ikeda, Shuji Ueda, Masao Mizuki, Hiroyuki Sugahara, Hirohiko Shibayama, Yukihiko Kitamura, and Yuzuru Kanakura From the Department of Pathology and the Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita; and the Department of Pathology, Hyogo College of Medicine, Nishinomiya, Japan. Substitution of valine (Val) for aspartic acid (Asp) at codon 814 constitutively activates murine c-kit receptor tyrosine kinase (KIT), and Asp816Val mutation, corresponding to murine Asp814Val mutation, is found in patients with mastocytosis and acute myelocytic leukemia. However, the signal transduction pathways responsible for oncogenesis by the Asp814Val mutant (KITVal814) are not fully understood. To examine the oncogenic signal transduction of KITVal814, we converted 20 tyrosine (Tyr) residues to phenylalanine (Phe) in the cytoplasmic domain of KITVal814 or deleted the C-terminal region containing 2 other tyrosine residues (Del). Among various KITVal814- derived mutants, KITVal814-Tyr719Phe and KITVal814-Del severely impaired receptor tyrosine phosphorylation and association with the p85 subunit of phosphatidylinositol 3'-kinase (p85 PI3-K). Moreover, KITVal814-Tyr719Phe and KITVal814-Del failed to induce ligand-independent growth in Ba/F3 cells, indicating that Tyr719, the binding site for p85PI3-K, and the C-terminal region are indispensable for factor-independent growth by KITVal814. Although the C-terminal region was also required for ligand-dependent growth by wild-type KIT (KITWT), the Tyr719Phe substitution had negligible effects on ligand-dependent growth by KITWT. Furthermore, dominant-negative PI3-K significantly inhibited ligand-independent growth by KITVal814. These results demonstrate that Tyr719 is crucial for constitutive activation of KITVal814, but not for the ligand-induced activation of KITWT, and that the downstream signaling of PI3-K plays an important role in ligand-independent growth and tumorigenicity by KITVal814, thereby suggesting that KITVal814 is a unique activating mutation that leads to a distinguishable function from the effects of KITWT. © 2003 by The American Society of Hematology.   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] V. Munugalavadla, E. C. Sims, J. Borneo, R. J. Chan, and R. Kapur Genetic and pharmacologic evidence implicating the p85{alpha}, but not p85{beta}, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis Blood, September 1, 2007; 110(5): 1612 - 1620. [Abstract] [Full Text] [PDF] A. Tefferi Mutant Kit: thwarting the message down below Blood, March 15, 2005; 105(6): 2240 - 2241. [Full Text] [PDF] G. Lefevre, A.-L. Glotin, A. Calipel, F. Mouriaux, T. Tran, Z. Kherrouche, C.-A. Maurage, C. Auclair, and F. Mascarelli Roles of Stem Cell Factor/c-Kit and Effects of Glivec(R)/STI571 in Human Uveal Melanoma Cell Tumorigenesis J. Biol. Chem., July 23, 2004; 279(30): 31769 - 31779. [Abstract] [Full Text] [PDF] R. Shivakrupa, A. Bernstein, N. Watring, and D. Linnekin Phosphatidylinositol 3'-Kinase Is Required for Growth of Mast Cells Expressing the Kit Catalytic Domain Mutant Cancer Res., August 1, 2003; 63(15): 4412 - 4419. [Abstract] [Full Text] [PDF]

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