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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 (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 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. Social Bookmarking                   What's this? Submitted January 22, 2002 Accepted September 2, 2002 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 D814V 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* Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan Department of Pathology, Hyogo College of Medicine, Nishinomiya, Japan * Corresponding author; email: kanakura{at}bldon.med.osaka-u.ac.jp. Substitution of valine(V) for asparatate(D) at codon 814 constitutively activates murine c-kit receptor tyrosine kinase(KIT), and D816V mutation, corresponding to murine D814V mutation, is found in patients with mastocytosis and acute myelocytic leukemia. However, the signal transduction pathways responsible for the oncogenesis by the D814V mutant(KITV814) are not fully understood. In order to examine the oncogenic signal transduction of KITV814, we converted twenty of tyrosine(Y) residues to phenylalanines(F) in the cytoplasmic domain of KITV814 or deleted the C-terminal region containing two other tyrosine residues. Among various KIT V814-derived mutants, KIT V814-Y719F and KIT V814-Del severely impaired receptor tyrosine phosphorylation and association with p85 subunit of phosphatidylinositol 3'-kinase (p85PI3-K). Moreover, KITV814-Y719F and KITV814-Del failed to induce ligand-independent growth in Ba/F3 cells, indicating that Y719, the binding site for p85PI3-K, and C-terminal region are indispensable for the factor-independent growth by KITV814. Although the C-terminal region was also required for ligand-dependent growth by wild-type KIT(KITWT), the Y719F substitution had negligible effects on ligand-dependent growth by KITWT. Furthermore, dominant negative PI3-K significantly inhibited ligand-independent growth by KITV814. These results demonstrate that Y719 is crucial for constitutive activation of KITV814, but not for the ligand-induced activation of KITWT, and that the downstream of PI3-K plays an important role in ligand-independent growth and tumorigenicity by KITV814, thereby suggesting that KITV814 is a unique activating mutation that leads to a distinguishable function from the effects of KIT WT. 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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