Investigation of Tec family of protein-tyrosine kinases in hematopoiesis and hematological disorders.

• Project/Area Number: 15591023
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Jichi Medical School
• Principal Investigator: YAMASHITA Yoshihiro Jichi Medical School, Department of Medicine, Research Associate, 医学部, 助手 (10326861)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000); Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: Sak kinase / Tec kinsase / tyrosine phosphorylation / PEST sequence

Research Abstract

The murine sak gene encodes a putative serine-threonine kinase which is homologous to the members of the Plk/Polo family. Although Sak protein is presumed to be involved in cell growth mechanism, efforts have failed to demonstrate its kinase activity. Little has been, therefore, elucidated how Sak is regulated and how Sak contributes to cell proliferation. Tec is a cytoplasmic protein-tyrosine kinase(PTK) which becomes activated by the stimulation of cytokine receptors, lymphocyte surface antigens, heterotrimeric G protein-linked receptors, and integrins. To clarify the in vivo function of Tec, we have tried to isolate the second messengers of Tec by using the yeast two-hybrid screening. One of such Tec-binding proteins turned out to be Sak. In human kidney 293 cells, Sak became tyrosine-phosphorylated by Tec, and the serine-threonine kinase activity of Sak was detected only under the presence of Tec, suggesting Sak to be an effector molecule of Tec. In addition, Tec activity efficiently protects Sak from the "PEST" sequence-dependent proteolysis. Internal deletion of the PEST sequences led to the stabilization of Sak proteins, and expression of these mutants acted suppressive to cell growth. Our data collectively supports a novel role of Sak acting in the PTK-mediated signaling pathway.

Research Products

• [Journal Article] Signal transducers and activators of transcription 3 augments the transcriptional activity of CCAAT/enhancer binding protein a in G-CSF signaling pathway (2005)
  • Author(s): Numata A. et al.
  • Journal Title: J Biol Chem. 280 Pages: 12621-12629
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Signal transducers and activators of transcription 3 augments the transcriptional activity of CCAAT/enhancer-binding protein alpha in granulocyte colony-stimulating factor signaling pathway (2005)
  • Author(s): Numata, A., Shimoda, K., Kamezaki, K., Haro, T., Kakumitsu, H., Shide, K., Kato, K., Miyamoto, T., Yamashita, Y., Oshima, Y., Nakajima, H., Iwama, A., Aoki, K., Takase, K., Gondo, H., Mano, H., Harada, M.
  • Journal Title: J Biol Chem (Epub 12005 Jan 12621) 280 Pages: 12621-12629
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The Tyr-kinase inhibitor AG879,that blocks the ETK-PAK1 interaction, suppresses the RAS-induced PAK1 activation and malignant transformation. (2004)
  • Author(s): He H.et al.
  • Journal Title: Cancer Biol Ther. 3 Pages: 96-101
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] High-throughput screening of genome fragments bound to differentially acetylated histones. (2004)
  • Author(s): Kaneda R. et al.
  • Journal Title: Genes Cells 9 Pages: 1167-1174
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] DNA microarray analysis of dysplastic morphology associated with acute myeloid leukemia. (2004)
  • Author(s): Tsutsumi C. et al.
  • Journal Title: Exp Hematol. 32 Pages: 828-835
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Reprogramming of human postmitotic neutrophils into macrophages by growth factors. (2004)
  • Author(s): Araki H. et al.
  • Journal Title: Blood. 103 Pages: 2973-2980
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] DNA microarray analysis of natural killer cell-type lymphoproliferative disease of granular lymphocytes with purified CD3-CD56+ fractions. (2004)
  • Author(s): Choi YI. et al.
  • Journal Title: Leukemia 18 Pages: 556-565
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The Tyr-kinase inhibitor AG879, that blocks the ETK-PAK1 interaction, suppresses the RAS-induced PAK1 activation and malignant transformation (2004)
  • Author(s): He, H., Hirokawa, Y., Gazit, A., Yamashita, Y., Mano, H., Kawakami, Y., Kawakami, Hsieh, C.Y., Kung, H.J., Lessene, G., Baell, J., Levitzki, A., Maruta, H.
  • Journal Title: Cancer Biol Ther (Epub 2004 Jan 2029) 3 Pages: 96-101
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] High-throughput screening of genome fragments bound to differentially acetylated histones (2004)
  • Author(s): Kaneda, R., Toyota, M., Yamashita, Y., Koinuma, K., Choi, Y.L., Ota, J., Kisanuki, H., Ishikawa, M., Takada, S., Shimada, K., Mano, H.
  • Journal Title: Genes Cells 9 Pages: 1167-1174
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] DNA microarray analysis of dysplastic morphology associated with acute myeloid leukemia (2004)
  • Author(s): Tsutsumi, C., Ueda, M., Miyazaki, Y., Yamashita, Y., Choi, Y.L., Ota, J., Kaneda, R., Koinuma, K., Fujiwara, S., Kisanuki, H., Ishikawa, M., Ozawa, K., Tomonaga, M., Mano, H.
  • Journal Title: Exp Hematol 32 Pages: 828-835
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Reprogramming of human postmitotic neutrophils into macrophages by growth factors (2004)
  • Author(s): Araki, H., Katayama, N., Yamashita, Y., Mano, H., Fujieda, A., Usui, E., Mitani, H., Ohishi, K., Nishii, K., Masuya, M., Minami, N., Nobori, T., Shiku, H.
  • Journal Title: Blood (Epub 2003 Dec 2930) 103 Pages: 2973-2980
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] DNA microarray analysis of natural killer cell-type lymphoproliferative disease of granular lymphocytes with purified CD3-CD56+ fractions (2004)
  • Author(s): Choi, Y.L., Makishima, H., Ohashi, J., Yamashita, Y., Ohki, R., Koinuma, K., Ota, J., Isobe, Y., Ishida, F., Oshimi, K., Mano, H.
  • Journal Title: Leukemia 18 Pages: 556-565
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The Tyr-kinase inhibitor AG879, that blocks the ETK-PAK1 interaction, suppresses the RAS-induced PAK1 activation and malignant transformation. (2004)
  • Author(s): He H.et al.
  • Journal Title: Cancer Biol Ther. 3 Pages: 96-101
• [Journal Article] Reprogramming of human postmitotic neutrophils into macrophages by growth factors. (2004)
  • Author(s): Araki H. et al.
  • Journal Title: Blood 103 Pages: 2973-2980
• [Journal Article] DNA microarray analysis of natural killer cell-type lymphoproliferative disease of granular lymphocytes with purified CD3-CD56+ fractions. (2004)
  • Author(s): Choi Yl. et al.
  • Journal Title: Leukemia 18 Pages: 556-565
• [Publications] He H.et al.: "The Tyr-Kinase Inhibitor AG879, That Blocks the ETK-PAK1 Interaction, Suppresses the RAS-Induced PAK1 Activation and Malignant Transformation"Cancer Biol Ther.. 3. 96-101 (2004)
• [Publications] Koinuma K. et al.: "Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas"Int J Cancer. 108. 237-242 (2004)
• [Publications] Choi Yl. et al.: "DNA microarray analysis of natural killer cell-type lymphoproliferative disease of granular lymphocytes with purified CD3-CD56+ fractions"Leukemia. 18. 556-565 (2004)
• [Publications] Yamashita Y. et al.: "Proteomic analysis of hematopoietic stem cell-like fractions in leukemic disorders"Oncogene. 22. 5720-5728 (2003)
• [Publications] Yoshida K. et al.: "Screening of genes specifically activated in the pancreatic juice ductal cells from the patients with pancreatic ductal carcinoma"Cancer Sci.. 94. 263-270 (2003)
• [Publications] Ueno S.et al.: "DNA microarray analysis of in vivo progression mechanism of heart failure"Biochem Biophys Res Commun.. 307. 771-777 (2003)