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J. Biol. Chem., Vol. 276, Issue 42, 39012-39020, October 19, 2001

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Sak Serine-Threonine Kinase Acts as an Effector of Tec Tyrosine Kinase^*

Yoshihiro Yamashita^§, Sachiko Kajigaya^¶, Koji Yoshida, Shuichi Ueno, Jun Ota, Ken Ohmine^**, Masuzu Ueda^**, Akira Miyazato^**, Ken-ichi Ohya, Toshio Kitamura^§§, Keiya Ozawa^**, and Hiroyuki Mano^¶¶

From the Divisions of  Functional Genomics,  Cardiology and ^** Hematology, Jichi Medical School, Kawachi-gun, Tochigi 329-0498, Japan, the ^¶ Hematology Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, and the ^§§ Department of Hemopoietic Factors, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) AB006972.

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