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J. Biol. Chem., Vol. 280, Issue 32, 28973-28980, August 12, 2005

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An Intramolecular Interaction between SH2-Kinase Linker and Kinase Domain Is Essential for the Catalytic Activity of Protein-tyrosine Kinase-6^*

Han Ie Kim and Seung-Taek Lee

From the National Research Laboratory of Cellular Biochemistry, Department of Biochemistry, College of Science, and Protein Network Research Center, Yonsei University, Seoul 120-749, Korea

Protein-tyrosine kinase-6 (PTK6, also known as Brk) is a non-receptor tyrosine kinase that contains SH3, SH2, and catalytic (Kinase) domains. We have identified an intramolecular interaction between the linker (Linker) region connecting the SH2 and Kinase domains and the Kinase domain. Residue Trp-184 within the Linker region is essential for the Linker-Kinase interaction but not for the Linker-SH3 interaction. A recombinant PTK6 Kinase domain connected to the Linker region had catalytic activity in terms of autophosphorylation, phosphorylation of a PTK6 substrate, BKS, and phosphorylation of an oligopeptide substrate, whereas the Kinase domain itself, or one connected to a Linker region containing a W184A substitution, did not. The introduction of the W184A mutation into PTK6 also abrogated autophosphorylation and phosphorylation of another PTK6 substrate, Sam68, as well as phosphorylation of intracellular proteins. It also abolished the ability of PTK6 to promote proliferation and prevent apoptosis of HEK 293 cells, as well as to permit anchorage-independent colony formation. Therefore, unlike Src family members, in which the Linker-Kinase interaction inhibits catalytic activity, in PTK6 this interaction has an essential positive role.

Received for publication, April 26, 2005 , and in revised form, June 3, 2005.

^* This work was supported by grants from the National Research Laboratory program of Ministry of Science and Technology National Research Development Program (2000-N-NL-01-C-244), MOST/Korea Science and Engineering Foundation through the Protein Network Research Center at Yonsei University (R11-2000-078-01001-0), and the Brain Korea 21 Project at Yonsei University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biochemistry, College of Science, Yonsei University, Seoul 120-749, Korea. Tel.: 82-2-2123-2703; Fax: 82-2-362-9897; E-mail: stlee{at}yonsei.ac.kr.

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