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First published online 21 December 2009
doi: 10.1242/jcs.053264

Journal of Cell Science 123, 236-245 (2010)
Published by The Company of Biologists 2010
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Research Articles

Identification of β-catenin as a target of the intracellular tyrosine kinase PTK6

Helena L. Palka-Hamblin1,*, Jessica J. Gierut1,*, Wenjun Bie1, Patrick M. Brauer1, Yu Zheng1, John M. Asara3 and Angela L. Tyner1,2,{ddagger}

1 Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA
2 Department of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA
3 Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA

{ddagger} Author for correspondence (atyner{at}uic.edu)

Accepted 26 October 2009

Disruption of the gene encoding protein tyrosine kinase 6 (PTK6) leads to increased growth, impaired enterocyte differentiation and higher levels of nuclear β-catenin in the mouse small intestine. Here, we demonstrate that PTK6 associates with nuclear and cytoplasmic β-catenin and inhibits β-catenin- and T-cell factor (TCF)-mediated transcription. PTK6 directly phosphorylates β-catenin on Tyr64, Tyr142, Tyr331 and/or Tyr333, with the predominant site being Tyr64. However, mutation of these sites does not abrogate the ability of PTK6 to inhibit β-catenin transcriptional activity. Outcomes of PTK6-mediated regulation appear to be dependent on its intracellular localization. In the SW620 colorectal adenocarcinoma cell line, nuclear-targeted PTK6 negatively regulates endogenous β-catenin/TCF transcriptional activity, whereas membrane-targeted PTK6 enhances β-catenin/TCF regulated transcription. Levels of TCF4 and the transcriptional co-repressor TLE/Groucho increase in SW620 cells expressing nuclear-targeted PTK6. Knockdown of PTK6 in SW620 cells leads to increased β-catenin/TCF transcriptional activity and increased expression of β-catenin/TCF target genes Myc and Survivin. Ptk6-null BAT-GAL mice, containing a β-catenin-activated LacZ reporter transgene, have increased levels of β-galactosidase expression in the gastrointestinal tract. The ability of PTK6 to negatively regulate β-catenin/TCF transcription by modulating levels of TCF4 and TLE/Groucho could contribute to its growth-inhibitory activities in vivo.

Key words: PTK6, BRK, Sik, β-catenin, Tyrosine kinase, Intestine, Colon


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