Traf2- and Nck-Interacting Kinase Is Essential for Wnt Signaling and Colorectal Cancer Growth

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 12; pp. 5024 - 5033
• Main Authors: SHITASHIGE, Miki, SATOW, Reiko, JIGAMI, Takafumi, AOKI, Kazunori, HONDA, Kazufumi, SHIBATA, Tatsuhiro, ONO, Masaya, HIROHASHI, Setsuo, YAMADA, Tesshi
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-06-2010
• Subjects: Adenoviridae - genetics; Animals; Antineoplastic agents; beta Catenin - genetics; beta Catenin - metabolism; Biological and medical sciences; Blotting, Western; Cell Proliferation; Chromatography, Liquid; Colony-Forming Units Assay; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Female; Gastroenterology. Liver. Pancreas. Abdomen; Germinal Center Kinases; Humans; Immunoblotting; Immunoenzyme Techniques; Immunoprecipitation; Luciferases - metabolism; Mass Spectrometry; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Pharmacology. Drug treatments; Phosphorylation; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - pharmacology; Signal Transduction; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; TNF Receptor-Associated Factor 2 - genetics; TNF Receptor-Associated Factor 2 - metabolism; Tumor Cells, Cultured; Tumors; Two-Hybrid System Techniques; Wnt Proteins - genetics; Wnt Proteins - metabolism; Rectal disease; Enzyme; Growth; Transferases; Tumor necrosis factor receptor associated factor 2; Colorectal cancer; Malignant tumor; Adaptor protein; Essential; Cell signaling; Colonic disease; Signal transduction; Kinase; Digestive diseases; Intestinal disease; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-0306

T-cell factor-4 (TCF4) is a transcription factor essential for maintaining the undifferentiated status and self-renewal of intestinal epithelial cells. It has therefore been considered that constitutive activation of TCF4 by aberrant Wnt signaling is a major force driving colorectal carcinogenesis. We previously identified Traf2- and Nck-interacting kinase (TNIK) as one of the proteins that interact with TCF4 in colorectal cancer cells, but its functional significance has not been elucidated. Here, we report that TNIK is an activating kinase for TCF4 and essential for colorectal cancer growth. TNIK, but not its catalytically inactive mutant, phosphorylated the conserved serine 154 residue of TCF4. Small interfering RNA targeting TNIK inhibited the proliferation of colorectal cancer cells and the growth of tumors produced by injecting colorectal cancer cells s.c. into immunodeficient mice. The growth inhibition was abolished by restoring the catalytic domain of TNIK, thus confirming that its enzyme activity is essential for the maintenance of colorectal cancer growth. Several ATP-competing kinase inhibitors have been applied to cancer treatment and have shown significant activity. Our findings suggest TNIK as a feasible target for pharmacologic intervention to ablate aberrant Wnt signaling in colorectal cancer.