Traf2- and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth.
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.
Chemotherapy Division, National Cancer Center Research Institute, Tokyo, Japan.
Miki
M
Shitashige
Reiko
R
Satow
Takafumi
T
Jigami
Kazunori
K
Aoki
Kazufumi
K
Honda
Tatsuhiro
T
Shibata
Masaya
M
Ono
Setsuo
S
Hirohashi
Tesshi
T
Yamada
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002853:Chromatography, Liquid; D003114:Colony-Forming Units Assay; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D000081410:Germinal Center Kinases; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D000081410:Germinal Center Kinases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D047992:TNF Receptor-Associated Factor 2; D051153:Wnt Proteins; D051176:beta Catenin; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; C000631454:TNIK protein, human