AIMP2 Controls Intestinal Stem Cell Compartments and Tumorigenesis by Modulating Wnt/β-Catenin Signaling.
Wnt/β-catenin (CTNNB1) signaling is crucial for the proliferation and maintenance of intestinal stem cells (ISC), but excessive activation leads to ISC expansion and eventually colorectal cancer. Thus, negative regulators are required to maintain optimal levels of Wnt/β-catenin signaling. Aminoacyl-tRNA synthetase-interacting multifunctional proteins (AIMP) function in protein synthesis, but have also been implicated in signaling cascades affecting angiogenesis, immunity, and apoptosis. In this study, we investigated the relationship between AIMP2 and Wnt/β-catenin signaling in a murine model of intestinal homeostasis and tumorigenesis. Hemizygous deletion of Aimp2 resulted in enhanced Wnt/β-catenin signaling, increased proliferation of cryptic epithelial cells, and expansion of ISC compartments. In an Apc(Min/+) background, Aimp2 hemizygosity increased adenoma formation. Mechanistically, AIMP2 disrupted the interaction between AXIN and Dishevelled-1 (DVL1) to inhibit Wnt/β-catenin signaling by competing with AXIN. Furthermore, AIMP2 inhibited intestinal organoid formation and growth by suppressing Wnt/β-catenin signaling in an Aimp2 gene dosage-dependent manner. Collectively, our results showed that AIMP2 acts as a haploinsufficient tumor suppressor that fine-tunes Wnt/β-catenin signaling in the intestine, illuminating the regulation of ISC abundance and activity. Cancer Res; 76(15); 4559-68. ©2016 AACR.
Department of Biological Sciences, Seoul National University, Seoul, South Korea.
Min Kyu
MK
Yum
Department of Biological Sciences, Seoul National University, Seoul, South Korea.
Jong-Seol
JS
Kang
College of Pharmacy, Seoul National University, Seoul, South Korea.
Al-Eum
AE
Lee
Department of Biological Sciences, Seoul National University, Seoul, South Korea.
Young-Woo
YW
Jo
Department of Biological Sciences, Seoul National University, Seoul, South Korea.
Ji-Yun
JY
Seo
Department of Biological Sciences, Seoul National University, Seoul, South Korea.
Hyun-A
HA
Kim
Department of Biological Sciences, Seoul National University, Seoul, South Korea.
Yoon-Young
YY
Kim
Department of Biological Sciences, Seoul National University, Seoul, South Korea.
Jinwoo
J
Seong
Department of Biological Sciences, Seoul National University, Seoul, South Korea.
Eun Byul
EB
Lee
Department of Biological Sciences, Seoul National University, Seoul, South Korea.
Ji-Hoon
JH
Kim
Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, South Korea. College of Pharmacy, Yonsei University, Incheon, South Korea.
Jung Min
JM
Han
College of Pharmacy, Seoul National University, Seoul, South Korea. Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Republic of Korea. Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, South Korea.
Sunghoon
S
Kim
Department of Biological Sciences, Seoul National University, Seoul, South Korea. ykong@snu.ac.kr.
Young-Yun
YY
Kong
D000818:Animals; D063646:Carcinogenesis; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D015398:Signal Transduction; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism*
C575685:AIMP2 protein, human; D009687:Nuclear Proteins; D051176:beta Catenin