AIMP2 controls intestinal stem cell compartments and tumorigenesis by modulating Wnt/β-catenin signaling

Min Kyu Yum, Jong Seol Kang, Al Eum Lee, Young Woo Jo, Ji Yun Seo, Hyun A. Kim, Yoon Young Kim, Jinwoo Seong, Eun Byul Lee, Ji Hoon Kim, Jung Min Han, Sunghoon Kim, Young Yun Kong

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

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 ApcMin/+ 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.

Original languageEnglish
Pages (from-to)4559-4568
Number of pages10
JournalCancer Research
Volume76
Issue number15
DOIs
Publication statusPublished - 2016 Aug 1

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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