Kinase activity of ERBB3 contributes to intestinal organoids growth and intestinal tumorigenesis
- 주제(키워드) Apc(Min) mouse , ERBB3 , intestinal organoid , intestinal polyp , tyrosine kinase activity
- 주제(기타) Oncology
- 설명문(일반) [Anh Thai-Quynh Nguyen; Lee, So-young; Chin, Hyun Jung; Lee, Daekee] Ewha Womans Univ, Dept Life Sci, Seoul, South Korea; [Quy Van-Chanh Le] Konkuk Univ, Dept Stem Cell & Regenerat Biotechnol, Seoul, South Korea
- 등재 SCIE, SCOPUS
- OA유형 Green Published, gold
- 발행기관 WILEY
- 발행년도 2020
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000165997
- 본문언어 영어
- Published As http://dx.doi.org/10.1111/cas.14235
- PubMed https://pubmed.ncbi.nlm.nih.gov/31724799
초록/요약
As a member of the epidermal growth factor receptor (EGFR) family, ERBB3 plays an essential role in development and disease independent of inherently inactive kinase domain. Recently, ERBB3 has been found to bind to ATP and has catalytic activity in vitro. However, the biological function of ERBB3 kinase activity remains elusive in vivo. Here we have identified the physiological function of inactivated ERBB3 kinase activity by creating Erbb3-K740M knockin mice in which ATP cannot bind to ERBB3. Unlike Erbb3 knockout mice, kinase-inactive Erbb3(K740M) homozygous mice were born in Mendelian ratios and showed normal development. After dextran sulfate sodium-induced colitis, the kinase-inactive Erbb3 mutant mice showed normal recovery. However, the outgrowth of ileal organoids by neuregulin-1 treatment was more attenuated in Erbb3 mutant mice than in WT mice. Moreover, in combination with the Apc(Min) mouse, the proportion of polyps less than 1 mm in diameter in mutant mice was higher than in control mice and an increase in the number of apoptotic cells was observed in polyps from mutant mice compared with polyps from control mice. Taken together, the ERBB3 kinase activity contributes to the outgrowth of ileal organoids and intestinal tumorigenesis, and the development of ERBB3 kinase inhibitors, including epidermal growth factor receptor family members, can be a potential way to target colorectal cancer.
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