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Cancer Sci. 2020 Jan;111(1):137-147. doi: 10.1111/cas.14235. Epub 2019 Dec 13.

Kinase activity of ERBB3 contributes to intestinal organoids growth and intestinal tumorigenesis.

Author information

1
Department of Life Science, Ewha Womans University, Seoul, South Korea.
2
Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, South Korea.

Abstract

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 Erbb3K740M 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 ApcMin 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.

KEYWORDS:

ApcMin mouse; ERBB3; intestinal organoid; intestinal polyp; tyrosine kinase activity

PMID:
31724799
PMCID:
PMC6942447
DOI:
10.1111/cas.14235
[Indexed for MEDLINE]
Free PMC Article

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