Cellular and molecular gastroenterology and hepatology · 2026
Opposing Effects of Leucine-Rich Repeats and Immunoglobulin-Like Domains 3 and Leucine-Rich Repeats and Immunoglobulin-Like Domains 1 on Epidermal Growth Factor Receptor Maintain Intestinal Homeostasis and Mitigate Likelihood of Colonic Neoplasia.
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Bechard Matthew E, Chen Zhengyi, Zhao Ping, Aramandla Radhika, Yang Yilin, Simmons Alan J, Washington M Kay, Franklin Jeffery L, Lau Ken S, Coffey Robert J
Аннотация
BACKGROUND & AIMS: Epidermal growth factor receptor signaling maintains intestinal homeostasis by modulating proliferation and differentiation within the stem cell compartment, with excess epidermal growth factor receptor signaling predisposing to neoplasia. Epidermal growth factor receptor protein levels are central to epidermal growth factor receptor function. These levels are negatively regulated by leucine-rich repeats and immunoglobulin-like domains 1, which accelerates receptor internalization and degradation, supporting a tumor suppressor role for leucine-rich repeats and immunoglobulin-like domains 1. Leucine-rich repeats and immunoglobulin-like domains 3 is a less-studied family member that has been reported, in a context-dependent manner, to both cooperate with and oppose the effects of leucine-rich repeats and immunoglobulin-like domains 1 on epidermal growth factor receptor.
METHODS: To examine the function of leucine-rich repeats and immunoglobulin-like domains 3 relative to leucine-rich repeats and immunoglobulin-like domains 1 on epidermal growth factor receptor levels and downstream signaling in vivo, we generated an Lrig3 floxed allele and intercrossed these mice with Lrig1CreERT2 mice that are Lrig1 null in the homozygous state. This allowed us to assess the effects of Lrig3 loss in Lrig1-null intestinal cells. We also tested how leucine-rich repeats and immunoglobulin-like domains 3 depletion in Lrig1-expressing cells affects colorectal tumors in Lrig1CreERT2/+; Apcfl/+ mice.
RESULTS: Unlike the heightened epidermal growth factor receptor and Wnt activity caused by Lrig1 loss, loss of Lrig3 in Lrig1Null cells markedly reduced activity in both pathways. In this setting, a widening of the intestinal crypt base was observed with the appearance of intermediate-lineage secretory cells at the expense of stem cells. In marked contrast to multiple distal colonic tumors in Lrig1CreERT2/+; Apcfl/+ mice, deletion of a single Lrig3 allele in Lrig1 haploinsufficient mice decreased epidermal growth factor receptor signaling and markedly reduced colonic tumor formation.
CONCLUSIONS: These findings indicate that leucine-rich repeats and immunoglobulin-like domains 3 and leucine-rich repeats and immunoglobulin-like domains 1 oppose one another to balance epidermal growth factor receptor signaling, maintain intestinal homeostasis, and minimize the likelihood of colonic neoplasia.
METHODS: To examine the function of leucine-rich repeats and immunoglobulin-like domains 3 relative to leucine-rich repeats and immunoglobulin-like domains 1 on epidermal growth factor receptor levels and downstream signaling in vivo, we generated an Lrig3 floxed allele and intercrossed these mice with Lrig1CreERT2 mice that are Lrig1 null in the homozygous state. This allowed us to assess the effects of Lrig3 loss in Lrig1-null intestinal cells. We also tested how leucine-rich repeats and immunoglobulin-like domains 3 depletion in Lrig1-expressing cells affects colorectal tumors in Lrig1CreERT2/+; Apcfl/+ mice.
RESULTS: Unlike the heightened epidermal growth factor receptor and Wnt activity caused by Lrig1 loss, loss of Lrig3 in Lrig1Null cells markedly reduced activity in both pathways. In this setting, a widening of the intestinal crypt base was observed with the appearance of intermediate-lineage secretory cells at the expense of stem cells. In marked contrast to multiple distal colonic tumors in Lrig1CreERT2/+; Apcfl/+ mice, deletion of a single Lrig3 allele in Lrig1 haploinsufficient mice decreased epidermal growth factor receptor signaling and markedly reduced colonic tumor formation.
CONCLUSIONS: These findings indicate that leucine-rich repeats and immunoglobulin-like domains 3 and leucine-rich repeats and immunoglobulin-like domains 1 oppose one another to balance epidermal growth factor receptor signaling, maintain intestinal homeostasis, and minimize the likelihood of colonic neoplasia.