Opposing effects of Lrig1 and Lrig3 on EGFR maintain intestinal homeostasis and mitigate likelihood of colonic neoplasia.

BACKGROUND AND AIMS: EGFR signaling maintains intestinal homeostasis by modulating proliferation and differentiation within the stem cell compartment with excess EGFR signaling predisposing to neoplasia. EGFR protein levels are central to EGFR function. These levels are negatively regulated by LRIG1, which accelerates receptor internalization and degradation, supporting a tumor suppressor role for LRIG1. LRIG3 is a less studied family member that has been reported, in a context-dependent manner, to both cooperate with and oppose the effects of LRIG1 on EGFR. METHODS: To examine the function of LRIG3 relative to LRIG1 on EGFR 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 LRIG3 depletion in Lrig1-expressing cells affects colorectal tumors in Lrig1CreERT2/+; Apcfl/+ mice. RESULTS: Unlike the heightened EGFR 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 EGFR signaling and markedly reduced colonic tumor formation. CONCLUSIONS: These findings indicate that LRIG3 and LRIG1 oppose one another to balance EGFR signaling, maintain intestinal homeostasis and minimize the likelihood colonic neoplasia.