PT  - JOURNAL ARTICLE
AU  - Yingbiao Ji
AU  - Yun Wei
AU  - JoonHyung Park
AU  - Li Yin Hung
AU  - Tanner Young
AU  - Karl Herbine
AU  - Taylor Oniskey
AU  - Christopher Pastore
AU  - Wildaliz Nieves
AU  - Ma Somsouk
AU  - De’Broski R. Herbert
TI  - TFF3 is a ligand for LINGO2 that de-represses EGFR to control disease outcome during colitis and gastrointestinal nematode infection
AID  - 10.1101/469700
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 469700
4099  - http://biorxiv.org/content/early/2018/11/13/469700.short
4100  - http://biorxiv.org/content/early/2018/11/13/469700.full
AB  - Intestinal epithelial cells (IEC) comprise diverse lineages that serve distinct roles necessary for regulation of nutrient absorption, regeneration, immunity, and homeostasis1,2. Goblet cells secrete Trefoil factor 3 (TFF3) to maintain mucus viscosity and drive mucosal healing by inhibiting cell death and influencing tight junction protein expression3. However, whether TFF3 signaling relies upon conventional ligand-receptor interactions has been unclear for decades. This study demonstrates that the orphan transmembrane protein leucine rich repeat receptor and nogo-interacting protein 2 (LINGO2) immunoprecipitates with TFF3, that LINGO2 and TFF3 co-localize at the IEC cell surface, and that TFF3/LINGO2 interactions block IEC apoptosis. Loss of function studies show that TFF3-driven STAT3 and EGFR activation are both LINGO2 dependent. Importantly, we demonstrate that TFF3 disrupts LINGO2/EGFR interactions that normally restrict EGFR activity, resulting in enhanced EGFR signaling. Excessive EGFR activation in Lingo2 gene deficient mice exacerbates colitic disease and accelerates host resistance to parasitic nematodes, whereas TFF3 deficiency results in host susceptibility. Thus, our data demonstrating that TFF3 functions through a previously unrecognized ligand-receptor interaction with LINGO2 to de-repress LINGO2-dependent inhibition of EGFR activation provides a novel conceptual framework explaining how TFF3-mediates mucosal wound healing through enhanced activation of the EGFR pathway.