TFF3 interacts with LINGO2 to regulate EGFR activation for protection against colitis and gastrointestinal helminths

Abstract

Intestinal epithelial cells (IEC) have important functions in nutrient absorption, barrier integrity, regeneration, pathogen-sensing, and mucus secretion. Goblet cells are a specialized cell type of IEC that secrete Trefoil factor 3 (TFF3) to regulate mucus viscosity and wound healing, but whether TFF3-responsiveness requires a receptor is unclear. Here, we show that leucine rich repeat receptor and nogo-interacting protein 2 (LINGO2) is essential for TFF3-mediated functions. LINGO2 immunoprecipitates with TFF3, co-localizes with TFF3 on the cell membrane of IEC, and allows TFF3 to block apoptosis. We further show that TFF3-LINGO2 interactions disrupt EGFR-LINGO2 complexes resulting in enhanced EGFR signaling. Excessive basal EGFR activation in Lingo2 deficient mice increases disease severity during colitis and augments immunity against helminth infection. Conversely, TFF3 deficiency reduces helminth immunity. Thus, TFF3-LINGO2 interactions de-repress inhibitory LINGO2-EGFR complexes, allowing TFF3 to drive wound healing and immunity.

Trefoil factors share a lectin activity that defines their role in mucus

“…While this work has focused on rigorously defining the interactions between TFFs and the soluble mucins, it remains unclear how TFF lectin activities might promote cell migration to achieve epithelial restitution. Conceivably, the divalent TFF lectins could promote the co-localisation of cell-surface glycoproteins like LINGO2, which immunoprecipitates with TFF3 19 , to facilitate signalling events that promote cell migration. Assessing the plausibility of this hypothesis is confounded by a paucity of knowledge concerning what proteins bear these unusual α-GlcNAc-terminated O-glycans, and in what biological contexts.…”

“…The different ways in which these proteins bring together two trefoil domains impacts the relative orientation, flexibility, and distance between the domains [16][17][18] , which likely contributes to their non-redundant biological activities. An extensive list of TFF binding partners has accumulated within the literature and includes many cell surface and extracellular glycoproteins 2,19 , including: β-integrin, CD71, CXCR4/7, FCGBP, DMBT1, GKN2, PAR1/4, LINGO2 and the mucins MUC2, MUC5AC, and MUC6. In the context of the mucusthickening properties of the TFFs, the soluble mucins MUC5AC and MUC6 are the most relevant binding partners.…”

Pretreatment with intestinal trefoil factor alleviates stress-induced gastric mucosal damage via Akt signaling

“…Whether ITF responsiveness requires a receptor is unclear. Belle and co-workers found that the leucine rich repeat receptor and nogo-interacting protein 2 (LINGO2) is essential for ITF-mediated functions, and ITF–LINGO2 interactions derepress inhibitory LINGO2–epidermal growth factor receptor complexes, allowing ITF to drive wound healing and immunity[ 25 ]. ITF has also been reported to interact with other receptors including chemokine CXC receptor 4 and 7, protease-activated receptors, and classic signaling pathways[ 26 - 28 ].…”

LSD1 promotes secretory cell specification to driveBRAFmutant colorectal cancer

“…For example, early EECs express ENPP2, which has been shown to promote cell migration. TFF3 is canonically considered a goblet cellsecreted factor that displaces an antagonist of the EGFR, thereby enabling enhanced activation of the PI3K-AKT pathway (Belle et al, 2019). Uniquely, TFF3 is highly expressed in all three secretory cell types.…”