# Hybrid Receptor-Mediated Molecular Delineations in TNF-α and IGF-1-Induced Costimulatory Effects

## TL;DR

This paper explores how TNF-α and IGF-1 together affect cell signaling, revealing new molecular mechanisms that explain their combined effects on inflammation and tumor suppression.

## Contribution

The study identifies hybrid receptor formation and a novel SOCS3 binding site on TNFR1, explaining divergent signaling outcomes during costimulation.

## Key findings

- TNFR1 can form hybrid receptors with IGF1R, preventing SOCS3 inhibition.
- A unique binding site on TNFR1 is identified where SOCS3 may block receptor export to the cell surface.
- Costimulatory effects of TNF-α and IGF-1 are linked to molecular pathways that inhibit SOCS3 expression.

## Abstract

The growth-promoting roles of IGF-1 (Insulin-like Growth Factor 1) and the inflammation-modulating cytokine TNF-α (Tumor Necrosis Factor-alpha) have been substantially deciphered in various pathological conditions. Also, their biphasic roles in modulating cellular inflammation have been reported. While their independent signaling pathways are sufficiently explored, recent studies have identified that their combined or costimulatory effects uniquely contribute to the regulation of different disease states. Such costimulatory effects appear to confer divergent and at times opposite effects on certain cellular processes. We and others in the literature have previously demonstrated that TNF-α and IGF-1 would independently induce the expression of SOCS3 (Suppressor of Cytokine Signaling-3, a tumor suppressor protein). However, their combined presence has been found to prevent SOCS3 expression. The cause of this divergent opposite effect remained unclear. Here, we provide structural evidence on the interactions between the receptors for TNF-α and IGF-1, and the expression patterns of intermediary proteins which play a prominent role in SOCS3 expression. Our analysis here presents new evidence which demonstrates that TNFR1 (Tumor Necrosis Factor Receptor-1) has the potential to form hybrid receptors with IGF1R (Insulin-like Growth Factor-1 Receptor). Formation of these hybrid receptors may preclude the intracellular signaling that leads to the inhibition of SOCS3. Additionally, we also identified a unique binding site on TNFR1, where SOCS3 by binding to this region is hypothesized to prevent the export of TNFR1 to cell surface. This could be one of negative feedback regulation mechanisms of SOCS3 associated with preventing inflammatory signaling. Our results described here delineate molecular mediators which could cause inhibition of SOCS3 when both TNF-α and IGF-1 induce their costimulatory effects.