# Synthetic receptor scaffolds significantly affect the efficiency of cell fate signals

## TL;DR

This study shows that the structure of synthetic receptors affects how well they can control cell behavior, with cytosolic types being most effective.

## Contribution

The first demonstration that synthetic receptor scaffold types significantly influence cell fate signaling efficiency.

## Key findings

- Cytosolic synthetic receptors maintain higher JAK phosphorylation and downstream signaling for efficient cell growth.
- Transmembrane receptors show motif-dependent decreases in JAK phosphorylation.
- Receptor scaffold design is critical for optimizing synthetic receptor signaling efficiency.

## Abstract

Mimicry of receptor functions by designing synthetic receptors would be one of the recently hot research trends in cell engineering. While several types of synthetic receptors have been designed to induce desired cell fates in response to external stimuli, little is known about which receptor type signals more efficiently for inducing a certain cell fate. In this study, we compared the performance of three types of synthetic receptor scaffolds, i.e. myristoylated, cytosolic, and transmembrane types that signal through JAK-dependent phosphorylation of tyrosine motifs to transduce growth signaling. As a result, the phosphorylation levels of JAK and subsequent downstream signaling molecules were significantly maintained in the cytosolic type receptors, leading to more efficient cell growth than the other types. In contrast, the phosphorylation levels of JAK decreased in a motif-dependent manner in the transmembrane type receptors. Although various studies on receptor engineering based on domain or motif engineering have been reported, to our knowledge this study is the first to demonstrate that synthetic receptor scaffolds significantly affect the efficiency of cell fate signals. These findings are important for both receptor biology and receptor engineering, providing guidelines for rationally designing synthetic receptors that can transduce as efficient signaling as possible.