# Threonyl-tRNA synthetase activates STAT3 by a nontranslational mechanism[image]

## TL;DR

This study shows that a protein involved in translation, TARS1, activates a cancer-related signaling protein, STAT3, through a non-translational mechanism in lung cancer.

## Contribution

The paper reveals a new non-translational role of TARS1 in activating STAT3 through a scaffold mechanism involving JAK.

## Key findings

- Elevated TARS1 expression in lung cancer correlates with poor patient survival.
- TARS1 activates STAT3 and promotes cancer cell proliferation and tumor formation.
- TARS1 functions as a scaffold to bring STAT3 and JAK together for phosphorylation.

## Abstract

Signal transducer and activator of transcription 3 (STAT3) is a major regulator of cell proliferation and survival, often found to be aberrantly activated in cancer. Here, we identify threonyl-tRNA synthetase 1 (TARS1) as an activator of STAT3. Elevated TARS1 expression in lung cancer correlates with poor patient survival. We find that overexpression of TARS1 supports non–small cell lung cancer cell proliferation in vitro, tumor formation of xenografts in mice, and hyperactivity of STAT3. Catalytically inactive TARS1 promotes STAT3 activation and cell proliferation, indicating that TARS1 functions in a nontranslational manner. Mechanistically, TARS1 physically associates with both STAT3 and Janus kinase (JAK), and TARS1 activation of STAT3 requires basal JAK activity. We propose a scaffold model in which TARS1 promotes proximity of STAT3 to JAK and subsequent phosphorylation of STAT3. This model is supported by the results of reconstitution experiments expressing recombinant TARS1, STAT3, and JAK1 in noncancer cells. Our study uncovers a novel mechanism of STAT3 dysregulation in cancer and provides a strong basis for therapeutic targeting of the noncanonical function of a housekeeping protein.