# Phosphoproteomics identification of ERK-dependent activation of Rps6kb1 in cardiac hypertrophy

## TL;DR

This study shows that ERK-dependent activation of Rps6kb1 is crucial for heart muscle growth and heart failure.

## Contribution

The paper reveals a new mechanism of Rps6kb1 activation independent of mTOR, involving ERK signaling in cardiac hypertrophy.

## Key findings

- Phosphoproteomics identified Rps6kb1 as a key kinase in cardiomyocyte growth.
- ERK signaling, not mTOR, regulates Rps6kb1 phosphorylation in cardiac hypertrophy.
- Deleting Rps6kb1 in mice reduced ERK- and pressure-induced heart growth.

## Abstract

Cardiomyocyte growth is tightly controlled by multiple signaling pathways. Identification of master kinases in this process is essential in exploring potential targets for the treatment of pathological cardiac hypertrophy and heart failure. Here we identified the mTOR-independent activation of ribosomal protein S6 kinase b1 (Rps6kb1) during cardiomyocyte growth. By utilizing phosphoproteomics in primary neonatal rat ventricular myocytes, we revealed Rps6kb1 as one of most activated kinases under growth stimulation. We further demonstrated the role of Rps6kb1 phosphorylation in pathological cardiac hypertrophy and heart failure. We showed that the phosphorylation of multiple sites in Rps6kb1, including T367 in the kinase domain and S418/T421/S424 in the C-terminal domain, is not directly regulated by the activity of mTOR but coupled with the activation of the MEK1/ERK axis. In mice, cardiomyocyte-specific deletion of Rps6kb1 significantly inhibited both constitutively active ERK– and pressure overload–induced cardiac hypertrophy. In contrast, cardiomyocyte-specific overexpression of wild-type Rps6kb1, rather than the phosphorylation-defective mutant, elevated cardiac hypertrophy and augmented pressure overload–induced heart failure. In conclusion, our findings reveal that the MEK/ERK axis primes Rps6kb1 activation through phosphorylation of 2 separate domains of Rps6kb1, which may play an essential role in cardiac hypertrophy and heart failure under hemodynamic stress.

Li and Zhang et al. show that ERK-dependent phosphorylation of Rps6kb1 plays an essential role in cardiac hypertrophic growth.