# Integrative role of Rps6kb1 in pathological cardiac remodeling

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2024 · $846,536

## Abstract

Project Summary
 Heart failure is a leading cause of morbidity and mortality worldwide. Hypertension is one of the most
important risk factors of heart failure. Despite paramount interests and urgent clinical needs, our understanding
of the mechanisms of heart failure development remains limited. To accommodate the elevated demand of
cardiac contractility under high blood pressure, the heart mounts an acute reaction through cardiomyocyte
hypertrophic growth. This once adaptive response may decompensate and progress into heart failure. The long-
term goal of this project is to identify novel mechanisms of the pathological transition from adaptive cardiac
hypertrophy to heart failure and explore therapeutic interventions.
 With an unbiased phosphoproteomic analysis, Rps6kb1 was identified as one of the most prominent
kinases in cardiomyocyte hypertrophic growth. Rps6kb1 is a classical downstream target of mTOR, however, its
role in hypertensive heart disease remains incompletely understood. Moreover, Rps6kb1, with its complex
activation mechanism, may integrate signals from multiple upstream pathways, above and beyond the mTOR
signaling. Preliminary studies showed that Rps6kb1 deletion in the heart suppresses adaptive cardiac
hypertrophic growth and consequently, cardiomyopathy and heart failure are accelerated under pressure
overload. Based on these findings, a central hypothesis is formulated that Rps6kb1 is an essential player in
adaptive hypertrophic growth by integrating signals from multiple upstream pathways. Additional preliminary data
showed that Rps6kb1 is directly phosphorylated by ERK, independent of the mTOR signaling. A novel threonine
site of phosphorylation by ERK was later identified by mass spectrometry. More importantly, ERK-mediated
phosphorylation of Rps6kb1 is required for full Rps6kb1 activation. Further pilot tests demonstrated that Rps6kb1
is subjected to another post-translational modification, K63 polyubiquitination. Lysine 85 was identified as the
critical site for this modification through multiple mutagenesis assays, and Lys85Ala mutation strongly diminished
both ubiquitination and activation of Rps6kb1. In this grant application, the role of ERK-mediated phosphorylation
of Rps6kb1 will be further characterized, and its implications in adaptive hypertrophic growth and heart failure
will be illustrated using both gain- and loss-of-function mouse models. In addition, the relevance and significance
of Lys85 ubiquitination in hypertensive heart disease will be delineated by identification of the responsible E3
ligase and evaluation of the novel Lys85Ala knock-in mouse model. Moreover, the interplay between this novel
phosphorylation and this new ubiquitination in cardiac hypertrophy will be interrogated. Primary cardiomyocyte
culture will be employed to complement in vivo animal models at the mechanistic level. Elucidation of the role of
Rps6kb1 as an integrative player in pathological cardiac remodeling will advance our u...

## Key facts

- **NIH application ID:** 10977873
- **Project number:** 1R01HL171309-01A1
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Zhao Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $846,536
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977873

## Citation

> US National Institutes of Health, RePORTER application 10977873, Integrative role of Rps6kb1 in pathological cardiac remodeling (1R01HL171309-01A1). Retrieved via AI Analytics 2026-06-07 from https://api.ai-analytics.org/grant/nih/10977873. Licensed CC0.

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