RSK3: A regulator of pathological cardiac remodeling

Abstract

The family of p90 ribosomal S6 kinases (RSKs) are pleiotropic effectors for extracellular signal-regulated kinase signaling pathways. Recently, RSK3 was shown to be important for pathological remodeling of the heart. Although cardiac myocyte hypertrophy can be compensatory for increased wall stress, in chronic heart diseases, this nonmitotic cell growth is usually associated with interstitial fibrosis, increased cell death, and decreased cardiac function. Although RSK3 is less abundant in the cardiac myocyte than other RSK family members, RSK3 appears to serve a unique role in cardiac myocyte stress responses. A potential mechanism conferring the unique function of RSK3 in the heart is anchoring by the scaffold protein muscle A-kinase anchoring protein β (mAKAPβ). Recent findings suggest that RSK3 should be considered as a therapeutic target for the prevention of heart failure, a clinical syndrome of major public health significance.

Keywords: Keywords ribosomal S6 kinase; heart; hypertrophy; mAKAP; remodeling; scaffold; signal transduction.

Fig. 1. RSK3 Structure

Like the related mitogen- and stress-activated kinases (MSK), all four RSKs contain two catalytic domains, N-terminal (NTKD) and C-terminal (CTKD) kinase domains (13). In inactive RSK, the CTKD binds the autoinhibitory domain (AID) α-helix. When activated, ERK pre-bound to the D-domain phosphorylates RSK residues, including the CTKD activation loop (T⁵⁷⁰). The CTKD then autophosphorylates S³⁷⁷, permitting PDK1 binding and PDK1 phosphorylation of the NTKD activation loop (S²¹⁸). The NTKD then phosphorylates RSK substrates.

Fig 2. Structures of the Known RSK Inhibitors

Fig. 3. Model for mAKAPβ-RSK3 Signaling

ERK pathways are activated by stress signaling, including α₁-adrenergic receptors (α₁-AR). Anchored by the perinuclear scaffold muscle A-kinase anchoring protein (mAKAPβ), RSK3 is an ERK effector that phosphorylates cytosolic and nuclear substrates, contributing to gene expression that promotes pathological remodeling.