ERG1 plays an essential role in rat cardiomyocyte fate decision by mediating AKT signaling

Abstract

ERG1, a potassium ion channel, is essential for cardiac action potential repolarization phase. However, the role of ERG1 for normal development of the heart is poorly understood. Using the rat embryonic stem cells (rESCs) model, we show that ERG1 is crucial in cardiomyocyte lineage commitment via interactions with Integrin β1. In the mesoderm phase of rESCs, the interaction of ERG1 with Integrin β1 can activate the AKT pathway by recruiting and phosphorylating PI3K p85 and focal adhesion kinase (FAK) to further phosphorylate AKT. Activation of AKT pathway promotes cardiomyocyte differentiation through two different mechanisms, (a) through phosphorylation of GSK3β to upregulate the expression levels of β-catenin and Gata4;(b) through promotion of nuclear translocation of nuclear factor-κB by phosphorylating IKKβ to inhibit cell apoptosis, which occurs due to increased Bcl2 expression. Our study provides solid evidence for a novel role of ERG1 on differentiation of rESCs into cardiomyocytes.

Ion Channels and Transporters in Muscle Cell Differentiation

“…Notably, it was proposed that SKCa activation induces efficient cardiac differentiation of ESCs by activating the Ras-Mek1/2-ERK1/2 signal transduction pathway [118]. A recent study showed that the K + channel ERG1 is involved in the cardiac differentiation of rat ESCs by interacting with integrin β1 and thus activating the AKT pathway (Figure 4) [119]. The sources of intracellular Ca 2+ signals vary with the differentiation stage of PSCderived cardiomyocytes and embryos maintained ex vivo [121][122][123].…”

KCNH2 encodes a nuclear-targeted polypeptide that mediates hERG1 channel gating and expression

“…This adds to a growing body of work that highlights roles for KCNH2 that are unrelated to cardiac repolarization. Recent work in rat cells demonstrated that rERG1 complexes with integrin β1 to activate FAK signaling during cardiac differentiation and cardiac recovery following sepsis ( 49 , 50 ). hERG1 displays a similar role in cancer lines, where hERG1 promotes proliferation and metastasis ( 51 , 52 ).…”

Focal Adhesion’s Role in Cardiomyocytes Function: From Cardiomyogenesis to Mechanotransduction

“…At the molecular level, during cardiomyocyte differentiation, the maturation process of FAs plays an important role in activating different pathways and genes, such as integrin/FAK/PI3K-P85, which is activated by the interaction between laminins and early growth response protein 1 (ERG1), forming a complex with b1D integrin. The consecutive phosphorylation of FAK and PI3K-P85 activates AKT, inhibiting Wnt-GSK3b, which, in turn, upregulates β-catenin and GATA-4, necessary for cardiac differentiation [35][36][37][38].…”

“…Integrin/FAK/PI3K-P85 pathway FA's maturation process in cardiac differentiation. [35][36][37][38] FAK-Tyr397 phosphorylation Myocardial development, activate survival-promoting pathways. [45][46][47] Proteins Involved in FA Maturation Mint1/Veli/SAP97/CASK complex Structural and functional support to the sarcomere.…”