Alteration in tyrosine phosphorylation of cardiac proteome and EGFR pathway contribute to hypertrophic cardiomyopathy

Abstract

Alterations of serine/threonine phosphorylation of the cardiac proteome are a hallmark of heart failure. However, the contribution of tyrosine phosphorylation (pTyr) to the pathogenesis of cardiac hypertrophy remains unclear. We use global mapping to discover and quantify site-specific pTyr in two cardiac hypertrophic mouse models, i.e., cardiac overexpression of ErbB2 (TgErbB2) and α myosin heavy chain R403Q (R403Q-αMyHC Tg), compared to control hearts. From this, there are significant phosphoproteomic alterations in TgErbB2 mice in right ventricular cardiomyopathy, hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM) pathways. On the other hand, R403Q-αMyHC Tg mice indicated that the EGFR1 pathway is central for cardiac hypertrophy, along with angiopoietin, ErbB, growth hormone, and chemokine signaling pathways activation. Surprisingly, most myofilament proteins have downregulation of pTyr rather than upregulation. Kinase-substrate enrichment analysis (KSEA) shows a marked downregulation of MAPK pathway activity downstream of k-Ras in TgErbB2 mice and activation of EGFR, focal adhesion, PDGFR, and actin cytoskeleton pathways. In vivo ErbB2 inhibition by AG-825 decreases cardiomyocyte disarray. Serine/threonine and tyrosine phosphoproteome confirm the above-described pathways and the effectiveness of AG-825 Treatment. Thus, altered pTyr may play a regulatory role in cardiac hypertrophic models.

ESCRT-III Component CHMP4C Attenuates Cardiac Hypertrophy by Targeting the Endo-Lysosomal Degradation of EGFR

“…The endosomal sorting complex required for transport III complex reportedly regulates endo-lysosomal trafficking and facilitates lysosome-mediated EGFR degradation, 8,13 which is crucial for the development of cardiac hypertrophy. 7,18,19 Therefore, we hypothesized that CHMP4C deficiency might impair EGFR trafficking and degradation, consequently promoting cardiac hypertrophy progression. To validate this hypothesis, we evaluated EGFR expression levels in the hypertrophic hearts of WT and CHMP4C KO mice.…”

EGFR/IGF1R Signaling Modulates Relaxation in Hypertrophic Cardiomyopathy

“…Thus, this raises the possibility that the EGFR/IGFR1 cluster is an especially potent target to treat diastolic dysfunction in HCM, which aligns with the previous observation that EGFR signaling is implicated in an HCM mouse model. 28 The EGFR signaling cluster comprises regulators of cardiac contractility that are less well studied. The receptor tyrosine kinases EGFR and IGFR1 phosphorylate and activate the downstream targets FAK (PTK2 [protein tyrosine kinase 2]), Src, and ROCK2 (Rho associated coiledcoil containing protein kinase 2).…”

“…Thus, this raises the possibility that the EGFR/IGFR1 cluster is an especially potent target to treat diastolic dysfunction in HCM, which aligns with the previous observation that EGFR signaling is implicated in an HCM mouse model. 28…”