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

Authors

Mingguo Xu
Kevin C. Bermea
Marzieh Ayati, The University of Texas Rio Grande ValleyFollow
Han Byeol Yang
Xiaomei Yang
Andres Medina, The University of Texas Rio Grande Valley
Zongming Fu
Amir Heravi
Xinyu Zhang
Chan Hyun Na
Allen Everett
Kathleen Gabrielson
D. Brian Foster
Nazareno Paolocci
Anne M. Murphy
Genaro A. Ramirez-Correa, The University of Texas Rio Grande Valley

Document Type

Article

Publication Date

11-15-2022

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.

Comments

Copyright © 2022, The Author(s)

Recommended Citation

Xu, M., Bermea, K.C., Ayati, M. et al. Alteration in tyrosine phosphorylation of cardiac proteome and EGFR pathway contribute to hypertrophic cardiomyopathy. Commun Biol 5, 1251 (2022). https://doi.org/10.1038/s42003-022-04021-4

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Publication Title

Communications Biology

DOI

10.1038/s42003-022-04021-4

Academic Level

faculty

Mentor/PI Department

Molecular Science