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Src/FAK complex phosphorylates cardiac myosin binding protein c (cMyBP-C) in vitro and in vivo

By Ling Wang, Yixin Jin, Jian Wang, Yang Liu, Rui Wang, Shenyuan L. Zhang, Mariappan Muthuchamy, Carl W. Tong, Xu Peng

Posted 29 Jan 2020
bioRxiv DOI: 10.1101/2020.01.28.923870

Cardiac myosin binding protein C (cMyBP-C) is a phosphorylation-dependent force regulator and plays an important role in controlling myosin and actin dynamic interaction. Point-mutations of cMyBP-C that interfere with cMyBP-C threonine/serine phosphorylation resulted in hypertrophic cardiomyopathy and cardiac failure. However, it remains largely unknown how cMyBP-C tyrosine phosphorylation is regulated during cardiac hypertrophy and heart failure. Integrins are receptors of extracellular matrix and are the sensors of cardiac mechanical stretch. Focal adhesion kinase (FAK) plays an essential role in integrin-initiated signal transduction and regulates multiple cellular functions in various types of cells including cardiomyocytes. To identify the regulatory mechanism of cMyBP-C tyrosine phosphorylation during cardiac hypertrophy, we examined the effect of FAK on phosphorylation of cMyBP-C. Immunoprecipitation analysis showed that FAK and cMyBP-C are associated within the intact mouse heart. Results from our mutagenesis experiments demonstrated that the FAK kinase domain was required for FAK to associate with cMyBP-C. Our data also documented that the FAK Y397 site is required for FAK and cMyBP-C association. Importantly, overexpression dominant active Src Y527F with FAK significantly enhanced cMyBP-C phosphorylation. Interestingly, overexpression of cMyBP-C inhibited FAK phosphorylation. Taken together, cMyBP-C is one of effectors of Src/FAK complex in cardiomyocyte.

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