Moreover, CLKs also play roles in processes other than RNA splicing. Functionally, CLKs act as putative high-level regulators of alternative splicing through phosphorylation of serine/arginine-rich domains on splicing factors (SR proteins), thus exerting regulatory effects in a plethora of biological processes, such as oncogenesis, cancer cell migration, and invasion, and virus replication 5, 6, 7. The CLK family consists of four members: CLK1, CLK2, CLK3, and CLK4. Although previous mechanistic studies have identified a multitude of signaling pathways that are crucial to pathological cardiac hypertrophy, there have been no breakthroughs in the treatment of the disease.ĬDC-like kinases (CLKs) are an evolutionarily conserved family of dual-specificity CMGC kinases that can autophosphorylate at tyrosine residues and phosphorylate their substrates exclusively on serine/threonine residues 3, 4. While it is initially an adaptive response to maintain cardiac output, prolonged hypertrophic growth is associated with pathological cardiac hypertrophy 1. In response to pathological stimuli, such as hypertension and valve defects, the heart undergoes hypertrophic growth characterized by an increase in cardiomyocyte size and re-expression of the fetal gene program 1, 2. CLK4 is a potential intervention target for the prevention and treatment of heart failure.
We conclude that CLK4 regulates cardiac function through phosphorylation of NEXN, and its deficiency may lead to pathological cardiac hypertrophy. Importantly, restoring phosphorylation of NEXN ameliorates myocardial hypertrophy in mice with cardiac-specific Clk4 deletion. Further investigation identifies nexilin (NEXN) as the direct substrate of CLK4, and overexpression of a phosphorylation-mimic mutant of NEXN is sufficient to reverse the hypertrophic growth of cardiomyocytes induced by Clk4 knockdown. Cardiac-specific Clk4-knockout mice manifest pathological myocardial hypertrophy with progressive left ventricular systolic dysfunction and heart dilation. Knockdown of Clk4 leads to pathological cardiomyocyte hypertrophy, while overexpression of Clk4 confers resistance to phenylephrine-induced cardiomyocyte hypertrophy. Here, we show that CDC-like kinase 4 (CLK4) is a critical regulator of cardiomyocyte hypertrophy and heart failure. Kinase-catalyzed phosphorylation plays a crucial role in pathological cardiac hypertrophy.
0 kommentar(er)
