Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without...

Area of Science:

• Molecular Biology
• Cardiovascular Research
• Oncology

Background:

• Dysregulated extracellular signal-regulated kinases (ERK1/2) signaling is implicated in heart failure, genetic syndromes, and cancer.
• Direct ERK1/2 inhibition causes cardiotoxicity, limiting therapeutic use.
• ERK^T188-autophosphorylation drives pathological cardiac hypertrophy.

Purpose of the Study:

• To investigate if inhibiting ERK dimerization, a prerequisite for ERK^T188-phosphorylation, can mitigate pathological ERK1/2 signaling.
• To evaluate the therapeutic potential of an ERK-dimerization inhibitory peptide (EDI) in heart failure and cancer models.
• To assess the safety profile of EDI, particularly regarding cardiac side effects.

Main Methods:

• Development and application of an ERK-dimerization inhibitory peptide (EDI).
• Assessment of EDI's effect on ERK^T188-phosphorylation, nuclear ERK1/2 signaling, and cardiomyocyte hypertrophy in vitro and in vivo.
• Evaluation of EDI's efficacy in a mouse model of pressure-overload-induced heart failure.
• Testing EDI's impact on cancer cell proliferation and cardiotoxicity.

Main Results:

• EDI effectively prevented ERK^T188-phosphorylation and subsequent cardiomyocyte hypertrophy.
• EDI protected against pressure-overload-induced heart failure in mice without adverse cardiac effects.
• EDI preserved essential ERK1/2 activity and cytosolic survival signaling.
• EDI suppressed cancer cell proliferation and demonstrated no cardiotoxicity.

Conclusions:

• Interference with ERK dimerization is a viable strategy to combat pathological ERK1/2 signaling.
• EDI offers a cardio-safe therapeutic approach for ERK1/2-related diseases, including heart failure and cancer.
• This strategy may broaden therapeutic options for various diseases linked to ERK1/2 dysregulation.