Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects
Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects
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DOI：
10.1038/s41467-020-15505-4
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发表时间：
2020-04-07
影响因子：
16.6
通讯作者：
Lorenz, Kristina
中科院分区：
文献类型：
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作者：
Tomasovic, Angela;Brand, Theresa;Lorenz, Kristina
细胞外信号调节激酶 (ERK1/2) 的失调与多种疾病有关，包括心力衰竭、遗传综合征和癌症。然而，抑制 ERK1/2 可能会导致严重的心脏副作用，从而妨碍其广泛的治疗应用。 ERKT188-自磷酸化被确定会导致病理性心脏肥大。在这里，我们报告，干扰 ERK-二聚化（ERKT188-磷酸化的先决条件）可最大限度地减少心脏肥大，而不引起心脏不良反应：ERK-二聚化抑制肽（EDI）可防止 ERKT188-磷酸化、核 ERK1/2-信号传导和心肌细胞肥大，从而防止压力超负荷引起的心力衰竭。 小鼠，同时保留 ERK1/2 活性和胞质生存信号。我们还研究了癌症中的这种替代 ERK1/2 靶向策略：事实上，ERKT188 磷酸化在癌症中强烈上调，EDI 有效抑制癌细胞增殖，而不引起心脏毒性。这种干扰 ERK 二聚化的强大心脏安全策略可以对抗心脏和癌症中的病理性 ERK1/2 信号传导，并可能扩大 ERK1/2 相关疾病（例如心力衰竭和遗传综合征）的治疗选择。针对失调的 ERK1/2 信号传导的药物可能会导致严重的心脏副作用，从而妨碍其广泛的治疗应用。在此，提出了一种新的心脏安全靶向策略，该策略干扰 ERK 二聚化，以防止心脏和癌症中的病理性 ERK1/2 信号传导。
Dysregulation of extracellular signal-regulated kinases (ERK1/2) is linked to several diseases including heart failure, genetic syndromes and cancer. Inhibition of ERK1/2, however, can cause severe cardiac side-effects, precluding its wide therapeutic application. ERKT188-autophosphorylation was identified to cause pathological cardiac hypertrophy. Here we report that interference with ERK-dimerization, a prerequisite for ERKT188-phosphorylation, minimizes cardiac hypertrophy without inducing cardiac adverse effects: an ERK-dimerization inhibitory peptide (EDI) prevents ERKT188-phosphorylation, nuclear ERK1/2-signaling and cardiomyocyte hypertrophy, protecting from pressure-overload-induced heart failure in mice whilst preserving ERK1/2-activity and cytosolic survival signaling. We also examine this alternative ERK1/2-targeting strategy in cancer: indeed, ERKT188-phosphorylation is strongly upregulated in cancer and EDI efficiently suppresses cancer cell proliferation without causing cardiotoxicity. This powerful cardio-safe strategy of interfering with ERK-dimerization thus combats pathological ERK1/2-signaling in heart and cancer, and may potentially expand therapeutic options for ERK1/2-related diseases, such as heart failure and genetic syndromes.Drugs targeting dysregulated ERK1/2 signaling can cause severe cardiac side effects, precluding their wide therapeutic application. Here, a new and cardio-safe targeting strategy is presented that interferes with ERK dimerization to prevent pathological ERK1/2 signaling in the heart and cancer.