LIM domain kinases as potential therapeutic targets for neurofibromatosis type 2.
LIM domain kinases as potential therapeutic targets for neurofibromatosis type 2.
复制标题
LIM 结构域激酶作为 2 型神经纤维瘤病的潜在治疗靶点。
作者：
2型神经纤维瘤病（NF2）是由2型神经纤维瘤病（NF2）基因突变引起的，该基因编码一种称为merlin的肿瘤抑制蛋白。NF2的特征是形成多发性神经鞘瘤、脑膜瘤和室管膜瘤。Merlin功能丧失与Rac和p21活化激酶（PAK）活性增加和细胞骨架组织失调有关。LIM结构域激酶（LIMK1和2）是Cdc42/Rac-PAK的底物，并通过磷酸化cofilin的丝氨酸-3来调节肌动蛋白动力学。这种修饰使cofilin的肌动蛋白切断和解聚合活性失活。LIMKs也转运到细胞核中并调节细胞周期进程。值得注意的是，LIMKs在几种肿瘤类型中过表达，包括皮肤、乳腺、肺、肝和前列腺。在这里，我们报告了由于Nf2外显子2缺失导致梅林功能丧失的小鼠雪旺细胞（MSCs） （Nf2ΔEx2）与野生型正常MSCs相比，表现出LIMK1， LIMK2和活性phospho-Thr508/505-LIMK1/2以及phospho-Ser3-cofilin水平升高。同样，与正常的人类雪旺细胞（SCs）相比，人类前庭神经鞘瘤中LIMK1和2总蛋白以及活性磷酸化形式的水平升高。将野生型NF2重新引入Nf2ΔEx2 MSC可降低LIMK1和LIMK2水平。我们发现，BMS-5对LIMK的药理学抑制，以剂量依赖的方式降低了Nf2ΔEx2间质干细胞的活力，但不影响对照间质干细胞的活力。同样，LIMK敲低可降低Nf2ΔEx2间充质干细胞的活力。Nf2ΔEx2间充质干细胞活力的下降不是由于caspase依赖性或非依赖性的凋亡，而是由于G2/M期细胞的积累所证明的细胞周期进程的抑制。抑制LIMKs通过降低Aurora A的激活来阻止细胞早期有丝分裂。我们的研究结果表明LIMKs是NF2和与梅林蛋白缺乏相关的肿瘤的潜在药物靶点。
Neurofibromatosis Type 2 (NF2) is caused by mutations in the neurofibromatosis 2 (NF2) gene that encodes a tumor suppressor protein called merlin. NF2 is characterized by formation of multiple schwannomas, meningiomas and ependymomas. Merlin loss of function is associated with increased activity of Rac and p21-activated kinases (PAK) and deregulation of cytoskeletal organization. LIM domain kinases (LIMK1 and 2) are substrate for Cdc42/Rac-PAK, and modulate actin dynamics by phosphorylating cofilin at serine-3. This modification inactivates cofilin’s actin severing and depolymerizing activity. LIMKs also translocate into the nucleus and regulate cell cycle progression. Significantly, LIMKs are overexpressed in several tumor types, including skin, breast, lung, liver and prostate. Here we report that mouse Schwann cells (MSCs) in which merlin function is lost as a result of Nf2 exon2 deletion (Nf2ΔEx2) exhibited increased levels of LIMK1, LIMK2, and active phospho-Thr508/505-LIMK1/2, as well as phospho-Ser3-cofilin, compared to wild-type normal MSCs. Similarly, levels of LIMK1 and 2 total protein and active phosphorylated forms were elevated in human vestibular schwannomas compared to normal human Schwann cells (SCs). Reintroduction of wild-type NF2 into Nf2ΔEx2 MSC reduced LIMK1 and LIMK2 levels. We show that pharmacological inhibition of LIMK with BMS-5, decreased the viability of Nf2ΔEx2 MSCs in a dose-dependent manner, but did not affect viability of control MSCs. Similarly, LIMK knockdown decreased viability of Nf2ΔEx2 MSCs. The decreased viability of Nf2ΔEx2 MSCs was not due to caspase-dependent or -independent apoptosis, but rather, to inhibition of cell cycle progression as evidenced by accumulation of cells in G2/M phase. Inhibition of LIMKs arrest cells in early mitosis by decreasing Aurora A activation. Our results suggest that LIMKs are potential drug targets for NF2 and tumors associated with merlin deficiency.
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37.3
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12.7
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通讯作者：
Ratner N