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首页> 外文期刊>Biology Open >Stability of the tumor suppressor merlin depends on its ability to bind paxillin LD3 and associate with β1 integrin and actin at the plasma membrane
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Stability of the tumor suppressor merlin depends on its ability to bind paxillin LD3 and associate with β1 integrin and actin at the plasma membrane

机译：抑癌蛋白merlin的稳定性取决于其结合paxillin LD3并与质膜上的β1整联蛋白和肌动蛋白结合的能力

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The NF2 gene encodes a tumor suppressor protein known as merlin or schwannomin whose loss of function causes Neurofibromatosis Type 2 (NF2). NF2 is characterized by the development of benign tumors, predominantly schwannomas, in the peripheral nervous system. Merlin links plasma membrane receptors with the actin cytoskeleton and its targeting to the plasma membrane depends on direct binding to the paxillin scaffold protein. Exon 2 of NF2 , an exon mutated in NF2 patients and deleted in a mouse model of NF2, encodes the merlin paxillin binding domain (PBD1). Here, we sought to determine the role of PBD1 in regulation of merlin stability and association with plasma membrane receptors and the actin cytoskeleton in Schwann cells. Using a fluorescence-based pulse-chase technique, we measured the half-life of Halo-tagged merlin variants carrying PBD1, exon 2, and exons 2 and 3 deletions in transiently transfected Schwann cells. We found that PBD1 alone was necessary and sufficient to increase merlin's half-life from approximately three to eleven hours. Merlin lacking PBD1 did not form a complex with surface β1 integrins or associate with the actin cytoskeleton. In addition, direct binding studies using purified merlin and paxillin domains revealed that merlin directly binds paxillin LD3 (leucine-aspartate 3) domain as well as the LD4 and LD5 domains. Together these results demonstrate that a direct interaction between merlin PBD1 and the paxillin LD3–5 domains targets merlin to the plasma membrane where it is stabilized by its association with surface β1 integrins and cortical actin.
机译：NF2基因编码一种称为merlin或schwannomin的肿瘤抑制蛋白，其功能丧失导致2型神经纤维瘤病（NF2）。 NF2的特征是在周围神经系统中出现良性肿瘤，主要是神经鞘瘤。 Merlin将质膜受体与肌动蛋白细胞骨架相连，其靶向质膜的作用取决于与Paxillin支架蛋白的直接结合。 NF2的外显子2是在NF2病人中突变并在NF2小鼠模型中缺失的外显子，编码merlin paxillin结合域（PBD1）。在这里，我们试图确定PBD1在调控Merlin稳定性以及与质膜受体和Schwann细胞中的肌动蛋白细胞骨架相关的作用。使用基于荧光的脉冲追踪技术，我们测量了在瞬时转染的施万细胞中带有PBD1，外显子2，外显子2和3缺失的Halo标记的merlin变体的半衰期。我们发现单独使用PBD1是必要的，而且足以将merlin的半衰期从大约3小时增加到11小时。缺乏PBD1的Merlin不会与表面β1整合素形成复合物，也不会与肌动蛋白细胞骨架结合。另外，使用纯化的merlin和paxillin结构域的直接结合研究表明，merlin直接结合paxillin LD3（亮氨酸-天冬氨酸3）结构域以及LD4和LD5结构域。这些结果共同表明，merlin PBD1和paxillin LD3-5结构域之间的直接相互作用将merlin靶向质膜，并通过与表面β1整合素和皮质肌动蛋白的结合而使其稳定。

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