Neurofibromin binds to caveolin-1 and regulates ras, FAK, and Akt
Neurofibromin binds to caveolin-1 and regulates ras, FAK, and Akt
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DOI：
10.1016/j.bbrc.2005.12.129
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发表时间：
2006-02-24
影响因子：
3.1
通讯作者：
Mikol, DD
中科院分区：
文献类型：
--
作者：
Boyanapalli, M;Lahoud, OB;Mikol, DD
神经纤维蛋白(NFL)是一种类似于280 kDa的具有肿瘤抑制功能的蛋白，可能是通过其GTP酶激活结构域，但对其效应通路的分子方面知之甚少。小窝蛋白-1(Cav-1)调节多种信号分子，并被认为是一种肿瘤抑制因子。在这里，我们证明了NFL结合到CAV-1的S支架结构域，并与CAV-1免疫共沉淀。对NFL一级结构的分析揭示了四个潜在的小窝蛋白结合域，有趣的是，在患有神经纤维瘤病1的个体中，4个假定结构域中的3个发生了高频率的错义突变。我们发现，NFL调节ras、Akt和粘着斑激酶通路，从而影响细胞骨架组织；此外，当脂筏和小窝被胆固醇耗竭破坏时，NFL对信号的影响被改变。这些新的发现为NFL可能的信号机制提供了洞察力，并提示NFL和Cav-1可能共同协调调节细胞的生长和分化。(C)2005 Elsevier Inc.保留所有权利。
Neurofibromin (Nfl) is a similar to 280 kDa protein having tumor suppressor function, presumably by virtue of its GTPase activating domain, but little is known regarding molecular aspects of its effector pathways. Caveolin-1 (Cav-1) regulates diverse signaling molecules and has itself been implicated as a tumor suppressor. Here we demonstrate that Nfl binds to Cav-1's scaffolding domain and co-immunoprecipitates with Cav-1. Analysis of Nfl's primary structure reveals four potential caveolin binding domains, and interestingly, in individuals with neurofibromatosis 1, missense mutations occur with high frequency in 3 of the 4 putative domains. We show that Nfl modulates ras, Akt, and focal adhesion kinase pathways, thereby affecting cytoskeletal organization; moreover, Nfl's effects on signaling are altered when lipid rafts and caveolae are disrupted by cholesterol depletion. These novel findings provide insight into possible signaling mechanisms of Nfl and suggest that together Nfl and Cav-1 may coordinately regulate cell growth and differentiation. (c) 2005 Elsevier Inc. All rights reserved.