Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel.
Mol Cell Neurosci. 2009 Dec;42(4):278-87. doi: 10.1016/j.mcn.2009.07.014. Epub 2009 Aug 7.
Neurofibromin contains several domains, most notably a GAP-related domain (GRD), that down-regulates Ras pathways. The functions of the non-GRD neurofibromin domains are largely known. Here we show that the pre-GRD region of neurofibromin alters the expression of genes involved in cell adhesion and migration and acts as a negative regulator of the Rac1/Pak1/LIMK1/cofilin pathway. Thus, neurofibromin-deficient glioblastoma and mouse fibroblasts are enriched in Rac1-GTP, p-Pak1, p-LIMK1 and p-cofilin, with all proteins exhibiting decreased expression upon expression of NF1(1-1163) polypeptide. Concomitantly, actin stress fibers and focal adhesion were disassembled and cell migration was halted. These effects were independent of the Ras signaling pathways. It seems that NF1(1-1163), through negative regulation of Rac-1, shifts the balance from a state of inactive phospho-cofilin to active unphosphorylated cofilin, resulting in severing of F-actin. Impairment of these cellular functions of neurofibromin provides novel insights into the invasiveness/progression of NF1-associated tumors.
神经纤维瘤蛋白包含几个结构域，特别是一个 GAP 相关结构域（GRD），可下调 Ras 通路。非 GRD 神经纤维瘤蛋白结构域的功能在很大程度上是已知的。在这里，我们表明神经纤维瘤蛋白的 GRD 前区域改变了参与细胞黏附和迁移的基因的表达，并作为 Rac1/Pak1/LIMK1/丝切蛋白途径的负调节剂。因此，神经纤维瘤蛋白缺陷型神经胶质瘤和小鼠成纤维细胞富含 Rac1-GTP、p-Pak1、p-LIMK1 和 p-丝切蛋白，所有蛋白在表达 NF1(1-1163)多肽后表达量降低。同时，肌动蛋白应力纤维和焦点黏附被解体，细胞迁移停止。这些效应独立于 Ras 信号通路。似乎 NF1(1-1163)通过负调控 Rac-1，将磷酸化丝切蛋白的无活性状态与活性非磷酸化丝切蛋白的平衡转移，导致 F-肌动蛋白的切断。神经纤维瘤蛋白这些细胞功能的损伤为 NF1 相关肿瘤的侵袭/进展提供了新的见解。
