Langhorst Matthias F, Jaeger Friederike A, Mueller Stephanie, Sven Hartmann L, Luxenhofer Georg, Stuermer Claudia A O
Department of Biology, University of Konstanz, Developmental Neurobiology Group, Universitätsstrasse 10, D-78457 Konstanz, Germany.
Eur J Cell Biol. 2008 Dec;87(12):921-31. doi: 10.1016/j.ejcb.2008.07.001. Epub 2008 Aug 21.
The reggies/flotillins were discovered as proteins upregulated during axon regeneration. Here, we show that expression of a trans-negative reggie-1/flotillin-2 deletion mutant, R1EA, which interferes with oligomerization of the reggies/flotillins, inhibited insulin-like growth factor (IGF)-induced neurite outgrowth in N2a neuroblastoma cells and impaired in vitro differentiation of primary rat hippocampal neurons. Cells expressing R1EA formed only short and broad membrane protrusions often with abnormally large growth cones. R1EA expression strongly perturbed the balanced activation of the Rho-family GTPases Rac1 and cdc42. Furthermore, focal adhesion kinase (FAK) activity was also enhanced by R1EA expression, while other signaling pathways like ERK1/2, PKC or PKB signaling were unaffected. These severe signaling defects were caused by an impaired recruitment of the reggie/flotillin-associated adaptor molecule CAP/ponsin to focal contacts at the plasma membrane. Thus, the reggies/flotillins are crucial for coordinated assembly of signaling complexes regulating cytoskeletal remodeling.
瑞吉蛋白/浮舰蛋白是在轴突再生过程中作为上调蛋白被发现的。在此，我们表明，一种反式负性瑞吉蛋白-1/浮舰蛋白-2缺失突变体R1EA的表达会干扰瑞吉蛋白/浮舰蛋白的寡聚化，它抑制了胰岛素样生长因子（IGF）诱导的N2a神经母细胞瘤细胞的神经突生长，并损害了原代大鼠海马神经元的体外分化。表达R1EA的细胞仅形成短而宽的膜突起，且常常伴有异常大的生长锥。R1EA的表达强烈扰乱了Rho家族小GTP酶Rac1和cdc42的平衡激活。此外，R1EA的表达还增强了粘着斑激酶（FAK）的活性，而其他信号通路如ERK1/2、PKC或PKB信号通路则未受影响。这些严重的信号缺陷是由瑞吉蛋白/浮舰蛋白相关衔接分子CAP/桥蛋白募集到质膜上的粘着斑受损所致。因此，瑞吉蛋白/浮舰蛋白对于调节细胞骨架重塑的信号复合物的协调组装至关重要。
