Regulation of GAP-43 at serine 41 acts as a switch to modulate both intrinsic and extrinsic behaviors of growing neurons, via altered membrane distribution.
Regulation of GAP-43 at serine 41 acts as a switch to modulate both intrinsic and extrinsic behaviors of growing neurons, via altered membrane distribution.
复制标题
DOI：
10.1016/j.mcn.2009.01.011
复制
发表时间：
2009-05
影响因子：
3.5
通讯作者：
Meiri, Karina F.
中科院分区：
文献类型：
--
作者：
Nguyen, Lilly;He, Qin;Meiri, Karina F.
关键词：
GAP-43是蛋白激酶C（PKC）的主要神经底物。它的磷酸化状态决定了GAP-43（+/-）生长锥在体内的寻路错误的严重程度，以及它在体外对肌动蛋白动力学的调节。这些实验表明，在维甲酸处理的SH-Sy 5 Y神经母细胞瘤细胞中，稳定过表达在其丝氨酸41处的单个PKC磷酸化位点处突变的cDNA调节生长神经元的内在和外在行为。内部，只有Wt和pseudophosphorylated GAP-43 Ser 41 Asp沉淀与F-肌动蛋白和增强F-肌动蛋白调节丝状伪足的形成。GAP-43 Ser 41 Asp抑制神经突的生长，而只有非磷酸化的GAP-43 Ser 41 Ala沉淀神经微管蛋白，增强神经微管蛋白在神经突中的积累，并增加生长。当PI 3-激酶被抑制时，GAP-43 Ser 41 Asp介导的丝状伪足形成被抑制，而GAP-43 Ser 41 Ala介导的神经突延伸被增强。在体外，只有Wt和GAP-43 Ser 41 Asp增强了NCAM表达单层上的同型粘附和神经突生长，并促进了NCAM的稳定性。关于潜在的机制，更多的F-肌动蛋白和NCAM与Wt和GAP-43 Ser 41 Asp共定位在从活细胞分离的抗洗涤剂膜（DRM）中，GAP-43 Ser 41 Asp介导的功能对胆固醇消耗不敏感。相反，GAP-43 Ser 41 Ala介导的功能对胆固醇消耗敏感。GAP-43 Ser 41 Asp和GAP-43 Ser 41 Ala都不能保护PIP 2抑制剂介导的生长锥塌陷。结果表明，GAP-43在其PKC磷酸化位点的修饰将其分布导向不同的膜微区，这些微区在生长神经元的内在和外在行为的调节中具有不同的作用。
GAP-43 is the major neuronal substrate of protein kinase C (PKC). Its phosphorylation status dictates the severity of pathfinding errors by GAP-43 (+/-) growth cones in vivo, as well as its modulation of actin dynamics in vitro. These experiments show that stably overexpressing cDNAs mutant at its single PKC phosphorylation site at serine41 in retinoic-acid treated SH-Sy5Y neuroblastoma cells regulates intrinsic and extrinsic behaviors of growing neurons. Intrinsically, only Wt and pseudophosphorylated GAP-43Ser41Asp precipitated with F-actin and potentiated F-actin – regulated filopodia formation. GAP-43Ser41Asp inhibited neurite outgrowth whereas only unphosphorylatable GAP-43Ser41Ala precipitated neurotubulin, potentiated neurotubulin accumulation in neurites and increased outgrowth. When PI3-kinase was inhibited GAP-43Ser41Asp-mediated filopodia formation was inhibited whereas GAP-43Ser41Ala-mediated neurite extension was potentiated. Extrinsically, only Wt and GAP-43Ser41Asp potentiated both homotypic adhesion and neurite outgrowth on NCAM-expressing monolayers and promoted NCAM stability. With respect to the underlying mechanism, more F-actin and NCAM colocalized with Wt and GAP-43Ser41Asp in detergent resistant membranes (DRMs) isolated from live cells and GAP-43Ser41Asp-mediated functions were insensitive to cholesterol depletion. In contrast, GAP-43Ser41Ala-mediated functions were sensitive to cholesterol depletion. Neither GAP-43Ser41Asp nor GAP-43Ser41Ala was able to protect against growth cone collapse mediated by PIP2 inhibitors. The results show that modification of GAP-43 at its PKC phosphorylation site directs its distribution to different membrane microdomains that have distinct roles in the regulation of intrinsic and extrinsic behaviors in growing neurons.
登录
查看更多内容
DOI：
10.1083/jcb.123.2.417
发表时间：
1993-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Aigner L;Caroni P
通讯作者：
Caroni P
影响因子：
16.2
作者：
Guirland, C;Suzuki, S;Zheng, JQ
通讯作者：
Zheng, JQ
DOI：
10.1007/978-0-387-76715-4_1
发表时间：
2007-01-01
期刊：
AXON GROWTH AND GUIDANCE
影响因子：
--
作者：
Bouquet, Celine;Nothias, Fatiha
通讯作者：
Nothias, Fatiha
影响因子：
4.8
作者：
Arni, S;Keilbaugh, SA;Brown, DA
通讯作者：
Brown, DA
影响因子：
64.5
作者：
AIGNER, L;ARBER, S;CARONI, P
通讯作者：
CARONI, P