Generation and Nuclear Translocation of Sumoylated Transmembrane Fragment of Cell Adhesion Molecule L1
Generation and Nuclear Translocation of Sumoylated Transmembrane Fragment of Cell Adhesion Molecule L1
复制标题
DOI：
10.1074/jbc.m112.346759
复制
发表时间：
2012-05-18
影响因子：
4.8
通讯作者：
Kleene, Ralf
中科院分区：
文献类型：
--
作者：
Lutz, David;Wolters-Eisfeld, Gerrit;Kleene, Ralf
细胞粘附分子L1在发育和成人神经系统中的功能是由亲同性和异性相互作用触发的，这种相互作用刺激信号转导，激活细胞反应。在这里，我们发现通过功能触发L1抗体或L1- fc刺激信号传导导致丝氨酸蛋白酶依赖的质膜全长L1的切割，并产生一个70 kda的跨膜转录片段，包括细胞内和跨膜结构域以及部分细胞外结构域。70 kda的跨膜片段从质膜运输到内体晚期腔室，从内体膜释放到细胞质，并通过依赖输入蛋白和染色质修饰蛋白1的途径从那里转移到细胞核。Lys的sumoylation位点（1172）或Lys的核定位信号（1147）的突变分别使l1刺激的产生或70 kda片段的核输入消失。70 kda片段的核输入可能与磷酸化依赖的信号通路平行或相关地激活细胞反应。在发育过程中、脊髓损伤后的成年或阿尔茨海默病小鼠模型中，70-kDa片段水平的变化表明，该片段在功能上与成熟神经系统的发育、再生、神经退行性变、肿瘤发生以及可能的突触可塑性有关。
The functions of the cell adhesion molecule L1 in the developing and adult nervous system are triggered by homophilic and heterophilic interactions that stimulate signal transductions that activate cellular responses. Here, we show that stimulation of signaling by function-triggering L1 antibodies or L1-Fc leads to serine protease-dependent cleavage of full-length L1 at the plasma membrane and generation of a sumoylated transmembrane 70-kDa fragment comprising the intracellular and transmembrane domains and part of the extracellular domain. The 70-kDa transmembrane fragment is transported from the plasma membrane to a late endosomal compartment, released from endosomal membranes into the cytoplasm, and transferred from there into the nucleus by a pathway that depends on importin and chromatin-modifying protein 1. Mutation of the sumoylation site at Lys(1172) or of the nuclear localization signal at Lys(1147) abolished L1-stimulated generation or nuclear import of the 70-kDa fragment, respectively. Nuclear import of the 70-kDa fragment may activate cellular responses in parallel or in association with phosphorylation-dependent signaling pathways. Alterations in the levels of the 70-kDa fragment during development and in the adult after spinal cord injury or in a mouse model of Alzheimer disease suggest that this fragment is functionally implicated in development, regeneration, neurode-generation, tumorigenesis, and possibly synaptic plasticity in the mature nervous system.