Serine phosphorylation by casein kinase II controls endocytic L1 trafficking and axon growth
Serine phosphorylation by casein kinase II controls endocytic L1 trafficking and axon growth
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DOI：
10.1002/jnr.21185
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发表时间：
2007-03-01
影响因子：
4.2
通讯作者：
Kamiguchi, Hiroyuki
中科院分区：
文献类型：
--
作者：
Nakata, Asuka;Kamiguchi, Hiroyuki
细胞粘附分子L1在轴突束发育中起着重要作用。在体外，作为培养基质的L1通过与生长锥上表达的L1结合来刺激轴突伸长。在迁移的生长锥，L1是内吞通过AP-2/网格蛋白介导的途径在中央域，然后由顺行囊泡运输和回收到质膜的领先的前线。先前已经表明，L1的这种内吞运输对于轴突伸长是至关重要的（Kamiguchi和Yoshihara [2001] J. Neurosci. 21：91949203）。邻近AP-2识别位点，L1胞质结构域具有一簇酸性氨基酸，其含有可被酪蛋白激酶II磷酸化的Ser 1181（CKII; Wong等人[1996 a] J. Neurochem. 66：779786）。在本文中，我们表明，Ser 1181磷酸化CKII是牵连在两个正常的enclocytic贩运L1和L1刺激轴突生长。而L1的内吞作用后，转铁蛋白阳性内体的排序，药理学抑制CKII导致一些人口的L1被内化到转铁蛋白阴性的车厢。在Ser 1181的单氨基酸突变，其阻止或模拟CKII的磷酸化，引起类似的内化L1的错误分选。此外，背根神经节神经元，已与CKII抑制剂或转染的L1突变体显示受损的能力，延长轴突上的L1基板，但不是在其他控制基板。这些结果表明CKII在L1介导的轴突伸长中的新作用，并强调了L1磷酸化和L1贩运在迁移生长锥中的功能联系的重要性。(c)2007 Wiley-Liss，Inc.
The cell adhesion molecule L1 plays crucial roles in axon tract development. In vitro, L1 presented as a culture substrate stimulates axon elongation by binding to L1 expressed on the growth cone. In migrating growth cones, L1 is endocytosed via the AP-2/clathrin-mediated pathway at the central domain, followed by anterograde vesicular transport and recycling to the plasma membrane of the leading front. It has previously been shown that this endocytic trafficking of L1 is critical for axon elongation (Kamiguchi and Yoshihara [2001] J. Neurosci. 21:91949203). Adjacent to the AP-2 recognition site, the L1 cytoplasmic domain has a cluster of acidic amino acids containing Serl 181 that can be phosphorylated by casein kinase II (CKII; Wong et al. [1996a] J. Neurochem. 66:779786). In this paper, we demonstrate that Ser1181 phosphorylation by CKII is implicated in both normal enclocytic trafficking of L1 and L1-stimulated axon growth. Whereas L1 is sorted into transferrin-positive endosomes after endocytosis, pharmacological inhibition of CKII caused some population of L1 to be internalized into transferrin-negative compartments. Single-amino-acid mutations at Serl 181, which either prevent or mimic phosphorylation by CKII, caused similar missorting of internalized L1. Furthermore, dorsal root ganglion neurons that had been treated with a CKII inhibitor or transfected with the L1 mutants showed impaired ability to extend axons on an L1 substrate but not on other control substrates. These results demonstrate the novel role of CKII in L1-mediated axon elongation and stress the importance of functional linkage between L1 phosphorylation and L1 trafficking in migrating growth cones. (c) 2007 Wiley-Liss,inc.