Fibroblast growth factor-regulated palmitoylation of the neural cell adhesion molecule determines neuronal morphogenesis.
Fibroblast growth factor-regulated palmitoylation of the neural cell adhesion molecule determines neuronal morphogenesis.
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DOI：
10.1523/jneurosci.2171-08.2008
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发表时间：
2008-09-03
期刊：
影响因子：
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通讯作者：
Dityatev A
中科院分区：
文献类型：
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作者：
Ponimaskin E;Dityateva G;Ruonala MO;Fukata M;Fukata Y;Kobe F;Wouters FS;Delling M;Bredt DS;Schachner M;Dityatev A
在神经系统的发育过程中，短程和长程信号合作促进轴突生长、引导和靶神经支配。特别地，短程信号转导子，神经细胞粘附分子（NCAM），通过需要NCAM的翻译后修饰和通过受体向长程信使，成纤维细胞生长因子（FGF）的信号传导的机制刺激神经突生长。在本研究中，我们进一步表征了调节NCAM和FGF受体之间的功能相互作用的机制。我们发现FGF 2激活FGF受体导致两种主要的跨膜NCAM亚型NCAM 140和NCAM 180棕榈酰化，NCAM易位到含有GM 1神经节苷脂的脂筏，并刺激海马神经元的轴突生长。消融NCAM、突变NCAM 140或NCAM 180棕榈酰化位点或药理学抑制NCAM信号传导抑制FGF 2刺激的神经突生长。在23个含有组氨酸-半胱氨酸（DHHC）结构域的蛋白质中，DHHC-7最强烈地刺激NCAM的棕榈酰化，并且FGF 2增强酶活性。因此，我们的研究揭示了生长因子通过激活棕榈酰化调节神经元形态发生的分子机制，棕榈酰化反过来又改变亚细胞位置，从而通过粘附分子发出信号。
During development of the nervous system, short- and long-range signals cooperate to promote axonal growth, guidance, and target innervation. Particularly, a short-range signal transducer, the neural cell adhesion molecule (NCAM), stimulates neurite outgrowth via mechanisms that require posttranslational modification of NCAM and signaling via receptors to a long-range messenger, the fibroblast growth factor (FGF). In the present study we further characterized a mechanism which regulates the functional interplay between NCAM and FGF receptor(s). We show that activation of FGF receptor(s) by FGF2 leads to palmitoylation of the two major transmembrane NCAM isoforms, NCAM140 and NCAM180, translocation of NCAM to GM1 ganglioside-containing lipid rafts, and stimulation of neurite outgrowth of hippocampal neurons. Ablation of NCAM, mutation of NCAM140 or NCAM180 palmitoylation sites, or pharmacological suppression of NCAM signaling inhibited FGF2-stimulated neurite outgrowth. Of the 23 members of the aspartate-histidine-histidine-cysteine (DHHC) domain containing proteins, DHHC-7 most strongly stimulated palmitoylation of NCAM, and enzyme activity was enhanced by FGF2. Thus, our study uncovers a molecular mechanism by which a growth factor regulates neuronal morphogenesis via activation of palmitoylation, which in turn modifies subcellular location and thus signaling via an adhesion molecule.