Ditlevsen Dorte K, Køhler Lene B, Pedersen Martin V, Risell Michael, Kolkova Kateryna, Meyer Morten, Berezin Vladimir, Bock Elisabeth
The Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Panum Institute, Copenhagen, Denmark.
J Neurochem. 2003 Feb;84(3):546-56. doi: 10.1046/j.1471-4159.2003.01538.x.
The neural cell adhesion molecule, NCAM, is known to stimulate neurite outgrowth from primary neurones and PC12 cells presumably through signalling pathways involving the fibroblast growth factor receptor (FGFR), protein kinase A (PKA), protein kinase C (PKC), the Ras-mitogen activated protein kinase (MAPK) pathway and an increase in intracellular Ca2+ levels. Stimulation of neurones with the synthetic NCAM-ligand, C3, induces neurite outgrowth through signalling pathways similar to the pathways activated through physiological, homophilic NCAM-stimulation. We present here data indicating that phosphatidylinositol 3-kinase (PI3K) is required for NCAM-mediated neurite outgrowth from PC12-E2 cells and from cerebellar and dopaminergic neurones in primary culture, and that the thr/ser kinase Akt/protein kinase B (PKB) is phosphorylated downstream of PI3K after stimulation with C3. Moreover, we present data indicating a survival-promoting effect of NCAM-stimulation by C3 on cerebellar and dopaminergic neurones induced to undergo apoptosis. This protective effect of C3 included an inhibition of both DNA-fragmentation and caspase-3 activation. The survival-promoting effect of NCAM-stimulation was also shown to be dependent on PI3K.
已知神经细胞黏附分子（NCAM）可通过涉及成纤维细胞生长因子受体（FGFR）、蛋白激酶A（PKA）、蛋白激酶C（PKC）、Ras-丝裂原活化蛋白激酶（MAPK）途径以及细胞内Ca2+水平升高的信号通路，刺激原代神经元和PC12细胞的神经突生长。用合成的NCAM配体C3刺激神经元，可通过与生理同源性NCAM刺激激活的途径相似的信号通路诱导神经突生长。我们在此展示的数据表明，磷脂酰肌醇3激酶（PI3K）是PC12-E2细胞以及原代培养的小脑和多巴胺能神经元中NCAM介导的神经突生长所必需的，并且在用C3刺激后，苏氨酸/丝氨酸激酶Akt/蛋白激酶B（PKB）在PI3K的下游被磷酸化。此外，我们展示的数据表明，C3刺激NCAM对诱导发生凋亡的小脑和多巴胺能神经元具有促存活作用。C3的这种保护作用包括抑制DNA片段化和半胱天冬酶-3激活。NCAM刺激的促存活作用也显示依赖于PI3K。
