Schmid R S, Graff R D, Schaller M D, Chen S, Schachner M, Hemperly J J, Maness P F
Department of Biochemistry, School of Medicine, University of North Carolina, Chapel Hill 27599-7260, USA.
J Neurobiol. 1999 Mar;38(4):542-58.
The neural cell adhesion molecule NCAM plays an important role in axonal growth, learning, and memory. A signaling pathway has been elucidated in which clustering of the NCAM140 isoform in the neural plasma membrane stimulated the activating phosphorylation of mitogen-activated protein kinases (MAPKs) and the transcription factor cyclic AMP response-element binding protein (CREB). NCAM clustering transiently induced dual phosphorylation (activation) of the MAPKs ERK1 and ERK2 (extracellular signal-regulated kinases) by a pathway regulated by the focal adhesion kinase p125fak, p59fyn, Ras, and MAPK kinase. CREB phosphorylation at serine 133 induced by NCAM was dependent in part on an intact MAPK pathway. c-Jun N-terminal kinase, which is associated with apoptosis and cellular stress, was not activated by NCAM. Inhibition of the MAPK pathway in rat cerebellar neuron cultures selectively reduced NCAM-stimulated neurite outgrowth. These results define an NCAM signal transduction mechanism with the potential for modulating the expression of genes needed for axonal growth, survival, and synaptic plasticity.
神经细胞黏附分子NCAM在轴突生长、学习和记忆中发挥重要作用。已阐明一条信号通路，其中神经细胞质膜中NCAM140亚型的聚集刺激了丝裂原活化蛋白激酶（MAPK）和转录因子环磷酸腺苷反应元件结合蛋白（CREB）的活化磷酸化。NCAM聚集通过由粘着斑激酶p125fak、p59fyn、Ras和MAPK激酶调节的途径瞬时诱导MAPK ERK1和ERK2（细胞外信号调节激酶）的双磷酸化（激活）。NCAM诱导的丝氨酸133处的CREB磷酸化部分依赖于完整的MAPK途径。与细胞凋亡和细胞应激相关的c-Jun氨基末端激酶未被NCAM激活。在大鼠小脑神经元培养物中抑制MAPK途径可选择性降低NCAM刺激的神经突生长。这些结果定义了一种NCAM信号转导机制，其具有调节轴突生长、存活和突触可塑性所需基因表达的潜力。
