Frebel K, Wiese S
Institute for Clinical Neurobiology, Julius-Maximilians University of Würzburg, Josef Schneider Strasse 11, D97080 Würzburg, Germany.
Biochem Soc Trans. 2006 Dec;34(Pt 6):1287-90. doi: 10.1042/BST0341287.
Motoneurons are made in excess throughout development. Initial analysis of the mechanisms that lead to apoptotic cell death during later stages of development and the early postnatal period led to the discovery of neurotrophic factors. These factors comprise different families acting through different tyrosine kinase receptors. Intracellular signalling cascades that lead to the survival of neurons are, on the one hand, the Ras/Raf (Ras-activated factor)/MAPK (mitogen-activated protein kinase) pathway and, on the other, the PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B) pathway. The initial thought of these factors acting as single molecules in separate cascades has been converted into a model in which the dynamics of interaction of these pathways and the subcellular diverse functions of the key regulators have been taken into account. Bag1 (Bcl-2-associated athanogene 1), a molecule that was originally found to act as a co-chaperone of Hsp70 (heat-shock protein 70), also interacts with B-Raf, C-Raf and Akt to phosphorylate Bad (Bcl-2/Bcl-X(L)-antagonist, causing cell death), a pro-apoptotic member of the Bcl-2 family, and leads to specific subcellular distribution of phosphorylated Akt and B-Raf. These functions lead to survival of embryonic neural stem cells and therefore serve as a key event to regulate the viability of these cells.
运动神经元在整个发育过程中产生过量。对发育后期和出生后早期导致凋亡性细胞死亡的机制进行的初步分析,促成了神经营养因子的发现。这些因子包括通过不同酪氨酸激酶受体起作用的不同家族。一方面,导致神经元存活的细胞内信号级联是Ras/Raf(Ras激活因子)/MAPK(丝裂原活化蛋白激酶)途径,另一方面是PI3K(磷脂酰肌醇3激酶)/Akt(蛋白激酶B)途径。这些因子在不同级联中作为单一分子起作用的最初想法,已转变为一个考虑了这些途径相互作用动力学以及关键调节因子亚细胞多种功能的模型。Bag1(Bcl-2相关抗凋亡基因1)最初被发现作为Hsp70(热休克蛋白70)的共伴侣分子,它还与B-Raf、C-Raf和Akt相互作用,使Bad(Bcl-2/Bcl-X(L)拮抗剂,导致细胞死亡)磷酸化,Bad是Bcl-2家族的促凋亡成员,并导致磷酸化的Akt和B-Raf在特定亚细胞分布。这些功能导致胚胎神经干细胞存活,因此是调节这些细胞活力的关键事件。