Fig. 6.

B-Raf and 14-3-3 in neurotrophic signaling. (A) B-Raf contains the catalytic conserved region 3 (CR3), the regulatory CR2, the Cys-rich domain 2 (CRD2), and the N-terminal RAS-binding domain (RBD). In its inactive form, B-Raf is stabilized by 14-3-3 proteins binding in the CR3 and CR2 region. (B) Neurotrophic factor binding to receptor tyrosine kinases (RTK) induces B-Raf recruitment to the membrane via RBD/CRD-Ras interaction and B-Raf phosphorylation at the critical activation site Serine-445 by kinases such as casein kinase 2 (CK2). The activated complex binds 14-3-3 via CR3 region only. Subsequent ATP-binding induces B-Raf kinase activity and the phosphorylation of its downstream target MEK. B-Raf, its activated and phosphorylated form as well as 14-3-3, are down-regulated in SMA motoneurons, which leads to motoneuron degeneration via the MEK/ERK signaling cascade.