FIG. 13.

Scheme for the MLK-dependent pathway for apoptotic neuronal death. NGF deprivation of neuronal cells induces the activation of Cdc42 and Rac1, which in turn activate the MLK family members, very likely with the mediation of a scaffold protein(s). Activated MLKs phosphorylate and activate MKK4 and -7 (and possibly other MKK family members) which, in turn, leads to the phosphorylation and activation of JNK and c-Jun subsequently. The activated JNK pathway induces the release of cytochrome c, which activates the caspase cascade and thus leads to cell death. CEP-1347 protects both NGF deprivation and expression of MLK-induced death. The protection is presumably due to its inhibition of the activity of MLK family.