Inactivation and activation of Ras by the neurotrophin receptor p75

The neurotrophin receptor p75 induces neurotrophic and/or apoptotic signalling pathways and can also cooperate with the neurotrophic Trk receptor tyrosine kinases. Its intracellular part encloses a so-called 'death domain' with a segment similar to the wasp venom mastoparan which binds small GTPases such as Rho. To study possible interactions of p75 and Ras (and Rho) we used wild-type and mutant genes of p75 stably expressed by MDCK cells which normally have neither Trk nor p75. We found that p75 can directly bind the GTPases Ras and Rho and that the unstimulated p75 inactivates total cellular Ras through a differential influence on the dissociation of GDP and GTP from Ras and an exchange of bound Ras.GDP for free Ras.GTP. These properties of p75 could also be demonstrated in vitro and should therefore be cell type-independent. Stimulation of p75 with nerve growth factor causes Ras activation via adapter proteins known from Trk signalling and induces rapid outgrowth of cellular processes. Both inactivation and activation of Ras by p75 are controlled by the phosphorylation state of the receptor's two intracellular tyrosines. p75 also influences Rho activation and inactivation, and the combined interactions of the receptor with the two GTPases Ras and Rho can regulate neurite formation in an efficient, synergistic way.