An Nogo-A fragment analysis has demonstrated the existence of 2 active sites for inhibition of neurite outgrowth. The Nogo-A-specific delta-20 active site binds with high affinity to the G-protein coupled receptor S1PR2 and activates G13 signalling to the small GTPase RhoA. The Nogo-66 sequence is known to bind to the Nogo receptor NgR-1 which also activates RhoA. RhoA and ROCK inactivate the membrane associated actin cytoskeleton, thereby leading to collapse of growth cones and growth arrest. Nogo-A and its receptors can be internalized and transported from axon terminals to the neuronal cell body as signalling endosomes. In the cell body, growth suppression occurs via downregulation of neuronal growth pathways.