Infection with the Zika virus (ZIKV) results in severe neurological disease in adults or congenital Zika syndrome in newborns. There is currently no authorized anti-ZIKV reagent. We employed the domain search strategy to study the Zika virus glycoprotein E in this work. The results revealed that E contains a NGF domain and is capable of interacting with TrkA. The E/TrkA complex increased E's interaction with receptors such as Axl and facilitated Zika virus endocytosis via clathrin. Rab5 retrograded transmission of Zika virus-containing E/TrkA endosomal signals to neuronal soma. Rab7 helped dissociation of E/TrkA in late acidic endosomes. The mature E protein of Zika lacks NGF action, but the immature E protein does. After membrane fusion with the endosome, the Zika virus was released into the neuron cell body. The retrograde trafficking of endosomal signals (E/TrkA) similar to NGF/TrkA enabled Zika virus to infect neuronal cells. E's interference with the TrkA signal impaired neuronal cell growth and results in neuronal cell apoptosis.