Amphoterin-Induced Gene and ORF 3 (AMIGO3), also known as Alvin-3, is a member of the AMIGO family of type I transmembrane proteins that contain 6 leucine‑rich repeats (LRRs) and one Ig domain in their extracellular domains. It is ubiquitously expressed and is detected in all tissues studied (1). Mouse AMIGO3 shows less than 40% amino acid sequence homology with AMIGO1 and AMIGO2. The extracellular domain of mouse AMIGO3 shares 90% and 75% amino acid sequence identity with both that of rat and human AMIGO3, respectively. AMIGO family proteins are cell adhesion molecules that exhibit homophilic and heterophilic binding properties and are thought to play roles in neuronal axon tract development and cell adhesion. AMIGO3 mRNA and protein levels are preferentially and significantly raised in DRGN and RGC immediately after central axotomy. Depression of AMIGO3 expression correlates with dorsal column (DC) and optic nerve regeneration. AMIGO3 interacts with NgR1 and p75/TROY forming a functional receptor complex that activates RhoGTP in cells exposed to CNS myelin extracts (CME). AMIGO3 substitutes for LINGO-1 in centrally axotomized DRGN and RGC in the acute phase of injury. AMIGO3-NgR1-p75/TROY receptor complex mediates immediate axon growth inhibitory responses to CNS myelin (2). Our in-house data showed that AMIGO-3 inhibited anti-CD3 induced IL-2 secretion on CD3 ⁺ cells, suggesting that AMIGO-3 may be involved in T cell activation.