An evolutionarily conserved transmembrane protein that is a novel downstream target of neurotrophin and ephrin receptors

Appropriate development of nervous system connectivity involves a variety o f processes, including neuronal life-and-death decisions, differentiation, axon guidance and migration, and synaptogenesis. Although these activities likely require specialized signaling events, few substrates unique to these neurotrophic functions have been identified. Here we describe the cloning of ankyrin repeat-rich membrane spanning (ARMS), which encodes a novel down stream target of neurotrophin and ephrin receptor tyrosine kinases, Trk and Eph, respectively. The amino acid sequence of ARMS is highly conserved fro m nematode to human, suggesting an evolutionarily conserved role for this p rotein. The ARMS protein consists of 1715 amino acids containing four putat ive transmembrane domains, multiple ankyrin repeats, a sterile alpha motif domain, and a potential PDZ-binding motif. In the rat, ARMS is specifically expressed in the developing nervous system and in highly plastic areas of the adult brain, regions enriched in Trks and Eph receptors. ARMS can physi cally associate with TrkA and p75 neurotrophin receptors. Moreover, endogen ous ARMS protein is tyrosine phosphorylated after neurotrophin treatment of pheochromocytoma 12 cells and primary hippocampal neurons or ephrin B trea tment of NG108-15 cells, demonstrating that ARMS is a downstream target for both neurotrophin and ephrin receptors.