Appropriate development of nervous system connectivity involves a variety of 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 downstream target of neurotrophin and ephrin receptor

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... tyrosine kinases, Trk and Eph, respectively. The amino acid sequence of ARMS is highly conserved from nematode to human, suggesting an evolutionarily conserved role for this protein. The ARMS protein consists of 1715 amino acids containing four putative transmembrane domains, multiple ankyrin repeats, a sterile ␣ motif domain, and a potential PDZbinding 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 physically associate with TrkA and p75 neurotrophin receptors. Moreover, endogenous ARMS protein is tyrosine phosphorylated after neurotrophin treatment of pheochromocytoma 12 cells and primary hippocampal neurons or ephrin B treatment of NG108-15 cells, demonstrating that ARMS is a downstream target for both neurotrophin and ephrin receptors. and HD 23315 to M.V.C., NS 10489 to H.K., DA 11836-02 to J.B., and NS 32367 to C.L. We thank J. Lee and A. MacDermott for their help and expertise in electrophysiological studies; Y. Amarillo and B. Rudy for help in oocyte studies; S. Chan for TrkB studies; D. Julius and A. Brake for reagents and insightful discussions throughout the course of these studies; H. Yano for sympathetic cultures; W. Walwyn for DRG sections; and E. Becker and E. Skolnik for NG108-15 cells, reagents, and helpful discussions.