Trk Uses ARMS to Sustain Signals

Similar signaling pathways are used in particular contexts to control a wide range of distinct biological processes. However, the molecular mechanisms by which specificity is attained are still relatively poorly understood. An example is signaling to mitogen-activated protein (MAP) kinases through the Trk receptor tyrosine kinase that binds nerve growth factor (NGF) and other neurotrophins. Activation of Trk causes a sustained (>40 min) activation of MAP kinase activity, whereas stimulation of the EGF (epidermal growth factor) receptor only transiently activates MAP kinase. Arevalo et al. now show that this is likely the result of association of Trk with the ankyrin-rich membrane-spanning protein (ARMS). Immunoprecipitation experiments showed that ARMS was associated with TrkB in detergent lysates of embryonic day 18 rat cortical neurons and underwent rapid and sustained phosphorylation in PC12 cells treated with NGF. Experiments with cells expressing truncated proteins indicated that ARMS and Trk interacted through their transmembrane domains. Overexpression of a transmembrane segment of ARMS could disrupt the interaction, and also inhibited prolonged (but not early) activation of MAP kinase. The adaptor protein Crk also associated with ARMS, but through a polyproline-rich region of ARMS. Stable expression of mutant ARMS without the polyproline sequence indicated that the interaction with Crk was required for activation of the small guanosine triphosphatase Rap1 and sustained MAP kinase signaling. Depletion of ARMS with small interference RNA similarly diminished activation of Rap1 and MAP kinase. The authors propose that ARMS is a new scaffolding protein that assembles signaling complexes that can account for the unusual propensity of Trk receptors to provide long-lasting MAP kinase signals that are required, for example, for stimulation of neurite outgrowth by NGF. J. C. Arevalo, H. Yano, K. K. Teng, M. V. Chao, A unique pathway for sustained neurotrophin signaling through an ankyrin-rich membrane-spanning protein. EMBO J. 23 , 2358-2368 (2004). [Abstract] [Full Text]