NEUROBIOLOGY Receptor Location and Signal Specificity

Abstract: An emerging question regarding the specificity of signaling molecules is whether biological responses elicited by a particular growth factor are dictated by the cellular location of its cognate receptor. This concept is supported by Watson et al., who report that retrograde signaling triggered by neurotrophin receptors (Trks) in neuronal axons is different from signaling elicited by Trks located in the cell body. Neurotrophin-bound receptors in axons are internalized by endocytosis and transported to the neuronal cell body where they initiate a signaling cascade that regulates gene expression. Although both cell body- and axon-localized Trk receptors activated the mitogen-activated protein (MAP) kinases Erk1, Erk2, and Erk5, only activation of Trks in the cell body caused all three MAP kinases to relocate to the nucleus. In contrast, only Erk5 moved to the nucleus when Trks in axons were stimulated. When Erk-5 signaling was inhibited in cultured neurons, phosphorylation of the CREB transcription factor and the survival response to nerve growth factor treatment of axons were reduced. Because different MAP kinases activate distinct groups of transcription factors, the authors propose that signals initiated from neurotrophin receptors in the axon may regulate nuclear activities that are different from those receptors located in the cell body.

F.L. Watson, H.M. Heerssen, A. Bhattacharyya, L. Kleese, M.Z. Lin, R.A. Segal, Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. Nature Neurosci. 4, 981-988 (2001). [Online Journal]