NEUROSCIENCE Neuronal Receptor Versatility

Two papers this week broaden the range of signaling functions for neuronal receptors. Bao et al. report on the neuregulin-1 (Nrg-1) family of proteins. Nrg-1 proteins are transmembrane proteins that act as ligands for erbB receptor tyrosine kinases, and interactions between these partners are implicated in promoting neuronal survival. Bao et al. present experiments showing that Nrg-1 can act as a receptor as well as a ligand. Binding to erbB receptors led to release of an intracellular domain (ICD) fragment of Nrg-1, which migrated to the nucleus where its presence is associated with decreased expression of proapoptotic proteins. Thus, interaction between Nrg-1 and erbB appears to produce both a classical receptor tyrosine kinase signal from erbB in one cell and a proteolytic event in the Nrg-1-expressing neuron that releases a transcriptional regulator. Paratcha et al. describe an expanded signaling role for another transmembrane protein, neural cell adhesion molecule (NCAM). NCAMs are important for neurite outgrowth and migration and function to provide adhesion through homophylic interactions and also to signal through associated nonreceptor tyrosine kinases. Paratcha et al. noticed that glial cell line-derived neurotrophic factor (GDNF), a growth factor that promotes neuronal growth and survival, produced signals similar to those initiated by NCAMs. GDNF is known to signal through a receptor complex containing the receptor tyrosine kinase Ret and the GDNF-binding subunit GFR (GDNF family receptor ). However, GDNF produced its NCAM-like signals even when RET was absent. Paratcha et al. found that NCAM associated with GFR and that this interaction altered NCAM binding properties such that it preferentially bound GDNF instead of engaging in homotypic interactions. Thus, NCAMs can switch from mediating short-range cell-cell contacts and adhesion to acting as a receptor for soluble growth factor. The interdependence of the two signaling modes may provide a means to coordinate various cellular functions.

J. Bao, D. Wolpowitz, L. W. Role, D. A. Talmage, Back signaling by the Nrg-1 intracellular domain. J. Cell Biol. 161, 1133-1141 (2003). [Abstract] [Full Text]

G. Paratcha, F. Ledda, C. F. Ibáñez, The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands. Cell 113, 867-879 (2003). [Online Journal]