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© The Rockefeller University Press, 0021-9525/2003/6/1133 $5.00
The Journal of Cell Biology, Volume 161, Number 6, 1133-1141

Back signaling by the Nrg-1 intracellular domain

¹ Department of Anatomy and Cell Biology, Columbia University, New York, NY 10032
² Department of Pediatrics, Columbia University, New York, NY 10032
³ Center for Neurobiology and Behavior, Columbia University, New York, NY 10032
⁴ Institute of Human Nutrition, Columbia University, New York, NY 10032

Address correspondence to David A. Talmage, Institute of Human Nutrition, 701 West 168th St., 5-503 New York, NY 10032. Tel.: (212) 305-2107. Fax: (212) 305-3079. E-mail: dat1{at}columbia.edu

Transmembrane isoforms of neuregulin-1 (Nrg-1), ligands for erbB receptors, include an extracellular domain with an EGF-like sequence and a highly conserved intracellular domain (ICD) of unknown function. In this paper, we demonstrate that transmembrane isoforms of Nrg-1 are bidirectional signaling molecules in neurons. The stimuli for Nrg-1 back signaling include binding of erbB receptor dimers to the extracellular domain of Nrg-1 and neuronal depolarization. These stimuli elicit proteolytic release and translocation of the ICD of Nrg-1 to the nucleus. Once in the nucleus, the Nrg-1 ICD represses expression of several regulators of apoptosis, resulting in decreased neuronal cell death in vitro. Thus, regulated proteolytic processing of Nrg-1 results in retrograde signaling that appears to mediate contact and activity-dependent survival of Nrg-1–expressing neurons.

Key Words: erbB receptors; apoptosis; -secretase; synaptic maintenance; neurodegeneration

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