Article
- The EMBO Journal (2006) 25, 1219 - 1230
- doi:10.1038/sj.emboj.7601017
Published online: 23 February 2006
Subject Categories:
Bex1, a novel interactor of the p75 neurotrophin receptor, links neurotrophin signaling to the cell cycle
Marçal Vilar1,ab, Maribel Murillo-Carretero1,a, Helena Mira2,c, Kalle Magnusson1, Valerie Besset1,d and Carlos F Ibáñez1
- Division of Molecular Neurobiology, Department of Neuroscience, Stockholm, Sweden
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
Correspondence to:
Carlos F Ibáñez, Division of Molecular Neurobiology, Department of Neuroscience, Karolinska Institute, Berzelius väg 35, Box 285, Stockholm 17177, Sweden. Tel.: +46 8 524 87660; Fax: +46 8 33 9548; E-mail: carlos.ibanez@neuro.ki.se
aThese authors contributed equally to this work
bPresent address: Structural Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA
cPresent address: Departamento de Biologia Celular, Universitat de Valencia, Spain
dPresent address: Sanofi-Aventis, 94400 Vitry sur Seine, France
Received 8 June 2005; Accepted 31 January 2006
Abstract
A screening for intracellular interactors of the p75 neurotrophin receptor (p75NTR) identified brain-expressed X-linked 1 (Bex1), a small adaptor-like protein of unknown function. Bex1 levels oscillated during the cell cycle, and preventing the normal cycling and downregulation of Bex1 in PC12 cells sustained cell proliferation under conditions of growth arrest, and inhibited neuronal differentiation in response to nerve growth factor (NGF). Neuronal differentiation of precursors isolated from the brain subventricular zone was also reduced by ectopic Bex1. In PC12 cells, Bex1 overexpression inhibited the induction of NF-
B activity by NGF without affecting activation of Erk1/2 and AKT, while Bex1 knockdown accelerated neuronal differentiation and potentiated NF-B activity in response to NGF. Bex1 competed with RIP2 for binding to the p75NTR intracellular domain, and elevating RIP2 levels restored the ability of cells overexpressing Bex1 to differentiate in response to NGF. Together, these data establish Bex1 as a novel link between neurotrophin signaling, the cell cycle, and neuronal differentiation, and suggest that Bex1 may function by coordinating internal cellular states with the ability of cells to respond to external signals.
Keywords:
- cell differentiation,
- growth arrest,
- NGF,
- TrkA,
- PC12 cells
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