Bex1, a novel interactor of the p75 neurotrophin receptor, links neurotrophin signaling to the cell cycle.
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-kappaB activity by NGF without affecting activation of Erk1/2 and AKT, while Bex1 knockdown accelerated neuronal differentiation and potentiated NF-kappaB 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.
Division of Molecular Neurobiology, Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
Marçal
M
Vilar
Maribel
M
Murillo-Carretero
Helena
H
Mira
Kalle
K
Magnusson
Valerie
V
Besset
Carlos F
CF
Ibáñez
D051698:Activating Transcription Factor 2; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D015398:Signal Transduction; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism
D051698:Activating Transcription Factor 2; D051017:Apoptosis Regulatory Proteins; C477719:Bex2 protein, rat; C485843:Bex3 protein, rat; D002352:Carrier Proteins; D016328:NF-kappa B; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020800:Receptor, Nerve Growth Factor; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D020932:Nerve Growth Factor; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3