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The Journal of Neuroscience, May 2, 2007, 27(18):4859-4869; doi:10.1523/JNEUROSCI.4587-06.2007

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Cellular/Molecular
The Tyrosine Kinase Fyn Determines the Localization of TrkB Receptors in Lipid Rafts

Daniela B. Pereira and Moses V. Chao

Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine and Departments of Cell Biology, Physiology and Neuroscience, and Psychiatry, New York University School of Medicine, New York, New York 10016

Correspondence should be addressed to Daniela B. Pereira at her present address: Department of Neurology, Columbia University, 650 West 168th Street, Black Building Room 308, New York, NY 10032. Email: dp2326{at}columbia.edu

Localization of Trk neurotrophin receptors is an important factor in directing cellular communication in developing and mature neurons. One potential site of action is in lipid raft membrane microdomains. Although Trk receptors have been localized to lipid rafts, little is known about how these neurotrophin receptors are directed there or how localization to these membrane microdomains regulates Trk signaling. Here, we report that the TrkB brain-derived neurotrophic factor (BDNF) receptor specifically localized to intracellular lipid rafts in cortical and hippocampal membranes in response to BDNF and that this process was critically dependent on the tyrosine kinase Fyn. BDNF-induced TrkB accumulation at lipid rafts was prevented by blocking the internalization of TrkB. BDNF stimulation also resulted in the association between endogenous TrkB and Fyn. Moreover, in neurons derived from Fyn knock-out mice, the translocation of TrkB to lipid rafts in response to BDNF was compromised, whereas the corticohippocampal region of Fyn mutants displayed lower amounts of TrkB in lipid rafts in vivo. In support of a role for lipid rafts in neurotrophin signaling, inhibiting TrkB translocation to lipid rafts, either by using Fyn knock-out neurons or lipid raft-disturbing agents, prevented the full activation of TrkB and of downstream phospholipase C-. These results indicate that the lipid raft localization of TrkB receptors is regulated by Fyn and represents an important factor in determining the outcome of BDNF signaling in neurons.

Key words: TrkB; Fyn; PLC; lipid rafts; intracellular; rat

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Received Oct. 23, 2006; revised Feb. 15, 2007; accepted March 16, 2007.

Correspondence should be addressed to Daniela B. Pereira at her present address: Department of Neurology, Columbia University, 650 West 168th Street, Black Building Room 308, New York, NY 10032. Email: dp2326{at}columbia.edu

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