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The Journal of Neuroscience, September 3, 2008, 28(36):9002-9012; doi:10.1523/JNEUROSCI.0767-08.2008

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Cellular/Molecular
Endophilin B1 as a Novel Regulator of Nerve Growth Factor/ TrkA Trafficking and Neurite Outgrowth

Jun Wan,^1 * Anthony Y. Cheung,^1 * Wing-Yu Fu,¹ Chengbiao Wu,² Mingjie Zhang,¹ William C. Mobley,² Zelda H. Cheung,¹ and Nancy Y. Ip¹

¹Department of Biochemistry, Biotechnology Research Institute and Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China, and ²Department of Neurology and Neurological Sciences, Pediatrics and Neurosurgery, and Neuroscience Institute, Stanford University, Stanford, California 94305

Correspondence should be addressed to Prof. Nancy Y. Ip, Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China. Email: boip{at}ust.hk

Neurotrophins and their cognate receptors Trks are important regulators of neuronal survival and differentiation. Recent studies reveal that internalization and trafficking of Trks play a critical role in neurotrophin-mediated signaling. At present, little is known of the molecular events that mediate this process. In the current study, we show that endophilin B1 is a novel regulator of nerve growth factor (NGF) trafficking. We found that endophilin B1 interacts with both TrkA and early endosome marker EEA1. Interestingly, knockdown of endophilin B1 results in enlarged EEA1-positive vesicles in NGF-treated PC12 cells. This is accompanied by increased lysosomal targeting of NGF/TrkA and TrkA degradation, and reduced total TrkA levels. In addition, knockdown of endophilin B1 attenuates Erk1/2 activation in the endosomal fraction after NGF treatment. This is accompanied by a marked inhibition of NGF-induced gene transcription and neurite outgrowth in endophilin B1-knocked down cells. Our observations implicate endophilin B1 as a novel regulator of NGF trafficking, thereby affecting TrkA levels and downstream signaling on endosomes to mediate biological functions of NGF.

Key words: neurotrophin; Trk receptors; receptor tyrosine kinase; receptor trafficking; neurite outgrowth; endosomes

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Received Feb. 20, 2008; revised July 11, 2008; accepted July 21, 2008.

Correspondence should be addressed to Prof. Nancy Y. Ip, Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China. Email: boip{at}ust.hk

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