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MBC in Press, published online ahead of print October 5, 2005
Mol. Biol. Cell 10.1091/mbc.E05-07-0651

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Submitted on July 19, 2005
Revised on September 11, 2005
Accepted on September 22, 2005

A Novel Endocytic Recycling Signal Distinguishes Biological Responses of Trk Neurotrophin Receptors

Zhe-Yu Chen,*{dagger} Alessandro Ieraci,* Michael Tanowitz,{ddagger} and Francis S. Lee*{sect}

Departments of *Psychiatry and {sect}Pharmacology, Weill Medical College of Cornell University, New York, NY 10021; {dagger}The Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University, Jinan, Shandong 250012, P. R. China, {ddagger}Departments of Psychiatry and Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, CA 94143

Monitoring Editor: Richard Assoian

Endocytic trafficking of signaling receptors to alternate intracellular pathways has been shown to lead to diverse biological consequences. In this study, we report that two neurotrophin receptors (TrkA, TrkB) traverse divergent endocytic pathways after binding to their respective ligands (NGF, BDNF). We provide evidence that TrkA receptors in neurosecretory cells and neurons predominantly recycle back to the cell surface in a ligand-dependent manner. We have identified a specific sequence in the TrkA juxtamembrane region, which is distinct from that in TrkB receptors, and is both necessary and sufficient for rapid recycling of internalized receptors. Conversely, TrkB receptors are predominantly sorted to the degradative pathway. Transplantation of the TrkA recycling sequence into TrkB receptors reroutes the TrkB receptor to the recycling pathway. Finally, we link these divergent trafficking pathways to alternate biological responses. On prolonged neurotrophin treatment, TrkA receptors produce prolonged activation of PI3 kinase/Akt signaling, as well as survival responses, as compared with TrkB receptors. These results indicate that TrkA receptors, which predominantly recycle in signal-dependent manner, have unique biological properties dictated by its specific endocytic trafficking itinerary.

Address correspondence to: Zhe-Yu Chen (zhc2003{at}med.cornell.edu) or Francis S. Lee (fslee{at}med.cornell.edu)




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