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Vol. 16, Issue 12, 5761-5772, December 2005

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

Zhe-Yu Chen ^* , Alessandro Ieraci ^*, Michael Tanowitz , and Francis S. Lee ^* 

^* Department of Psychiatry, Weill Medical College of Cornell University, New York, NY 10021; Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10021; The Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University, Jinan, Shandong 250012, People's Republic of China; and Departments of Psychiatry and Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143

Submitted July 19, 2005; Revised September 11, 2005; Accepted September 22, 2005
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 (tropomyosin-related kinase TrkA and TrkB) traverse divergent endocytic pathways after binding to their respective ligands (nerve growth factor and brain-derived neurotrophic factor). 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 phosphatidylinositol 3-kinase/Akt signaling as well as survival responses, 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.

Abbreviations used: BDNF, brain-derived neurotrophic factor; EGFR, epidermal growth factor receptor; GPCR, G protein-coupled receptor; LAMP1, lysosome-associated membrane protein 1; NGF, nerve growth factor; Trk, tropomyosin-related kinase.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

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

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