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The Journal of Neuroscience, August 1, 2000, 20(15):5671-5678

Cell Surface Trk Receptors Mediate NGF-Induced Survival While Internalized Receptors Regulate NGF-Induced Differentiation

Yan-zhen Zhang^{1, 2}, Daniel B. Moheban^{1, 2}, Bevil R. Conway¹, Anita Bhattacharyya³, and Rosalind A. Segal^{1, 2}

¹ Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and Departments of ² Pediatric Oncology and ³ Cancer Biology, Dana-Farber-Cancer Institute, Boston, Massachusetts 02115

Internalization and transport of a ligand-receptor complex are required to initiate cell body responses to target-derived neurotrophin. However, it is not known whether internalized receptors and cell surface receptors initiate the same signaling pathways and biological responses. Here we use a temperature-sensitive mutant of dynamin (G273D) to control the subcellular localization of activated NGF receptors (Trks). We show that dynamin function is required for ligand-dependent endocytosis of Trk receptors. In PC12 cells, nerve growth factor (NGF) stimulation promotes both survival and neuronal differentiation. These distinct biological responses to NGF are controlled by receptors signaling from different locations within the cell. Neuronal differentiation is promoted by catalytically active Trks within endosomes in the cell interior. In contrast, survival responses are initiated by activated receptors at the cell surface where they orchestrate prolonged activation of the kinase Akt. Thus, interactions between Trk receptor tyrosine kinases and intracellular signaling molecules are dictated both by phosphotyrosine motifs within the receptors and by the intracellular location of phosphorylated receptors.

Key words: nerve growth factor; neurotrophin; receptor tyrosine kinase; dynamin; endocytosis; survival; Akt

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20155671-08$05.00/0

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