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J. Biol. Chem., Vol. 283, Issue 19, 12709-12716, May 9, 2008

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Proneurotrophins Require Endocytosis and Intracellular Proteolysis to Induce TrkA Activation^*

Jacqueline Boutilier¹, Claire Ceni², Promila C. Pagdala, Alison Forgie^¶, Kenneth E. Neet, and Philip A. Barker³

From the Department of Neurology and Neurosurgery, McGill University, Montreal Neurological Institute, Montreal H3A 2B4, Canada, Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, and ^¶Rinat Neuroscience, San Francisco, California 94080

The uncleaved, pro-form of nerve growth factor (proNGF) functions as a pro-apoptotic ligand for the p75 neurotrophin receptor (p75NTR). However, some reports have indicated that proneurotrophins bind and activate Trk receptors. In this study, we have examined proneurotrophin receptor binding and activation properties in an attempt to reconcile these findings. We show that proNGF readily binds p75NTR expressed in HEK293T cells but does not interact with TrkA expressed under similar circumstances. Importantly, proNGF activates TrkA tyrosine phosphorylation, induces Erk and Akt activation, and causes PC12 cell differentiation. We show that inhibiting endocytosis or furin activity reduced TrkA activation induced by proNGF but not that induced by mature NGF and that proNGF123, a mutant form of NGF lacking dibasic cleavage sites in the prodomain, does not induce TrkA phosphorylation in PC12 cells. Therefore, endocytosis and cleavage appear to be prerequisites for proNGF-induced TrkA activity. We also found that proBDNF induces activation of TrkB in cerebellar granule neurons and that proBDNF cleavage by furin and metalloproteases facilitates this effect. Taken together, these data indicate that under physiological conditions, proneurotrophins do not directly bind or activate Trk receptors. However, endocytosis and cleavage of proneurotrophins produce processed forms of neurotrophins that are capable of inducing Trk activation.

Received for publication, December 10, 2007 Accepted for publication February 14, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant NS24380. This work was also supported by Grant MOP37850 from the Canadian Institute of Health Research (CIHR) and a grant from the United States Public Health Service. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Supported by a McGill major studentship.

² Supported by a fellowship from the Canadian Institutes of Health Research.

³ An investigator of the Canadian Institutes of Health Research. To whom correspondence should be addressed: Montreal Neurological Institute, 3801 University St., Montreal, Quebec H3A 2B4, Canada. Fax: 514-398-5214; E-mail: phil.barker{at}mcgill.ca.

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