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J. Biol. Chem., Vol. 278, Issue 27, 24808-24817, July 4, 2003

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Individual and Combined Effects of TrkA and p75^NTR Nerve Growth Factor Receptors

A ROLE FOR THE HIGH AFFINITY RECEPTOR SITE^*

Shivanand P. Lad  , Daniel A. Peterson ¶, Ralph A. Bradshaw || and Kenneth E. Neet  **

From the Department of Biochemistry and Molecular Biology and the ^¶Department of Neuroscience, Finch University of Health Sciences/The Chicago Medical School, North Chicago, Illinois 60064 and the ^||Departments of Physiology and Biophysics, and Anatomy and Neurobiology, University of California College of Medicine, Irvine, California 92697

A long-standing question in neurotrophin signal transduction is whether heteromeric TrkA-p75^NTR complexes possess signaling capabilities that are significantly different from homo-oligomeric TrkA or p75^NTR alone. To address this issue, various combinations of transfected PC12 cells expressing a platelet-derived growth factor receptor-TrkA chimera and the p75^NTR-selective nerve growth factor mutant (9/13 NGF) were utilized to selectively stimulate TrkA or p75^NTR signaling, respectively. The contribution of individual and combined receptor effects was analyzed in terms of downstream signaling and certain end points. The results suggest two unique functions for the high affinity heteromeric NGF receptor site: (a) integration of both the MAPK and Akt pathways in the production of NGF-induced neurite outgrowth, and (b) rapid and sustained activation of the Akt pathway, with consequent long term cellular survival. Whereas activation of TrkA signaling is sufficient for eliciting neurite outgrowth in PC12 cells, signaling through p75^NTR plays a modulatory role, especially in the increased formation of fine, synaptic "bouton-like" structures, in which both TrkA and p75^NTR appear to co-localize. In addition, a new interaction in the TrkA/p75^NTR heteromeric receptor signal transduction network was revealed, namely that NGF-induced activation of the MAPK pathway appears to inhibit the parallel NGF-induced Akt pathway.

Received for publication, December 3, 2002 , and in revised form, April 15, 2003.

^* This work was supported by United States Public Health Service Grants NS24380 (to K. E. N.) and AG09735 (to R. A. B.) from the National Institutes of Health. 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.

Submitted as partial fulfillment of the requirements for the degree of Doctor of Philosophy, Finch University of Health Sciences/The Chicago Medical School.

^** To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Finch University of Health Sciences/The Chicago Medical School, 3333 Green Bay Rd., North Chicago, IL 60064. Tel.: 847-578-3220; Fax: 847-578-3240; E-mail: neetk{at}finchcms.edu.

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