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J Biol Chem, Vol. 273, Issue 52, 34933-34940, December 25, 1998

A TrkA-selective, Fast Internalizing Nerve Growth Factor-Antibody Complex Induces Trophic but Not Neuritogenic Signals

H. Uri SaragoviDagger §, WenHua ZhengDagger , Sergei MaliartchoukDagger , Gianni M. DiGugliemoparallel , Yogesh R. MawalDagger , Amine Kamen**, Sang B. WooDagger Dagger , A. Claudio CuelloDagger , Thomas DebeirDagger , and Kenneth E. NeetDagger Dagger

From the Dagger  Department of Pharmacology and Therapeutics, § Oncology/Cancer Center, and parallel  Department of Cell Biology, McGill University and the ** Biotechnology Research Institute, National Research Council, Montréal, Quebec H3G 1Y6, Canada, and the Dagger Dagger  Department of Biological Chemistry, Finch University of Health Sciences/The Chicago Medical School, North Chicago, Illinois 60064

Nerve growth factor (NGF) is a neurotrophin that induces neuritogenic and trophic signals by binding to TrkA and/or p75 receptors. We report a comparative study of the binding, internalization, and biological activity of NGF versus that of NGF in association with an anti-NGF monoclonal antibody (mAb NGF30), directed against the C termini of NGF. NGF·mAb complexes do not bind p75 effectively but bind TrkA with high affinity. After binding, NGF·mAb complexes stimulate internalization faster and to a larger degree than NGF. NGF·mAb-induced activation of TrkA, Shc, and MAPK is transient compared with NGF-induced activation; yet NGF and NGF·mAb afford identical trophic responses. In contrast, NGF induces Suc-1-associated neurotrophic activating protein phosphorylation and neuritogenic differentiation, but NGF·mAb does not. Thus, an absolute separation of trophic and neuritogenic function is seen for NGF·mAb, suggesting that biological response modifiers of neurotrophins can afford ligands with selected activities.


Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.



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