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J. Biol. Chem., Vol. 282, Issue 23, 16754-16763, June 8, 2007

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TrkA Receptor "Hot Spots" for Binding of NT-3 as a Heterologous Ligand^*

Ljubica Ivanisevic¹, WenHua Zheng, Sang B. Woo^¶, Kenneth E. Neet^¶2, and H. Uri Saragovi^||3

From the Lady Davis Institute-Jewish General Hospital, Department of Pharmacology and Therapeutics, ^||Oncology/Cancer Center, McGill University, Montreal, Quebec H3T 1E2, Canada and the ^¶Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064

Neurotrophins signal via Trk tyrosine kinase receptors. Nerve growth factor (NGF) is the cognate ligand for TrkA, the brain-derived neurotrophic factor for TrkB, and NT-3 for TrkC. NT-3 also binds TrkA as a lower affinity heterologous ligand. Because neurotrophin-3 (NT-3) interactions with TrkA are biologically relevant, we aimed to define the TrkA "hot spot" functional docking sites of NT-3. The Trk extracellular domain consists of two cysteine-rich subdomains (D1 and D3), flanking a leucine-rich subdomain (D2), and two immunoglobulin-like subdomains IgC1(D4) and IgC2(D5). Previously, the D5 subdomain was defined as the primary ligand-binding site of neurotrophins for their cognate receptors (e.g. NGF binds and activates through TRKA-D5 hot spots). Here binding studies with trun-cated and chimeric extracellular subdomains show that TRKA-D5 also includes an NT-3 docking and activation hot spot (site 1), and competition studies show that the NGF and NT-3 hot spots on TRKA-D5 are distinct but partially overlapping. In addition, ligand binding studies provide evidence for an NT-3-binding/allosteric site on TRKA-D4 (site 2). NT-3 docking on sites 1 and/or 2 partially blocks NGF binding. Functional survival studies showed that sites 1 and 2 regulate TrkA activation. NT-3 docking on both sites 1 and 2 affords full agonism, which can be additive with NGF activation of Trk. However, NT-3 docking solely on site 1 is partially agonistic but noncompetitively antagonizes NGF binding and activation of Trk. This study demonstrates that Trk signaling is more complex than previously thought because it involves several receptor subdomains and hot spots.

Received for publication, March 7, 2007 , and in revised form, April 17, 2007.

^* This work was supported in part by Canadian Institutes of Health Research Grant MOP13265 (to H. U. S.) and National Institutes of Health Grants 5R01NS38569, CA82642, NS36700, and NS24380 (to K. E. N.). 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.

¹ Supported by the Montreal Center for Experimental Therapeutics in Cancer and the Maysie McSporran Foundation and the McGill Faculty of Medicine.

² To whom correspondence may be addressed. E-mail: Kenneth.neet{at}rosalindfranklin.edu. ³ To whom correspondence may be addressed. E-mail: uri.saragovi{at}mcgill.ca.

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