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Molecular and Cellular Biology, August 2000, p. 5908-5916, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

TrkA Immunoglobulin-Like Ligand Binding Domains Inhibit Spontaneous Activation of the Receptor

Juan C. Arevalo,1 Blanca Conde,2 Barbara L. Hempstead,3 Moses V. Chao,4 Dionisio Martin-Zanca,1 and Pilar Perez1,*

Instituto de Microbiologia Bioquimica, Departamento de Microbiologia y Genetica, CSIC, Universidad de Salamanca. 37007 Salamanca,1 and Departamento de Ciencias Morfologicas, Universidad de Zaragoza, Zaragoza,2 Spain; Hematology/Oncology Division, Weill Medical College of Cornell University, New York, New York 100213; and Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 100164

Received 11 February 2000/Returned for modification 21 March 2000/Accepted 2 May 2000

The extracellular region of the nerve growth factor (NGF) receptor, TrkA, contains two immunoglobulin (Ig)-like domains that are required for specific ligand binding. We have investigated the possible role of these two Ig-like domains in receptor dimerization and activation by using different mutants of the TrkA extracellular region. Deletions of each Ig-like domain, of both, and of the entire extracellular region were made. To probe the structural constraints on ligand-independent receptor dimerization, chimeric receptors were generated by swapping the Ig-like domains of the TrkA receptor for the third or fourth Ig-like domain of c-Kit. We also introduced single-amino-acid changes in conserved residues within the Ig-like domains of TrkA. Most of these TrkA variants did not bind NGF, and their expression in PC12nnr5 cells, which lack endogenous TrkA, promoted ligand-independent neurite outgrowth. Some TrkA mutant receptors induced malignant transformation of Rat-1 cells, as assessed by measuring proliferation in the absence of serum, anchorage-independent growth, and tumorigenesis in nude mice. These mutants exhibited constitutive phosphorylation and spontaneous dimerization consistent with their biological activities. Our data suggest that spontaneous dimerization of TrkA occurs when the structure of the Ig-like domains is altered, implying that the intact domains inhibit receptor dimerization in the absence of NGF.

* Corresponding author. Mailing address: Instituto de Microbiologia Bioquimica, Departamento de Microbiologia y Genetica, CSIC, Universidad de Salamanca, 37007 Salamanca, Spain. Phone: 34-923-121644. Fax: 34-923-224876. E-mail: piper{at}gugu.usal.es.

Molecular and Cellular Biology, August 2000, p. 5908-5916, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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