Upon binding to nerve growth factor (NGF), the receptor tyrosine kinase TrkA dimerizes and becomes activated. Two immunoglobulin-like regions in the receptor's extracellular domain bind to NGF. However, in the absence of ligand, Arevalo et al. report that these two domains may actually prevent receptor dimers from forming and keep TrkA monomers apart. Expression of deletion mutants indicated that in the absence of these domains, the receptor cannot bind to ligand effectively. Yet, these mutants can spontaneously dimerize and cause receptor activation. Upon activation, the mutant receptors promoted neurite outgrowth in cultured cells, malignant transformation, and tumorigenesis in mice. The authors propose that the intact immunoglobulin domains serve as a barrier to inhibit receptor dimerization in the absence of ligand. This repulsion may then be negated by ligand binding. Arevalo, J.C., Conde, B., Hempstead, B.L., Chao, M.V., Martin-Zanca, D., and Perex, P. (2000) TrkA immunoglobulin-like ligand binding domains inhibit spontaneous activation of the receptor. Mol. Cell. Biol. 20 : 5908-5916. [Abstract] [Full Text]