To date more than twenty five different oncogenes have been identified in human neoplasias. One of these oncogenes is trk, a transforming gene originally isolated from a colon carcinoma biopsy by using gene transfer assays. This oncogene encodes a chimeric molecule that contains the 221 amino terminal residues of a non-muscle tropomyosin followed by the transmembrane and cytoplasmic domains of the trk proto-oncogene product, a tyrosine protein kinase receptor. trk oncogenes have also been identified in a significant fraction of thyroid papillary carcinomas. Some of these trk oncogenes contain sequences derived from genes other than tropomyosin. One such gene is tpr, a gene first identified as a component of the human met oncogene. The trk proto-oncogene, non-muscle tropomyosin and tpr map in the long arm of chromosome 1. Therefore, trk oncogenes are likely to result from internal rearrangements or from unequal cross-overs between two chromosome 1s. Recent studies have demonstrated that the product of the trk proto-oncogene, gp140trk, is the functional receptor for nerve growth factor (NGF). NGF elicits the rapid phosphorylation of gp140trk on tyrosine residues. Moreover, addition of NGF to NIH3T3 cells expressing gp140trk induces the transient expression of c-Fos, DNA synthesis and morphologic transformation. Finally, transfection of the trk proto-oncogene into NGF non-responsive PC12 mutant cells restores NGF responsiveness. Two additional genes designated trkB and trkC have recently been isolated in our laboratory. These genes are highly related to the trk proto-oncogene and encode tyrosine protein kinases which serve as functional receptors for the NGF-related neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophic-3 (NT-3), respectively. Whether mutations in these novel members of the trk family of receptor genes are also implicated in human cancer remains to be determined.