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The epidermal growth factor receptor (EGFR) gives name to a family of receptors formed by four members in mammals (EGFR, ErbB2, ErbB3, and ErbB4). Members of this family can be activated to become potent oncogenes, and many human and animal tumors express qualitatively or quantitatively altered receptors from this group. We have isolated and characterized a second egfr gene in the melanoma model fish Xiphophorus. Both Xiphophorus egfra and egfrb duplicates are co-orthologs of the mammalian egfr gene. Database analysis showed that not only egfr but also erbB3 and erbB4 are present as duplicates in some fish species. They originated from ancient duplication events that might be consistent with the hypothesis of a fish-specific genome duplication. In Xiphophorus, the egfrb gene underwent a second duplication that generated the melanoma-inducing oncogene Xmrk. The study and comparison of some of the functional characteristics of both Xiphophorus EGF receptors, including expression profile, ligand-binding abilities, and intracellular signal transduction revealed that Xiphophorus Egfra not only shares common features with Egfrb and the human EGFR but also shows significant differences in its functional characteristics. The mechanism of maintenance of these duplicates remains to be clarified.