An Ancestral Trk Receptor

No true invertebrate homologs of the vertebrate neurotrophin Trk receptors have been identified in the genomes of the model organisms Drosophila melanogaster and Caenorhabditis elegans , which has led to the hypothesis that the Trk signaling arose in vertebrates. Benito-Gutiérrez et al. challenge this hypothesis with the identification of a Trk receptor in the genome of the lancelet Branchiostoma floridae , which is the present-day relative of the lancelet-like organism believed to be the ancestor of vertebrates. Lancelets are invertebrate fish-like animals that lack a complex nervous system. They have named the lancelet gene AmphiTrk , and the encoded protein has the same domain structure as vertebrate Trk receptors: The extracellular region contained two leucine-rich repeats flanked by cysteine-rich clusters and followed by two C2-type immunoglobulin repeats, and the intracellular domain included a tyrosine kinase domain, two putative cyclic nucleotide-dependent kinase phosphorylation sites, and various protein-protein interaction motifs also found in vertebrate Trk receptors. Thus, the ligand-binding domain and the intracellular signaling regions of AmphiTrk are consistent with this receptor's being an invertebrate homolog of Trk. Phylogenetic analysis showed that AmphiTrk formed a clade (an evolutionarily related group) with the vertebrate Trk receptors that excluded the two closest relatives from fruit fly and mollusk. Transfection of AmphiTrk into a Trk-negative PC12 cell line showed that AmphiTrk was stimulated by several neurotrophins (NGF, NT3, NT4, and BDNF). The cellular response was not completely identical to that of native receptors in that AmphiTrk did not stimulate phospholipase C activity (which is consistent with the sequence of AmphiTrk lacking the necessary motif) and exposure of the cells expressing AmphiTrk to NGF did not further stimulate neurite outgrowth beyond that observed in the absence of ligand. (AmphiTrk in the absence of ligand did stimulate neurite outgrowth.) Analysis of the expression of AmphiTrk in vivo during development suggested that AmphiTrk was present in migrating sensory neurons. Thus, AmphiTrk appears to represent a true invertebrate member of the Trk receptor family with functional and sequence homology. È. Benito-Gutiérrez, C. Nake, M. Llovera, J. X. Comella, J. Garcia-Fernàndez, The single AmphiTrk receptor highlights increased complexity of neurotrophin signalling in vertebrates and suggests an early role in developing sensory neuroepidermal cells. Development 132 , 2191-2202 (2005). [Abstract] [Full Text]