Paralogy and Orthology of Tyrosine Kinases that Can Extend the Life Span of Caenorhabditis elegans

Modification of any one of three transmembrane protein tyrosine kinase (PTK) genes, old-1, old-2 (formerly tkr-1 and tkr-2, respectively), and daf-2 can extend the mean and maximum life span of the nematode Caenorhabditis elegans. To identify paralogs and orthologs, we delineated relationships between these three PTKs and all known transmembrane PTKs and all known mammalian nontransmembrane PTKs using molecular phylogenetics. The tree includes a number of invertebrate receptor PTKs and a novel mammalian receptor PTK (inferred from the expressed-sequence tag database) that have not previously been analyzed. old-1 and old-2 were found to be members of a surprisingly large C. elegans PTK family having 16 members. Interestingly, only four members of this transmembrane family appeared to have receptor domains (immunoglobulin-like in each case). The C-terminal domain of this family was found to have a unique sequence motif that could be important for downstream signaling. Among mammalian PTKs, the old-1/old-2 family appeared to be most closely related to the Pdgfr, Fgfr, Ret, and Tie/Tek families. However, these families appeared to have split too early from the old-1/old-2 family to be orthologs, suggesting that a mammalian ortholog could yet be discovered. An extensive search of the expressed-sequence tag database suggested no additional candidate orthologs. In contrast to old-1 and old-2, daf-2 had no C. elegans paralogs. Although daf-2 was most closely related to the mammalian insulin receptor family, a hydra insulin receptor–like sequence suggested that daf-2 might not be an ortholog of the insulin receptor family. Among PTKs, the old-1/old-2 family and daf-2 were not particularly closely related, raising the possibility that other PTK families might extend life span. On a more general note, our survey of the expressed-sequence tag database suggested that few, if any, additional mammalian PTK families are likely to be discovered. The one novel family that was discovered could represent a novel oncogene family, given the prevalence of oncogenes among PTKs. Finally, the PTK tree was consistent with nematodes and fruit flies being as divergent as nematodes and mammals, suggesting that life extension mechanisms shared by nematodes and fruit flies would be reasonable candidates for extending mammalian life spans.