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 c an extend the mean and maximum life span of the nematode Caenorhabditis ele gans. To identify paralogs and orthologs, we delineated relationships betwe en these three PTKs and all known transmembrane PTKs and all known mammalia n nontransmembrane PTKs using molecular phylogenetics. The tree includes a number of invertebrate receptor PTKs and a novel mammalian receptor PTK (in ferred from the expressed-sequence tag database) that have not previously b een analyzed. old-1 and old-2 were found to be members of a surprisingly la rge C. elegans PTK family having 16 members. Interestingly, only four membe rs of this transmembrane family appeared to have receptor domains (immunogl obulin-like in each case). The C-terminal domain of this family was found t o have a unique sequence motif that could be important for downstream signa ling. Among mammalian PTKs, the old-1/old-2 family appeared to be most clos ely related to the Pdgfr, Fgfr, Ret, and Tie/Tek families. However, these f amilies 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 addit ional 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 t hat daf-2 might not be an ortholog of the insulin receptor family. Among PT Ks, 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. O n a more general note, our survey of the expressed-sequence tag database su ggested that few, if any, additional mammalian PTK families are likely to b e discovered. The one novel family that was discovered could represent a no vel oncogene family, given the prevalence of oncogenes among PTKs. Finally, the PTK tree was consistent with nematodes and fruit flies being as diverg ent as nematodes and mammals, suggesting that life extension mechanisms sha red by nematodes and fruit flies would be reasonable candidates fur extendi ng mammalian life spans.