Role of tyrosine kinase in the evolution of multicellular animals

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The Src family of tyrosine kinases play pivotal roles in regulating cellular functions characteristic of multicellular animals, including cell-cell interactions, cell-substrate adhesion and cell migration. To investigate the functional alteration of Src kinases during evolution from a unicellular ancestor to multicellular animals, we characterized Src orthologs from the unicellular choanoflagellate Monosiga ovata and the primitive multicellular sponge Ephydatia fluviatilis. Here, we show that the src gene family and its C-terminal Src kinase (Csk)-mediated regulatory system were already established in the unicellular M.ovata and that this Src has unique features relative to multicellular Src : it can be phosphorylated by Csk at the negative regulatory site, but still exhibits substantial activity even in the phosphorylated form. Analyses of chimera molecules between M.ovata and E. fluviatilis Src orthologs reveal that structural alterations in the kinase domain are responsible for the … More inefficient negative regulation of M.ovata Src. When expressed in vertebrate fibroblasts, M.ovata Src can induce cell transformation irrespective of the presence of Csk. These findings suggest that a structure of Src required for the stable Csk-mediated negative regulation is still immature in the unicellular M.ovata, and that the development of stable negative regulation of Src may correlate with the evolution of multicellularity in animals.To address the fundamental roles Src in the multicellular animals, Effects of loss-of-function of Src in C.elegans was analyzed. Here we show that SRC-1, an orthologue of SFK, plays an essential role in directing cell migration in Caenorhabditis elegans. The mutation in the src-l gene results in defective distal tip cell (DTC)-directed gonad morphogenesis in an activity-dependent and DTC cell-autonomous manners. In the src-1 mutants, DTCs fail to turn and continue their centrifugal migration along the ventral muscles. The effect of the src-l mutation is suppressed by mutations in genes that function in the CED/Rac pathway, suggesting that SRC-1 in DTCs is an upstream regulator of a Rac pathway that controls cytoskeletal remodeling. In the src-1 mutant, the expression of unc-5/netrin receptor is normally regulated, and either the precocious expression of UNC-5 or the mutation in the unc-5 gene does not significantly affect the DTC migration defect. These data suggest that SRC-1 acts in the netrin signaling in DTCs. The src-1 mutant also exhibits cell-autonomous defects in the migration and growth cone path finding of Q neuroblast descendants AVM and PVM. However, these roles of SRC-1 do not appear to involve the CED/Rac pathway. These findings show that SRC-1 functions in responding to various extracellular guidance cues that direct the cell migration via disparate signaling pathways in different cell types. Less