Genetic, cellular, biochemical and structural evidence suggested that nematode steerin is a central regulator of 'directional' cell motility, by transducing receptor tyrosine-kinase signals into recruitment of F-actin and microtubuli in the nematode and in mammalian cells; indicating the existance of a conserved pathway in mammals and hence the existance human steerins (see also Vandecraen et al., 1999). A human steerin gene family has been cloned. Steerins comprise a N-terminal F-actin binding domain and a C-terminal predicted nucleotide binding domain and a middle domain of alpha-helical structure comprising a microtubule binding domain, coiled-coils I, II and III and 2 Pro-rich SH3 binding-like signatures. Human steerins display five more highly conserved boxes, discriminating them from nematode steerin. Funcional equivalence with nematode steerin was confirmed for human steerin-1 for activation of the F-actin cytoskeleton and binding to microtubule (+)-ends. Steerin-1 immunoreactivity localised to the microtubule (+)-ends in G361 melanoma cells (polyclonals). Expression of the human steerins is complex, both in terms of variants per tissue and tissue specificity (multiple tissue Northern blots). The chromosomal loci of both steerins are indicative of a putative role in neoplasms. A nematode screening platform was developed to search for inhibitors of the steerin/unc-53 pathway in the nematode. A first compound discovered induces pharmacologically an
unc-53 (lf) phenotype in the sex myoblasts of wild type C. elegans (see Ver Donck et al., 1999, Celegans99 meeting abstract). In conclusion, animal steerins emerge as a novel structurally and functionally conserved animal protein family operational in a conserved pathway that transduces positional signals over e.g. receptor tyrosine kinase pathways into recruitment of the F-actin cytoskeleton. Steerins appear to perform this function from the microtubule (+)-end. Indicative evidence exists for a role of steerins in neoplastic disease and amenability of the pathway to pharmacology was shown using the nematode as a drug screening model.