A single amino acid substitution in the v-Eyk intracellular domain resultsin activation of Stat3 and enhances cellular transformation

The receptor tyrosine kinase Eyk, a member of the Axl/Tyro3 subfamily, acti vates the STAT pathway and transforms cells when constitutively activated. Here, we compared the potentials of the intracellular domains of Eyk molecu les derived from c-Eyk and v-Eyk to transform rat 3Y1 fibroblasts. The v-Ey k molecule induced higher numbers of transformants in soft agar and stronge r activation of Stat3; levels of Stat1 activation by the two Eyk molecules were similar. A mutation in the sequence (YVPL)-V-933, present in c-Eyk, to the v-Eyk sequence Y(933)VPQ led to increased activation of Stat3 and incr eased transformation efficiency. However, altering another sequence, (YVNT) -V-862, present in both Eyk molecules to (FVNT)-V-862 markedly decreased tr ansformation without impairing Stat3 activation. These results indicate tha t activation of Stat3 enhances transformation efficiency and cooperates wit h another pathway to induce transformation.