UNIQUE SIGNAL-TRANSDUCTION OF EYK - CONSTITUTIVE STIMULATION OF THE JAK-STAT PATHWAY BY AN ONCOGENIC RECEPTOR-TYPE TYROSINE KINASE

The proto-oncogene c-eyk, the cellular counterpart of a transforming o ncogene, v-eyk, encodes a receptor protein tyrosine kinase with a dist inctive extracellular region, We now demonstrate that c-Eyk can be con stitutively activated through dimerization, and that the active Eyk di splays a unique signaling pattern, When the kinase domain of c-Eyk was fused to the extracellular and transmembrane domains of CD8, the resu lting chimera showed elevated kinase activity and caused cellular tran sformation. We found that the activated Eyk kinases, both v- and c-Eyk , constitutively stimulate the JAK-STAT pathway, while exerting little effect on other signaling routes such as the Ras-MAP kinase and the J NK pathways, The activated Eyk kinases specifically stimulate tyrosine phosphorylation of STAT1, STAT3 and JAK1, These downstream molecules also co-immunoprecipitate with the constitutively dimerized form of Ey k, The Eyk kinase activity is required for STAT1 stimulation, We found that the activation of STAT1 but not STAT3 correlates well with cellu lar transformation, In constitutively stimulating the JAK-STAT pathway , particularly STAT1, Eyk is unique in its downstream signaling and ma y be dependent on this pathway for cellular transformation.