A DOMINANT ROLE OF THE JUXTAMEMBRANE REGION OF THE TRKA NERVE GROWTH-FACTOR RECEPTOR DURING NEURONAL CELL-DIFFERENTIATION

All receptor tyrosine kinases share a common intracellular signaling m achinery, including ras activation, whereas cellular responses vary fr om mitogenesis to cell differentiation. To investigate the structural basis for receptor tyrosine kinase action for nerve growth factor, the juxtamembrane region of TrkA was transferred to a corresponding regio n of the epidermal growth factor (EGF) receptor. The resulting chimeri c receptor contains an additional She site, Tyr(490), in the juxtamemb rane region. In transfected PC12 cell lines, neuronal differentiation was observed with EGF treatment, as evidenced by increased neurite ext ension. The action of the chimeric receptor was correlated with prolon ged activation of MAP kinases and a 3-4-fold increase in phosphatidyli nositol 3-kinase activity. The effect of the juxtamembrane chimera was dependent upon the She site at Tyr(490), because expression of a chim eric receptor containing a Y490F mutation resulted in a complete loss of neuritogenesis by EGF treatment. These findings indicate that the j uxtamembrane region of the TrkA receptor serves as a key functional do main that can confer a dominant effect upon neuronal differentiation.