SPECIFIC TRKA SURVIVAL SIGNALS INTERFERE WITH DIFFERENT APOPTOTIC PATHWAYS

Survival signalling by ligand-activated tyrosine kinase receptors play s a crucial role in maintaining the balance between cell viability and apoptosis in multicellular organisms. To identify receptor domains an d pathways involved in survival signalling, the nerve growth factor re ceptor TrkA was expressed in Rat-1/MycER(TM) fibroblasts. We demonstra te that wt-TrkA receptor delays c-Myc-, U.V.- and Cycloheximide-induce d apoptosis and activates targets such as the mitogen-activated protei n kinase (MAPK) Erk2 and the serine/threonine kinase Akt/PKB, both of which have been implicated in survival signalling. TrkA mutated within its SHC binding site (Y490F) delays c-Myc-induced apoptosis without a ctivating endogenous Akt/PKB. In contrast, the TrkA Y490F mutant recep tor does not delay U.V.-induced apoptosis whilst TrkA mutated at its P LC-gamma binding site (Y785F) is capable of protecting from apoptosis induced by c-Myc or U.V. treatment. The double mutant TrkA YY490/785FF fails to block either of these two apoptotic stimuli. While PI3-kinas e inhibitors LY294002 and Wortmannin competely block survival signalli ng following U.V. treatment, neither drug affects the ability of TrkA to block c-Myc-induced apoptosis. We show that the Akt/PKB pathway is essential for NGF stimulated TrkA survival signalling in the case of U .V.-induced apoptosis, but that apoptosis induced by c-Myc is also blo cked by a novel, Akt/PKB-independent, pathway. These observations sugg est that TrkA can activate different survival signalling pathways, whi ch can interfere with specific apoptotic pathways.