Specific TrkA survival signals interfere with different apoptotic pathways

Abstract

Survival signalling by ligand-activated tyrosine kinase receptors plays a crucial role in maintaining the balance between cell viability and apoptosis in multicellular organisms. To identify receptor domains and pathways involved in survival signalling, the nerve growth factor receptor TrkA was expressed in Rat-1/MycER^TM fibroblasts. We demonstrate that wt-TrkA receptor delays c-Myc-, U.V.- and Cycloheximide-induced apoptosis and activates targets such as the mitogen-activated protein 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 activating endogenous Akt/PKB. In contrast, the TrkA Y490F mutant receptor does not delay U.V.-induced apoptosis whilst TrkA mutated at its PLC-γ 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-kinase inhibitors LY294002 and Wortmannin competely block survival signalling 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 blocked by a novel, Akt/PKB-independent, pathway. These observations suggest that TrkA can activate different survival signalling pathways, which can interfere with specific apoptotic pathways.