Trk-dependent ADAM17 activation facilitates neurotrophin survival signaling

Signaling by TrkA and TrkB receptor tyrosine kinase is required for peripheral neuron survival. TrkA and TrkB signaling is facilitated by the p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor (TNF) receptor superfamily, through mechanisms that remain obscure. Here, we demonstrate that TrkA and TrkB induces MEK-dependent phosphorylation of the transmembrane cysteine protease ADAM17 (a disintegrin and metalloprotease 17) at the intracellular residue threonine 735. Phosphorylation at this site activates ADAM17 and causes cleavage of p75NTR and production of the receptors' intracellular domain (p75NTR(ICD)) in PC12 cells and in primary cerebellar granule neurons. We show that Trk-induced ADAM17 phosphorylation and generation of the p75NTR(ICD) is required for neurotrophin-induced Erk and Akt activation and for neurotrophin-dependent survival signaling. Survival of PC12 cells maintained in 10 ng/ml nerve growth factor drops by 47% in cells depleted of ADAM17; this survival deficit is resolved if the p75NTR(ICD) is overexpressed in the ADAM17 depleted cells. These studies identify a novel signaling circuit in which Trk activates ADAM17-dependent p75NTR(ICD) production to feedback to sustain Trk signaling and Trk-dependent survival.